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RNA editing (also RNA modification) is a molecular process through which some cells can make discrete changes to specific nucleotide sequences within an RNA molecule after it has been generated by RNA polymerase. It occurs in all living organisms and is one of the most evolutionarily conserved properties of RNAs.^[1]^[2]^[3] RNA editing may include the insertion, deletion, and base substitution of nucleotides within the RNA molecule. RNA editing is relatively rare, with common forms of RNA processing (e.g. splicing, 5'-capping, and 3'-polyadenylation) not usually considered as editing. It can affect the activity, localization as well as stability of RNAs, and has been linked with human diseases.^[1]^[2]^[3]^[4]

RNA editing has been observed in some tRNA, rRNA, mRNA, or miRNA molecules of eukaryotes and their viruses, archaea, and prokaryotes.^[5] RNA editing occurs in the cell nucleus, as well as within mitochondria and plastids. In vertebrates, editing is rare and usually consists of a small number of changes to the sequence of the affected molecules. In other organisms, such as squids,^[6] extensive editing (pan-editing) can occur; in some cases the majority of nucleotides in an mRNA sequence may result from editing. More than 160 types of RNA modifications have been described so far.^[7]

RNA-editing processes show great molecular diversity, and some appear to be evolutionarily recent acquisitions that arose independently. The diversity of RNA editing phenomena includes nucleobase modifications such as cytidine (C) to uridine (U) and adenosine (A) to inosine (I) deaminations, as well as non-template nucleotide additions and insertions. RNA editing in mRNAs effectively alters the amino acid sequence of the encoded protein so that it differs from that predicted by the genomic DNA sequence.^[8]

Detection of RNA editing

Next generation sequencing

To identify diverse post-transcriptional modifications of RNA molecules and determine the transcriptome-wide landscape of RNA modifications by means of next generation RNA sequencing, recently many studies have developed conventional^[9] or specialised sequencing methods.^[1]^[2]^[3] Examples of specialised methods are MeRIP-seq,^[10] m6A-seq,^[11] PA-m⁵C-seq ^[12], methylation-iCLIP,^[13] m6A-CLIP,^[14] Pseudo-seq,^[15] Ψ-seq,^[16] CeU-seq,^[17] Aza-IP^[18] and RiboMeth-seq^[19]). Many of these methods are based on specific capture of the RNA species containing the specific modification, for example through antibody binding coupled with sequencing of the captured reads. After the sequencing these reads are mapped against the whole transcriptome to see where they originate from.^[20] Generally with this kind of approach it is possible to see the location of the modifications together with possible identification of some consensus sequences that might help identification and mapping further on. One example of the specialize methods is PA-m⁵C-seq. This method was further developed from PA-m⁶A-seq method to identify m⁵C modifications on mRNA instead of the original target N6-methyladenosine. The easy switch between different modifications as target is made possible with a simple change of the capturing antibody form m6A specific to m⁵C specific.^[12] Application of these methods have identified various modifications (e.g. pseudouridine, m⁶A, m5C, 2′-O-Me) within coding genes and non-coding genes (e.g. tRNA, lncRNAs, microRNAs) at single nucleotide or very high resolution.^[4]

Mass Spectrometry

Mass spectrometry is a way to quantify RNA modifications.^[21] More often than not, modifications cause an increase in mass for a given nucleoside. This gives a characteristic readout for the nucleoside and the modified counterpart.^[21] Moreover, mass spectrometry allows the investigation of modification dynamics by labelling RNA molecules with stable (non-radioactive) heavy isotopes in vivo. Due to the defined mass increase of heavy isotope labeled nucleosides they can be distinguished from their respective unlabelled isotopomeres by mass spectrometry. This method, called NAIL-MS (nucleic acid isotope labelling coupled mass spectrometry), enables a variety of approaches to investigate RNA modification dynamics.^[22]^[23]^[24]

Types of RNA

Messenger RNA modification

Recently, functional experiments have revealed many novel functional roles of RNA modifications. Most of the RNA modifications are found on transfer-RNA and ribosomal-RNA, but also eukaryotic mRNA has been shown to be modified with multiple different modifications. 17 naturally occurring modifications on mRNA have been identified, from which the N6-methyladenosine is the most abundant and studied.^[25] mRNA modifications are linked to many functions in the cell. They ensure the correct maturation and function of the mRNA, but also at the same time act as part of cell's immune system.^[26] Certain modifications like 2’O-methylated nucleotides has been associated with cells ability to distinguish own mRNA from foreign RNA.^[27] For example, m⁶A has been predicted to affect protein translation and localization,^[1]^[2]^[3] mRNA stability,^[28] alternative polyA choice ^[14] and stem cell pluripotency.^[29] Pseudouridylation of nonsense codons suppresses translation termination both in vitro and in vivo, suggesting that RNA modification may provide a new way to expand the genetic code.^[30] 5-methylcytosine on the other hand has been associated with mRNA transport from the nucleus to the cytoplasm and enhancement of translation. These functions of m⁵C are not fully known and proven but one strong argument towards these functions in the cell is the observed localization of m⁵C to translation initiation site.^[31] Importantly, many modification enzymes are dysregulated and genetically mutated in many disease types.^[1] For example, genetic mutations in pseudouridine synthases cause mitochondrial myopathy, sideroblastic anemia (MLASA) ^[32] and dyskeratosis congenital.^[33]

Compared to the modifications identified from other RNA species like tRNA and rRNA, the amount of identified modifications on mRNA is very small. One of the biggest reasons why mRNA modifications are not so well known is missing research techniques. In addition to the lack of identified modifications, the knowledge of associated proteins is also behind other RNA species. Modifications are results of specific enzyme interactions with the RNA molecule.^[25] Considering mRNA modifications most of the known related enzymes are the writer enzymes that add the modification on the mRNA. The additional groups of enzymes readers and erasers are for most of the modifications either poorly known of not known at all.^[34] For these reasons there has been during the past decade huge interest in studying these modifications and their function.^[20]

Transfer RNA modifications

Transfer RNA or tRNA is the most abundantly modified type of RNA.^[35] Modifications in tRNA play crucial roles in maintaining translation efficiency through supporting structure, anticodon-codon interactions, and interactions with enzymes.^[36]

Anticodon modifications are important for proper decoding of mRNA. Since the genetic code is degenerate, anticodon modifications are necessary to properly decode mRNA. Particularly, the wobble position of the anticodon determines how the codons are read. For example, in eukaryotes an adenosine at position 34 of the anticodon can be converted to inosine. Inosine is a modification that is able to base-pair with cytosine, adenine, and uridine.^[37]

Another commonly modified base in tRNA is the position adjacent to the anticodon. Position 37 is often hypermodified with bulky chemical modifications. These modifications prevent frameshifting and increase anticodon-codon binding stability through stacking interactions.^[37]

Ribosomal RNA modification

Ribosomal RNA (rRNA) is essential to the makeup of ribosomes and peptide transfer during translation processes.^[38] Ribosomal RNA modifications are made throughout ribosome synthesis, and often occur during and/or after translation. Modifications primarily play a role in the structure of the rRNA in order to protect translational efficiency.^[38] Chemical modification in rRNA consists of methylation of ribose sugars, isomerization of uridines, and methylation and acetylation of individual bases.^[39]

Methylation

Methylation of rRNA upholds structural rigidity by blocking base pair stacking and surrounds the 2’-OH group to block hydrolysis. It occurs at specific parts of eukaryotic rRNA. The template for methylation consists of 10-21 nucleotides.^[38] 2'-O-methylation of the ribose sugar is one of the most common rRNA modifications.^[40] Methylation is primarily introduced by small nucleolar RNA's, referred to as snoRNPs. There are two classes of snoRNPs that target methylation sites, and they are referred to box C/D and box H/ACA.^[39]^[40] One type of methylation, 2′-O-methylation, contributes to helical stabilization.^[38]

Isomerization

The isomerization of uridine to pseudouridine is the second most common rRNA modification. These pseudouridines are also introduced by the same classes of snoRNPs that participate in methylation. Pseudouridine synthases are the major participating enzymes in the reaction.^[41] The H/ACA box snoRNPs introduce guide sequences that are about 14-15 nucleotides long.^[39] Pseudouridylation is triggered in numerous places of rRNAs at once to preserve the thermal stability of RNA.^[39] Pseudouridine allows for increased hydrogen bonding and alters translation in rRNA and tRNA.^[40]^[41] It alters translation by increasing the affinity of the ribosome subunit to specific mRNAs.^[38]

Base Editing:

Base editing is the third major class of rRNA modification, specifically in eukaryotes. There are 8 categories of base edits that can occur at the gap between the small and large ribosomal subunits.^[38] RNA methyltransferases are the enzymes that introduce base methylation.^[38] Acetyltransferases are the enzymes responsible for acetylation of cytosine in rRNA. Base methylation plays a role in translation. These base modifications all work in conjunction with the two other main classes of modification to contribute to RNA structural stability. An example of this occurs in N7-methylation, which increases the nucleotide's charge to increase ionic interactions of proteins attaching to the RNA before translation.

Editing by insertion or deletion

The effect of uracil insertion in pre-mRNA transcripts

RNA editing through the addition and deletion of uracil has been found in kinetoplasts from the mitochondria of Trypanosoma brucei.^[42] Because this may involve a large fraction of the sites in a gene, it is sometimes called "pan-editing" to distinguish it from topical editing of one or a few sites.

Pan-editing starts with the base-pairing of the unedited primary transcript with a guide RNA (gRNA), which contains complementary sequences to the regions around the insertion/deletion points. The newly formed double-stranded region is then enveloped by an editosome, a large multi-protein complex that catalyzes the editing.^[43]^[44] The editosome opens the transcript at the first mismatched nucleotide and starts inserting uridines. The inserted uridines will base-pair with the guide RNA, and insertion will continue as long as A or G is present in the guide RNA and will stop when a C or U is encountered.^[45]^[46] The inserted nucleotides cause a frameshift, and result in a translated protein that differs from its gene.

The mechanism of the editosome involves an endonucleolytic cut at the mismatch point between the guide RNA and the unedited transcript. The next step is catalyzed by one of the enzymes in the complex, a terminal U-transferase, which adds Us from UTP at the 3' end of the mRNA.^[47] The opened ends are held in place by other proteins in the complex. Another enzyme, a U-specific exoribonuclease, removes the unpaired Us. After editing has made mRNA complementary to gRNA, an RNA ligase rejoins the ends of the edited mRNA transcript.^[48]^[49] As a consequence, the editosome can edit only in a 3' to 5' direction along the primary RNA transcript. The complex can act on only a single guide RNA at a time. Therefore, a RNA transcript requiring extensive editing will need more than one guide RNA and editosome complex.

Editing by deamination

C-to-U editing

The effect of C-to-U RNA editing on the human ApoB gene

The editing involves cytidine deaminase that deaminates a cytidine base into a uridine base. An example of C-to-U editing is with the apolipoprotein B gene in humans. Apo B100 is expressed in the liver and apo B48 is expressed in the intestines. In the intestines, the mRNA has a CAA sequence edited to be UAA, a stop codon, thus producing the shorter B48 form. C-to-U editing often occurs in the mitochondrial RNA of flowering plants. Different plants have different degrees of C-to-U editing; for example, eight editing events occur in mitochondria of the moss Funaria hygrometrica, whereas over 1,700 editing events occur in the lycophytes Isoetes engelmanii.^[50] C-to-U editing is performed by members of the pentatricopeptide repeat (PPR) protein family. Angiosperms have large PPR families, acting as trans -factors for cis -elements lacking a consensus sequence; Arabidopsis has around 450 members in its PPR family. There have been a number of discoveries of PPR proteins in both plastids and mitochondria.^[51]

A-to-I editing

Adenosine-to-inosine (A-to-I) modifications contribute to nearly 90% of all editing events in RNA. The deamination of adenosine is catalyzed by the double-stranded RNA-specific adenosine deaminase (ADAR), which typically acts on pre-mRNAs. The deamination of adenosine to inosine disrupts and destabilizes the dsRNA base pairing, therefore rendering that particular dsRNA less able to produce siRNA, which interferes with the RNAi pathway.

The wobble base pairing causes deaminated RNA to have a unique but different structure, which may be related to the inhibition of the initiation step of RNA translation. Studies have shown that I-RNA (RNA with many repeats of the I-U base pair) recruits methylases that are involved in the formation of heterochromatin and that this chemical modification heavily interferes with miRNA target sites.^[52] There is active research into the importance of A-to-I modifications and their purpose in the novel concept of epitranscriptomics, in which modifications are made to RNA that alter their function.^[53]^[54] A long established consequence of A-to-I in mRNA is the interpretation of I as a G, therefore leading to functional A-to-G substitution, e.g. in the interpretation of the genetic code by ribosomes. Newer studies, however, have weakened this correlation by showing that inosines can also be decoded by the ribosome (although in a lesser extent) as adenosines or uracils. Furthermore, it was shown that I's lead to the stalling of ribosomes on the I-rich mRNA.^[55]

The development of high-throughput sequencing in recent years has allowed for the development of extensive databases for different modifications and edits of RNA. RADAR (Rigorously Annotated Database of A-to-I RNA editing) was developed in 2013 to catalog the vast variety of A-to-I sites and tissue-specific levels present in humans, mice, and flies. The addition of novel sites and overall edits to the database are ongoing.^[56] The level of editing for specific editing sites, e.g. in the filamin A transcript, is tissue-specific.^[57] The efficiency of mRNA-splicing is a major factor controlling the level of A-to-I RNA editing.^[58]^[59] Interestingly, ADAR1 and ADAR2 also affect alternative splicing via both A-to-I editing ability and dsRNA binding ability.^[60]^[61]

Alternative mRNA editing

Alternative U-to-C mRNA editing was first reported in WT1 (Wilms Tumor-1) transcripts,^[62] and non-classic G-A mRNA changes were first observed in HNRNPK (heterogeneous nuclear ribonucleoprotein K) transcripts in both malignant and normal colorectal samples.^[63] The latter changes were also later seen alongside non-classic U-to-C alterations in brain cell TPH2 (tryptophan hydroxylase 2) transcripts.^[64] Although the reverse amination might be the simplest explanation for U-to-C changes, transamination and transglycosylation mechanisms have been proposed for plant U-to-C editing events in mitochondrial transcripts.^[65] A recent study reported novel G-to-A mRNA changes in WT1 transcripts at two hotspots, proposing the APOBEC3A (apolipoprotein B mRNA editing enzyme, catalytic polypeptide 3A) as the enzyme implicated in this class of alternative mRNA editing.^[66] It was also shown that alternative mRNA changes were associated with canonical WT1 splicing variants, indicating their functional significance.

RNA editing in plant mitochondria and plastids

It has been shown in previous studies that the only types of RNA editing seen in the plants' mitochondria and plastids are conversion of C-to-U and U-to-C (very rare).^[67]^[68]^[69]^[70]^[71]^[72]^[73]^[74]^[75]^[76]^[77]^[78]^[79] RNA-editing sites are found mainly in the coding regions of mRNA, introns, and other non-translated regions.^[69] In fact, RNA editing can restore the functionality of tRNA molecules.^[71]^[72] The editing sites are found primarily upstream of mitochondrial or plastid RNAs. While the specific positions for C to U RNA editing events have been fairly well studied in both the mitochondrion and plastid,^[80] the identity and organization of all proteins comprising the editosome have yet to be established. Members of the expansive PPR protein family have been shown to function as trans-acting factors for RNA sequence recognition.^[81] Specific members of the MORF (Multiple Organellar RNA editing Factor) family are also required for proper editing at several sites. As some of these MORF proteins have been shown to interact with members of the PPR family, it is possible MORF proteins are components of the editosome complex.^[82] An enzyme responsible for the trans- or deamination of the RNA transcript remains elusive, though it has been proposed that the PPR proteins may serve this function as well.

RNA editing is essential for the normal functioning of the plant's translation and respiration activity. Editing can restore the essential base-pairing sequences of tRNAs, restoring functionality.^[83] It has also been linked to the production of RNA-edited proteins that are incorporated into the polypeptide complexes of the respiration pathway. Therefore, it is highly probable that polypeptides synthesized from unedited RNAs would not function properly and hinder the activity of both mitochondria and plastids.

C-to-U RNA editing can create start and stop codons, but it cannot destroy existing start and stop codons. A cryptic start codon is created when the codon ACG is edited to be AUG.

Summary of the Various Functions of RNA Editing

RNA editing in viruses

Viruses (i.e., measles, mumps, or parainfluenza), especially viruses that have an RNA genome, have been shown to have evolved to utilize RNA modifications in many ways when taking over the host cell. Viruses are known to utilize the RNA modifications in different parts of their infection cycle from immune evasion to protein translation enhancement.^[27] RNA editing is used for stability and generation of protein variants.^[84]^[85] Viral RNAs are transcribed by a virus-encoded RNA-dependent RNA polymerase, which is prone to pausing and "stuttering" at certain nucleotide combinations. In addition, up to several hundred non-templated A's are added by the polymerase at the 3' end of nascent mRNA.^[86] These As help stabilize the mRNA. Furthermore, the pausing and stuttering of the RNA polymerase allows the incorporation of one or two Gs or As upstream of the translational codon.^[86] The addition of the non-templated nucleotides shifts the reading frame, which generates a different protein.

Additionally, the RNA modifications are shown to have both positive and negative effects on the replication and translation efficiency depending on the virus. For example, Courtney et al.^[12] showed that an RNA modification called 5-methylcytosine is added to the viral mRNA in infected host cells in order to enhance the protein translation of HIV-1 virus. The inhibition of the m⁵C modification on viral mRNA results in significant reduction in viral protein translation, but interestingly it has no effect on the expression of viral mRNAs in the cell. On the other hand, Lichinchi et al.^[87] showed that the N6-methyladenosine modification on ZIKV mRNA inhibits the viral replication.

Origin and Evolution of RNA editing

The RNA-editing system seen in the animal may have evolved from mononucleotide deaminases, which have led to larger gene families that include the apobec-1 and adar genes. These genes share close identity with the bacterial deaminases involved in nucleotide metabolism. The adenosine deaminase of E. coli cannot deaminate a nucleoside in the RNA; the enzyme's reaction pocket is too small for the RNA strand to bind to. However, this active site is widened by amino acid changes in the corresponding human analog genes, APOBEC1 and ADAR, allowing deamination.^[88]^[89] The gRNA-mediated pan-editing in trypanosome mitochondria, involving templated insertion of U residues, is an entirely different biochemical reaction. The enzymes involved have been shown in other studies to be recruited and adapted from different sources.^[43]^[90] But the specificity of nucleotide insertion via the interaction between the gRNA and mRNA is similar to the tRNA editing processes in the animal and Acanthamoeba mitochondria.^[91] Eukaryotic ribose methylation of rRNAs by guide RNA molecules is a similar form of modification.^[92]

Thus, RNA editing evolved more than once. Several adaptive rationales for editing have been suggested.^[93] Editing is often described as a mechanism of correction or repair to compensate for defects in gene sequences. However, in the case of gRNA-mediated editing, this explanation does not seem possible because if a defect happens first, there is no way to generate an error-free gRNA-encoding region, which presumably arises by duplication of the original gene region. A more plausible alternative for the evolutionary origins of this system is through constructive neutral evolution, where the order of steps is reversed, with the gratuitous capacity for editing preceding the "defect".^[94]

Therapeutic mRNA Editing

Directing edits to correct mutated sequences was first proposed and demonstrated in 1995.^[95] This initial work used synthetic RNA antisense oligonucleotides complementary to a pre-mature stop codon mutation in a dystrophin sequence to activate A-to-I editing of the stop codon to a read through codon in a model xenopus cell system.^[95] While this also led to nearby inadvertent A-to-I transitions, A to I (read as G) transitions can correct all three stop codons, but cannot create a stop codon. Therefore, the changes led >25% correction of the targeted stop codon with read through to a downstream luciferase reporter sequence. Follow on work by Rosenthal achieved editing of mutated mRNA sequence in mammalian cell culture by directing an oligonucleotide linked to a cytidine deaminase to correct a mutated cystic fibrosis sequence.^[96] More recently, CRISPR-Cas13 fused to deaminases has been employed to direct mRNA editing.^[97]

In 2022, therapeutic RNA editing for Cas7-11 was reported.^[98]^[99] It enables sufficiently targeted cuts and an early version of it was used for in vitro editing in 2021.^[100]

Comparison to DNA editing

Unlike DNA editing, which is permanent, the effects of RNA editing − including potential off-target mutations in RNA − are transient and are not inherited. RNA editing is therefore considered to be less risky. Furthermore, it may only require a guide RNA by using the ADAR protein already found in humans and many other eukaryotes' cells instead of needing to introduce a foreign protein into the body.^[101]

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+{{short description|Molecular process}}
 {{missing information|pseudouracil|date=December 2020}}
+{{genetics sidebar}}
-'''RNA editing''' (also '''RNA modification''') is a molecular process through which some cells can make discrete changes to specific [[nucleotide sequences]] within an [[RNA]] molecule after it has been generated by [[RNA polymerase]]. It occurs in all living organisms and is one of the most evolutionarily conserved properties of [[RNA]]s.<ref name="li2013">{{cite journal | vauthors = Li S, Mason CE | title = The pivotal regulatory landscape of RNA modifications | journal = Annual Review of Genomics and Human Genetics | volume = 15 | pages = 127–50 | date = 2013 | pmid = 24898039 | doi = 10.1146/annurev-genom-090413-025405 }}</ref><ref name="song2012">{{cite journal | vauthors = Song CX, Yi C, He C | title = Mapping recently identified nucleotide variants in the genome and transcriptome | journal = Nature Biotechnology | volume = 30 | issue = 11 | pages = 1107–16 | date = November 2012 | pmid = 23138310 | pmc = 3537840 | doi = 10.1038/nbt.2398 }}</ref><ref name="Meyer2014">{{cite journal | vauthors = Meyer KD, Jaffrey SR | title = The dynamic epitranscriptome: N6-methyladenosine and gene expression control | journal = Nature Reviews. Molecular Cell Biology | volume = 15 | issue = 5 | pages = 313–26 | date = May 2014 | pmid = 24713629 | pmc = 4393108 | doi = 10.1038/nrm3785 }}</ref> RNA editing may include the insertion, deletion, and base substitution of nucleotides within the RNA molecule. RNA editing is relatively rare, with common forms of RNA processing (e.g. [[RNA splicing|splicing]], 5'-[[capping enzyme|capping]], and 3'-[[polyadenylation]]) not usually considered as editing. It can affect the activity, localization as well as stability of RNAs, and has been linked with human diseases.<ref name="li2013"/><ref name="song2012"/><ref name="Meyer2014"/><ref name="sun2015">{{cite journal | vauthors = Sun WJ, Li JH, Liu S, Wu J, Zhou H, Qu LH, Yang JH | title = RMBase: a resource for decoding the landscape of RNA modifications from high-throughput sequencing data | journal = Nucleic Acids Research | volume = 44 | issue = D1 | pages = D259-65 | date = January 2016 | pmid = 26464443 | pmc = 4702777 | doi = 10.1093/nar/gkv1036 }}</ref>
+'''RNA editing''' (also '''RNA modification''') is a molecular process through which some cells can make discrete changes to specific [[nucleotide sequence]]s within an [[RNA]] molecule after it has been generated by [[RNA polymerase]]. It occurs in all living organisms and is one of the most evolutionarily conserved properties of [[RNA]]s.<ref name="li2013">{{cite journal | vauthors = Li S, Mason CE | title = The pivotal regulatory landscape of RNA modifications | journal = Annual Review of Genomics and Human Genetics | volume = 15 | pages = 127–150 | date = 2013 | pmid = 24898039 | doi = 10.1146/annurev-genom-090413-025405 | doi-access = free }}</ref><ref name="song2012">{{cite journal | vauthors = Song CX, Yi C, He C | title = Mapping recently identified nucleotide variants in the genome and transcriptome | journal = Nature Biotechnology | volume = 30 | issue = 11 | pages = 1107–1116 | date = November 2012 | pmid = 23138310 | pmc = 3537840 | doi = 10.1038/nbt.2398 }}</ref><ref name="Meyer2014">{{cite journal | vauthors = Meyer KD, Jaffrey SR | title = The dynamic epitranscriptome: N6-methyladenosine and gene expression control | journal = Nature Reviews. Molecular Cell Biology | volume = 15 | issue = 5 | pages = 313–326 | date = May 2014 | pmid = 24713629 | pmc = 4393108 | doi = 10.1038/nrm3785 }}</ref> RNA editing may include the insertion, deletion, and base substitution of nucleotides within the RNA molecule. RNA editing is relatively rare, with common forms of RNA processing (e.g. [[RNA splicing|splicing]], 5'-[[capping enzyme|capping]], and 3'-[[polyadenylation]]) not usually considered as editing. It can affect the activity, localization as well as stability of RNAs, and has been linked with human diseases.<ref name="li2013"/><ref name="song2012"/><ref name="Meyer2014"/><ref name="sun2015">{{cite journal | vauthors = Sun WJ, Li JH, Liu S, Wu J, Zhou H, Qu LH, Yang JH | title = RMBase: a resource for decoding the landscape of RNA modifications from high-throughput sequencing data | journal = Nucleic Acids Research | volume = 44 | issue = D1 | pages = D259–D265 | date = January 2016 | pmid = 26464443 | pmc = 4702777 | doi = 10.1093/nar/gkv1036 }}</ref>
-RNA editing has been observed in some [[tRNA]], [[rRNA]], [[mRNA]], or [[microRNA|miRNA]] molecules of [[eukaryotes]] and their [[viruses]], [[archaea]], and [[prokaryotes]].<ref>{{cite journal |vauthors= Su AA, Randau L |title= A-to-I and C-to-U editing within transfer RNAs |journal= Biochemistry. Biokhimiia |volume= 76 |issue=8 |pages= 932–7 |date= August 2011 |pmid= 22022967 |doi= 10.1134/S0006297911080098 |s2cid= 11283810 }}</ref> RNA editing occurs in the cell nucleus and [[cytosol]], as well as within [[mitochondria]] and [[plastids]]. In vertebrates, editing is rare and usually consists of a small number of changes to the sequence of the affected molecules. In other organisms, such as [[squid]]s,<ref>{{cite news |title=New genetic editing powers discovered in squid |url=https://phys.org/news/2020-03-genetic-powers-squid.html |access-date=2020-04-05 |work=phys.org |language=en-us}}</ref> extensive editing (''pan-editing'') can occur; in some cases the majority of nucleotides in an mRNA sequence may result from editing. More than 160 types of RNA modifications have been described so far.<ref>{{cite journal | vauthors = Boccaletto P, Machnicka MA, Purta E, Piatkowski P, Baginski B, Wirecki TK, de Crécy-Lagard V, Ross R, Limbach PA, Kotter A, Helm M, Bujnicki JM | title = MODOMICS: a database of RNA modification pathways. 2017 update | journal = Nucleic Acids Research | volume = 46 | issue = D1 | pages = D303–D307 | date = January 2018 | pmid = 29106616 | pmc = 5753262 | doi = 10.1093/nar/gkx1030 }}</ref>
+RNA editing has been observed in some [[tRNA]], [[rRNA]], [[mRNA]], or [[microRNA|miRNA]] molecules of [[eukaryote]]s and their [[virus]]es, [[archaea]], and [[prokaryote]]s.<ref>{{cite journal | vauthors = Su AA, Randau L | title = A-to-I and C-to-U editing within transfer RNAs | journal = Biochemistry. Biokhimiia | volume = 76 | issue = 8 | pages = 932–937 | date = August 2011 | pmid = 22022967 | doi = 10.1134/S0006297911080098 | s2cid = 11283810 }}</ref> RNA editing occurs in the cell nucleus, as well as within [[mitochondria]] and [[plastids]]. In vertebrates, editing is rare and usually consists of a small number of changes to the sequence of the affected molecules. In other organisms, such as [[squid]]s,<ref>{{cite news |title=New genetic editing powers discovered in squid |url=https://phys.org/news/2020-03-genetic-powers-squid.html |access-date=2020-04-05 |work=phys.org |language=en-us}}</ref> extensive editing (''pan-editing'') can occur; in some cases the majority of nucleotides in an mRNA sequence may result from editing. More than 160 types of RNA modifications have been described so far.<ref>{{cite journal | vauthors = Boccaletto P, Machnicka MA, Purta E, Piatkowski P, Baginski B, Wirecki TK, de Crécy-Lagard V, Ross R, Limbach PA, Kotter A, Helm M, Bujnicki JM | display-authors = 6 | title = MODOMICS: a database of RNA modification pathways. 2017 update | journal = Nucleic Acids Research | volume = 46 | issue = D1 | pages = D303–D307 | date = January 2018 | pmid = 29106616 | pmc = 5753262 | doi = 10.1093/nar/gkx1030 }}</ref>
-RNA-editing processes show great molecular diversity, and some appear to be evolutionarily recent acquisitions that arose independently. The diversity of RNA editing phenomena includes [[nucleobase]] modifications such as [[cytidine]] (C) to [[uridine]] (U) and [[adenosine]] (A) to [[inosine]] (I) [[deamination]]s, as well as non-template nucleotide additions and insertions. RNA editing in mRNAs effectively alters the [[amino acid sequence]] of the encoded protein so that it differs from that predicted by the genomic DNA sequence.<ref>{{cite journal |vauthors= Brennicke A, Marchfelder A, Binder S |title= RNA editing | journal= FEMS Microbiology Reviews |volume= 23 |issue=3 |pages= 297–316 |date= June 1999 |pmid= 10371035 |doi= 10.1111/j.1574-6976.1999.tb00401.x |doi-access= free }}</ref>
+RNA-editing processes show great molecular diversity, and some appear to be evolutionarily recent acquisitions that arose independently. The diversity of RNA editing phenomena includes [[nucleobase]] modifications such as [[cytidine]] (C) to [[uridine]] (U) and [[adenosine]] (A) to [[inosine]] (I) [[deamination]]s, as well as non-template nucleotide additions and insertions. RNA editing in mRNAs effectively alters the [[amino acid sequence]] of the encoded protein so that it differs from that predicted by the genomic DNA sequence.<ref>{{cite journal | vauthors = Brennicke A, Marchfelder A, Binder S | title = RNA editing | journal = FEMS Microbiology Reviews | volume = 23 | issue = 3 | pages = 297–316 | date = June 1999 | pmid = 10371035 | doi = 10.1111/j.1574-6976.1999.tb00401.x | doi-access = free }}</ref>
 [[File:Editosome.PNG|350px|thumb|The Editosome Complex]]
 == Detection of RNA editing ==
 === Next generation sequencing ===
-To identify diverse post-transcriptional modifications of RNA molecules and determine the transcriptome-wide landscape of RNA modifications by means of next generation RNA sequencing, recently many studies have developed conventional<ref>"Accurate Mapping of tRNA Reads"; Anne Hoffmann et al.; Bioinformatics, btx756, https://doi.org/10.1093/bioinformatics/btx756</ref> or specialised sequencing methods.<ref name="li2013"/><ref name="song2012"/><ref name="Meyer2014"/> Examples of specialised methods are [[MeRIPseq|MeRIP-seq]],<ref>{{cite journal | vauthors = Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE, Jaffrey SR | title = Comprehensive analysis of mRNA methylation reveals enrichment in 3' UTRs and near stop codons | journal = Cell | volume = 149 | issue = 7 | pages = 1635–46 | date = June 2012 | pmid = 22608085 | pmc = 3383396 | doi = 10.1016/j.cell.2012.05.003 }}</ref> m6A-seq,<ref>{{cite journal | vauthors = Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, Cesarkas K, Jacob-Hirsch J, Amariglio N, Kupiec M, Sorek R, Rechavi G | s2cid = 3517716 | title = Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq | journal = Nature | volume = 485 | issue = 7397 | pages = 201–6 | date = April 2012 | pmid = 22575960 | doi = 10.1038/nature11112 | bibcode = 2012Natur.485..201D }}</ref> PA-m<sup>5</sup>C-seq <ref name=":1">{{Cite journal|last1=Courtney|first1=David G.|last2=Tsai|first2=Kevin|last3=Bogerd|first3=Hal P.|last4=Kennedy|first4=Edward M.|last5=Law|first5=Brittany A.|last6=Emery|first6=Ann|last7=Swanstrom|first7=Ronald|last8=Holley|first8=Christopher L.|last9=Cullen|first9=Bryan R.|date=August 2019|title=Epitranscriptomic Addition of m5C to HIV-1 Transcripts Regulates Viral Gene Expression|url= |journal=Cell Host & Microbe|language=en|volume=26|issue=2|pages=217–227.e6|doi=10.1016/j.chom.2019.07.005|pmc=6714563|pmid=31415754}}</ref>''',''' methylation-iCLIP,<ref>{{cite journal | vauthors = Hussain S, Sajini AA, Blanco S, Dietmann S, Lombard P, Sugimoto Y, Paramor M, Gleeson JG, Odom DT, Ule J, Frye M | title = NSun2-mediated cytosine-5 methylation of vault noncoding RNA determines its processing into regulatory small RNAs | journal = Cell Reports | volume = 4 | issue = 2 | pages = 255–61 | date = July 2013 | pmid = 23871666 | pmc = 3730056 | doi = 10.1016/j.celrep.2013.06.029 }}</ref> m6A-CLIP,<ref name="ke2015">{{cite journal | vauthors = Ke S, Alemu EA, Mertens C, Gantman EC, Fak JJ, Mele A, Haripal B, Zucker-Scharff I, Moore MJ, Park CY, Vågbø CB, Kusśnierczyk A, Klungland A, Darnell JE, Darnell RB | title = A majority of m6A residues are in the last exons, allowing the potential for 3' UTR regulation | journal = Genes & Development | volume = 29 | issue = 19 | pages = 2037–53 | date = October 2015 | pmid = 26404942 | pmc = 4604345 | doi = 10.1101/gad.269415.115 }}</ref> Pseudo-seq,<ref>{{cite journal | vauthors = Carlile TM, Rojas-Duran MF, Zinshteyn B, Shin H, Bartoli KM, Gilbert WV | title = Pseudouridine profiling reveals regulated mRNA pseudouridylation in yeast and human cells | journal = Nature | volume = 515 | issue = 7525 | pages = 143–6 | date = November 2014 | pmid = 25192136 | pmc = 4224642 | doi = 10.1038/nature13802 | bibcode = 2014Natur.515..143C }}</ref> Ψ-seq,<ref>{{cite journal | vauthors = Schwartz S, Bernstein DA, Mumbach MR, Jovanovic M, Herbst RH, León-Ricardo BX, Engreitz JM, Guttman M, Satija R, Lander ES, Fink G, Regev A | title = Transcriptome-wide mapping reveals widespread dynamic-regulated pseudouridylation of ncRNA and mRNA | journal = Cell | volume = 159 | issue = 1 | pages = 148–162 | date = September 2014 | pmid = 25219674 | pmc = 4180118 | doi = 10.1016/j.cell.2014.08.028 }}</ref> CeU-seq,<ref>{{cite journal | vauthors = Li X, Zhu P, Ma S, Song J, Bai J, Sun F, Yi C | title = Chemical pulldown reveals dynamic pseudouridylation of the mammalian transcriptome | journal = Nature Chemical Biology | volume = 11 | issue = 8 | pages = 592–7 | date = August 2015 | pmid = 26075521 | doi = 10.1038/nchembio.1836 }}</ref> Aza-IP<ref>{{cite journal | vauthors = Khoddami V, Cairns BR | title = Identification of direct targets and modified bases of RNA cytosine methyltransferases | journal = Nature Biotechnology | volume = 31 | issue = 5 | pages = 458–64 | date = May 2013 | pmid = 23604283 | pmc = 3791587 | doi = 10.1038/nbt.2566 }}</ref> and RiboMeth-seq<ref>{{cite journal | vauthors = Birkedal U, Christensen-Dalsgaard M, Krogh N, Sabarinathan R, Gorodkin J, Nielsen H | title = Profiling of ribose methylations in RNA by high-throughput sequencing | journal = Angewandte Chemie | volume = 54 | issue = 2 | pages = 451–5 | date = January 2015 | pmid = 25417815 | doi = 10.1002/anie.201408362 }}</ref>). Many of these methods are based on specific capture of the RNA species containing the specific modification, for example through antibody binding coupled with sequencing of the captured reads. After the sequencing these reads are mapped against the whole transcriptome to see where they originate from.<ref name=":2">{{Cite journal|last1=Chen|first1=Li-Qian|last2=Zhao|first2=Wen-Shuo|last3=Luo|first3=Guan-Zheng|date=2020|title=Mapping and editing of nucleic acid modifications|url= |journal=Computational and Structural Biotechnology Journal|language=en|volume=18|pages=661–667|doi=10.1016/j.csbj.2020.03.010|pmc=7113611|pmid=32257049}}</ref> Generally with this kind of approach it is possible to see the location of the modifications together with possible identification of some consensus sequences that might help identification and mapping further on. One example of the specialize methods is PA-m<sup>5</sup>C-seq. This method was further developed from PA-m<sup>6</sup>A-seq method to identify m<sup>5</sup>C modifications on mRNA instead of the original target N6-methyladenosine. The easy switch between different modifications as target is made possible with a simple change of the capturing antibody form m6A specific to m<sup>5</sup>C specific.<ref name=":1" /> Application of these methods have identified various modifications (e.g. pseudouridine, [[N6-Methyladenosine|m<sup>6</sup>A]], m5C, 2′-O-Me) within coding genes and non-coding genes (e.g. tRNA, lncRNAs, microRNAs) at single nucleotide or very high resolution.<ref name="sun2015"/>
+To identify diverse post-transcriptional modifications of RNA molecules and determine the transcriptome-wide landscape of RNA modifications by means of next generation RNA sequencing, recently many studies have developed conventional<ref name="Hoffmann_2018">{{cite journal | vauthors = Hoffmann A, Fallmann J, Vilardo E, Mörl M, Stadler PF, Amman F | title = Accurate mapping of tRNA reads | journal = Bioinformatics | location = Oxford, England | volume = 34 | issue = 7 | pages = 1116–1124 | date = April 2018 | pmid = 29228294 | doi = 10.1093/bioinformatics/btx756 | url = | doi-access = free }}</ref> or specialised sequencing methods.<ref name="li2013"/><ref name="song2012"/><ref name="Meyer2014"/> Examples of specialised methods are [[MeRIPseq|MeRIP-seq]],<ref>{{cite journal | vauthors = Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE, Jaffrey SR | title = Comprehensive analysis of mRNA methylation reveals enrichment in 3' UTRs and near stop codons | journal = Cell | volume = 149 | issue = 7 | pages = 1635–1646 | date = June 2012 | pmid = 22608085 | pmc = 3383396 | doi = 10.1016/j.cell.2012.05.003 }}</ref> m6A-seq,<ref>{{cite journal | vauthors = Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, Cesarkas K, Jacob-Hirsch J, Amariglio N, Kupiec M, Sorek R, Rechavi G | display-authors = 6 | title = Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq | journal = Nature | volume = 485 | issue = 7397 | pages = 201–206 | date = April 2012 | pmid = 22575960 | doi = 10.1038/nature11112 | s2cid = 3517716 | bibcode = 2012Natur.485..201D }}</ref> PA-m<sup>5</sup>C-seq <ref name="Courtney_2019">{{cite journal | vauthors = Courtney DG, Tsai K, Bogerd HP, Kennedy EM, Law BA, Emery A, Swanstrom R, Holley CL, Cullen BR | display-authors = 6 | title = Epitranscriptomic Addition of m<sup>5</sup>C to HIV-1 Transcripts Regulates Viral Gene Expression | journal = Cell Host & Microbe | volume = 26 | issue = 2 | pages = 217–227.e6 | date = August 2019 | pmid = 31415754 | pmc = 6714563 | doi = 10.1016/j.chom.2019.07.005 }}</ref>''',''' methylation-iCLIP,<ref>{{cite journal | vauthors = Hussain S, Sajini AA, Blanco S, Dietmann S, Lombard P, Sugimoto Y, Paramor M, Gleeson JG, Odom DT, Ule J, Frye M | display-authors = 6 | title = NSun2-mediated cytosine-5 methylation of vault noncoding RNA determines its processing into regulatory small RNAs | journal = Cell Reports | volume = 4 | issue = 2 | pages = 255–261 | date = July 2013 | pmid = 23871666 | pmc = 3730056 | doi = 10.1016/j.celrep.2013.06.029 }}</ref> m6A-CLIP,<ref name="ke2015">{{cite journal | vauthors = Ke S, Alemu EA, Mertens C, Gantman EC, Fak JJ, Mele A, Haripal B, Zucker-Scharff I, Moore MJ, Park CY, Vågbø CB, Kusśnierczyk A, Klungland A, Darnell JE, Darnell RB | display-authors = 6 | title = A majority of m6A residues are in the last exons, allowing the potential for 3' UTR regulation | journal = Genes & Development | volume = 29 | issue = 19 | pages = 2037–2053 | date = October 2015 | pmid = 26404942 | pmc = 4604345 | doi = 10.1101/gad.269415.115 }}</ref> Pseudo-seq,<ref>{{cite journal | vauthors = Carlile TM, Rojas-Duran MF, Zinshteyn B, Shin H, Bartoli KM, Gilbert WV | title = Pseudouridine profiling reveals regulated mRNA pseudouridylation in yeast and human cells | journal = Nature | volume = 515 | issue = 7525 | pages = 143–146 | date = November 2014 | pmid = 25192136 | pmc = 4224642 | doi = 10.1038/nature13802 | bibcode = 2014Natur.515..143C }}</ref> Ψ-seq,<ref>{{cite journal | vauthors = Schwartz S, Bernstein DA, Mumbach MR, Jovanovic M, Herbst RH, León-Ricardo BX, Engreitz JM, Guttman M, Satija R, Lander ES, Fink G, Regev A | display-authors = 6 | title = Transcriptome-wide mapping reveals widespread dynamic-regulated pseudouridylation of ncRNA and mRNA | journal = Cell | volume = 159 | issue = 1 | pages = 148–162 | date = September 2014 | pmid = 25219674 | pmc = 4180118 | doi = 10.1016/j.cell.2014.08.028 }}</ref> CeU-seq,<ref>{{cite journal | vauthors = Li X, Zhu P, Ma S, Song J, Bai J, Sun F, Yi C | title = Chemical pulldown reveals dynamic pseudouridylation of the mammalian transcriptome | journal = Nature Chemical Biology | volume = 11 | issue = 8 | pages = 592–597 | date = August 2015 | pmid = 26075521 | doi = 10.1038/nchembio.1836 }}</ref> Aza-IP<ref>{{cite journal | vauthors = Khoddami V, Cairns BR | title = Identification of direct targets and modified bases of RNA cytosine methyltransferases | journal = Nature Biotechnology | volume = 31 | issue = 5 | pages = 458–464 | date = May 2013 | pmid = 23604283 | pmc = 3791587 | doi = 10.1038/nbt.2566 }}</ref> and RiboMeth-seq<ref>{{cite journal | vauthors = Birkedal U, Christensen-Dalsgaard M, Krogh N, Sabarinathan R, Gorodkin J, Nielsen H | title = Profiling of ribose methylations in RNA by high-throughput sequencing | journal = Angewandte Chemie | volume = 54 | issue = 2 | pages = 451–455 | date = January 2015 | pmid = 25417815 | doi = 10.1002/anie.201408362 }}</ref>). Many of these methods are based on specific capture of the RNA species containing the specific modification, for example through antibody binding coupled with sequencing of the captured reads. After the sequencing these reads are mapped against the whole transcriptome to see where they originate from.<ref name="Chen_2020">{{cite journal | vauthors = Chen LQ, Zhao WS, Luo GZ | title = Mapping and editing of nucleic acid modifications | journal = Computational and Structural Biotechnology Journal | volume = 18 | pages = 661–667 | date = 2020 | pmid = 32257049 | pmc = 7113611 | doi = 10.1016/j.csbj.2020.03.010 }}</ref> Generally with this kind of approach it is possible to see the location of the modifications together with possible identification of some consensus sequences that might help identification and mapping further on. One example of the specialize methods is PA-m<sup>5</sup>C-seq. This method was further developed from PA-m<sup>6</sup>A-seq method to identify m<sup>5</sup>C modifications on mRNA instead of the original target N6-methyladenosine. The easy switch between different modifications as target is made possible with a simple change of the capturing antibody form m6A specific to m<sup>5</sup>C specific.<ref name="Courtney_2019" /> Application of these methods have identified various modifications (e.g. pseudouridine, [[N6-Methyladenosine|m<sup>6</sup>A]], m5C, 2′-O-Me) within coding genes and non-coding genes (e.g. tRNA, lncRNAs, microRNAs) at single nucleotide or very high resolution.<ref name="sun2015"/>
 === Mass Spectrometry ===
-[[Mass spectrometry]] is a way to qualitatively and (relatively) quantify RNA modifications.<ref name="Wetzel_2016">{{cite journal | vauthors = Wetzel C, Limbach PA | title = Mass spectrometry of modified RNAs: recent developments | journal = The Analyst | volume = 141 | issue = 1 | pages = 16–23 | date = January 2016 | pmid = 26501195 | pmc = 4679475 | doi = 10.1039/C5AN01797A | bibcode = 2016Ana...141...16W }}</ref> More often than not, modifications cause an increase in mass for a given nucleoside. This gives a characteristic readout for the nucleoside and the modified counterpart.<ref name="Wetzel_2016" /> Moreover, mass spectrometry allows the investigation of modification dynamics by labeling RNA molecules with stable (non-radioactive) heavy isotopes ''in vivo''. Due to the defined mass increase of heavy isotope labeled nucleosides they can be distinguished from their respective unlabeled isotopomeres by mass spectrometry. This method, called [[NAIL-MS]] (nucleic acid isotope labeling coupled mass spectrometry), enables a variety of approaches to investigate RNA modification dynamics.<ref>{{cite journal | vauthors = Heiss M, Reichle VF, Kellner S | title = Observing the fate of tRNA and its modifications by nucleic acid isotope labeling mass spectrometry: NAIL-MS | journal = RNA Biology | volume = 14 | issue = 9 | pages = 1260–1268 | date = September 2017 | pmid = 28488916 | pmc = 5699550 | doi = 10.1080/15476286.2017.1325063 }}</ref><ref>{{cite journal | vauthors = Reichle VF, Weber V, Kellner S | title = NAIL-MS in E. coli Determines the Source and Fate of Methylation in tRNA | journal = ChemBioChem | volume = 19 | issue = 24 | pages = 2575–2583 | date = December 2018 | pmid = 30328661 | pmc = 6582434 | doi = 10.1002/cbic.201800525 }}</ref><ref>{{cite journal | vauthors = Reichle VF, Kaiser S, Heiss M, Hagelskamp F, Borland K, Kellner S | title = Surpassing limits of static RNA modification analysis with dynamic NAIL-MS | journal = Methods | volume = 156 | pages = 91–101 | date = March 2019 | pmid = 30395967 | doi = 10.1016/j.ymeth.2018.10.025 | doi-access = free }}</ref>
+[[Mass spectrometry]] is a way to quantify RNA modifications.<ref name="Wetzel_2016">{{cite journal | vauthors = Wetzel C, Limbach PA | title = Mass spectrometry of modified RNAs: recent developments | journal = The Analyst | volume = 141 | issue = 1 | pages = 16–23 | date = January 2016 | pmid = 26501195 | pmc = 4679475 | doi = 10.1039/C5AN01797A | bibcode = 2016Ana...141...16W }}</ref> More often than not, modifications cause an increase in mass for a given nucleoside. This gives a characteristic readout for the nucleoside and the modified counterpart.<ref name="Wetzel_2016" /> Moreover, mass spectrometry allows the investigation of modification dynamics by labelling RNA molecules with stable (non-radioactive) heavy isotopes ''in vivo''. Due to the defined mass increase of heavy isotope labeled nucleosides they can be distinguished from their respective unlabelled isotopomeres by mass spectrometry. This method, called [[NAIL-MS]] (nucleic acid isotope labelling coupled mass spectrometry), enables a variety of approaches to investigate RNA modification dynamics.<ref>{{cite journal | vauthors = Heiss M, Reichle VF, Kellner S | title = Observing the fate of tRNA and its modifications by nucleic acid isotope labeling mass spectrometry: NAIL-MS | journal = RNA Biology | volume = 14 | issue = 9 | pages = 1260–1268 | date = September 2017 | pmid = 28488916 | pmc = 5699550 | doi = 10.1080/15476286.2017.1325063 }}</ref><ref>{{cite journal | vauthors = Reichle VF, Weber V, Kellner S | title = NAIL-MS in E. coli Determines the Source and Fate of Methylation in tRNA | journal = ChemBioChem | volume = 19 | issue = 24 | pages = 2575–2583 | date = December 2018 | pmid = 30328661 | pmc = 6582434 | doi = 10.1002/cbic.201800525 }}</ref><ref>{{cite journal | vauthors = Reichle VF, Kaiser S, Heiss M, Hagelskamp F, Borland K, Kellner S | title = Surpassing limits of static RNA modification analysis with dynamic NAIL-MS | journal = Methods | volume = 156 | pages = 91–101 | date = March 2019 | pmid = 30395967 | doi = 10.1016/j.ymeth.2018.10.025 | doi-access = free }}</ref>
 == Types of RNA ==
 === Messenger RNA modification ===
-Recently, functional experiments have revealed many novel functional roles of RNA modifications. Most of the RNA modifications are found on transfer-RNA and ribosomal-RNA, but also eukaryotic mRNA has been shown to be modified with multiple different modifications. Till today there has been identified roughly ten modification on mRNA, from which the N6-methyladenosine is the most abundant and studied.<ref name="McCown">{{Cite journal|last1=McCown|first1=Phillip J.|last2=Ruszkowska|first2=Agnieszka|last3=Kunkler|first3=Charlotte N.|last4=Breger|first4=Kurtis|last5=Hulewicz|first5=Jacob P.|last6=Wang|first6=Matthew C.|last7=Springer|first7=Noah A.|last8=Brown|first8=Jessica A.|date=September 2020|title=Naturally occurring modified ribonucleosides|url= |journal=WIREs RNA|language=en|volume=11|issue=5|pages=e1595|doi=10.1002/wrna.1595|issn=1757-7004|pmc=7694415|pmid=32301288}}</ref> mRNA modifications are linked to many functions in the cell. They ensure the correct maturation and function of the mRNA, but also at the same time act as part of cell’s immune system.<ref>{{Cite journal|last1=Ontiveros|first1=R. Jordan|last2=Stoute|first2=Julian|last3=Liu|first3=Kathy Fange|date=2019-04-30|title=The chemical diversity of RNA modifications|url=https://portlandpress.com/biochemj/article/476/8/1227/219545/The-chemical-diversity-of-RNA-modifications|journal=Biochemical Journal|language=en|volume=476|issue=8|pages=1227–1245|doi=10.1042/BCJ20180445|pmid=31028151|issn=0264-6021}}</ref> Certain modifications like 2’O-methylated nucleotides has been associated with cells ability to distinguish own mRNA from foreign RNA.<ref name=":3">{{Cite journal|last1=Pereira-Montecinos|first1=Camila|last2=Valiente-Echeverría|first2=Fernando|last3=Soto-Rifo|first3=Ricardo|date=April 2017|title=Epitranscriptomic regulation of viral replication|url=https://linkinghub.elsevier.com/retrieve/pii/S1874939916302243|journal=Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms|language=en|volume=1860|issue=4|pages=460–471|doi=10.1016/j.bbagrm.2017.02.002|pmid=28219769}}</ref> For example, m<sup>6</sup>A has been predicted to affect protein translation and localization,<ref name="li2013" /><ref name="song2012" /><ref name="Meyer2014" /> mRNA stability,<ref>{{cite journal | vauthors = Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D, Fu Y, Parisien M, Dai Q, Jia G, Ren B, Pan T, He C | title = N6-methyladenosine-dependent regulation of messenger RNA stability | journal = Nature | volume = 505 | issue = 7481 | pages = 117–20 | date = January 2014 | pmid = 24284625 | pmc = 3877715 | doi = 10.1038/nature12730 | bibcode = 2014Natur.505..117W }}</ref> alternative polyA choice <ref name="ke2015" /> and stem cell pluripotency.<ref>{{cite journal | vauthors = Geula S, Moshitch-Moshkovitz S, Dominissini D, Mansour AA, Kol N, Salmon-Divon M, Hershkovitz V, Peer E, Mor N, Manor YS, Ben-Haim MS, Eyal E, Yunger S, Pinto Y, Jaitin DA, Viukov S, Rais Y, Krupalnik V, Chomsky E, Zerbib M, Maza I, Rechavi Y, Massarwa R, Hanna S, Amit I, Levanon EY, Amariglio N, Stern-Ginossar N, Novershtern N, Rechavi G, Hanna JH | s2cid = 206562941 | title = Stem cells. m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation | journal = Science | volume = 347 | issue = 6225 | pages = 1002–6 | date = February 2015 | pmid = 25569111 | doi = 10.1126/science.1261417 }}</ref> [[Pseudouridine|Pseudouridylation]] of nonsense codons suppresses translation termination both ''in vitro'' and ''in vivo'', suggesting that RNA modification may provide a new way to expand the genetic code.<ref>{{cite journal | vauthors = Karijolich J, Yu YT | title = Converting nonsense codons into sense codons by targeted pseudouridylation | journal = Nature | volume = 474 | issue = 7351 | pages = 395–8 | date = June 2011 | pmid = 21677757 | pmc = 3381908 | doi = 10.1038/nature10165 }}</ref> 5-methylcytosine on the other hand has been associated with mRNA transport from the nucleus to the cytoplasm and enhancement of translation. These functions of m<sup>5</sup>C are not fully known and proven but one strong argument towards these functions in the cell is the observed localization of m<sup>5</sup>C to translation initiation site.<ref>{{Cite journal|last1=Yang|first1=Xin|last2=Yang|first2=Ying|last3=Sun|first3=Bao-Fa|last4=Chen|first4=Yu-Sheng|last5=Xu|first5=Jia-Wei|last6=Lai|first6=Wei-Yi|last7=Li|first7=Ang|last8=Wang|first8=Xing|last9=Bhattarai|first9=Devi Prasad|last10=Xiao|first10=Wen|last11=Sun|first11=Hui-Ying|date=May 2017|title=5-methylcytosine promotes mRNA export — NSUN2 as the methyltransferase and ALYREF as an m5C reader|url= |journal=Cell Research|language=en|volume=27|issue=5|pages=606–625|doi=10.1038/cr.2017.55|issn=1001-0602|pmc=5594206|pmid=28418038}}</ref> Importantly, many modification enzymes are dysregulated and genetically mutated in many disease types.<ref name="li2013" /> For example, genetic mutations in pseudouridine synthases cause mitochondrial myopathy, sideroblastic anemia (MLASA) <ref>{{cite journal | vauthors = Bykhovskaya Y, Casas K, Mengesha E, Inbal A, Fischel-Ghodsian N | title = Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA) | journal = American Journal of Human Genetics | volume = 74 | issue = 6 | pages = 1303–8 | date = June 2004 | pmid = 15108122 | pmc = 1182096 | doi = 10.1086/421530 }}</ref> and dyskeratosis congenital.<ref>{{cite journal | vauthors = Heiss NS, Knight SW, Vulliamy TJ, Klauck SM, Wiemann S, Mason PJ, Poustka A, Dokal I | s2cid = 205342127 | title = X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions | journal = Nature Genetics | volume = 19 | issue = 1 | pages = 32–8 | date = May 1998 | pmid = 9590285 | doi = 10.1038/ng0598-32 }}</ref>
+Recently, functional experiments have revealed many novel functional roles of RNA modifications. Most of the RNA modifications are found on transfer-RNA and ribosomal-RNA, but also eukaryotic mRNA has been shown to be modified with multiple different modifications. 17 naturally occurring modifications on mRNA have been identified, from which the N6-methyladenosine is the most abundant and studied.<ref name="McCown">{{cite journal | vauthors = McCown PJ, Ruszkowska A, Kunkler CN, Breger K, Hulewicz JP, Wang MC, Springer NA, Brown JA | display-authors = 6 | title = Naturally occurring modified ribonucleosides | journal = Wiley Interdisciplinary Reviews. RNA | volume = 11 | issue = 5 | pages = e1595 | date = September 2020 | pmid = 32301288 | pmc = 7694415 | doi = 10.1002/wrna.1595 }}</ref> mRNA modifications are linked to many functions in the cell. They ensure the correct maturation and function of the mRNA, but also at the same time act as part of cell's immune system.<ref>{{cite journal | vauthors = Ontiveros RJ, Stoute J, Liu KF | title = The chemical diversity of RNA modifications | journal = The Biochemical Journal | volume = 476 | issue = 8 | pages = 1227–1245 | date = April 2019 | pmid = 31028151 | pmc = 9073955 | doi = 10.1042/BCJ20180445 | s2cid = 135425191 }}</ref> Certain modifications like 2’O-methylated nucleotides has been associated with cells ability to distinguish own mRNA from foreign RNA.<ref name="Pereira-Montecinos_2017">{{cite journal | vauthors = Pereira-Montecinos C, Valiente-Echeverría F, Soto-Rifo R | title = Epitranscriptomic regulation of viral replication | journal = Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms | volume = 1860 | issue = 4 | pages = 460–471 | date = April 2017 | pmid = 28219769 | doi = 10.1016/j.bbagrm.2017.02.002 }}</ref> For example, m<sup>6</sup>A has been predicted to affect protein translation and localization,<ref name="li2013" /><ref name="song2012" /><ref name="Meyer2014" /> mRNA stability,<ref>{{cite journal | vauthors = Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D, Fu Y, Parisien M, Dai Q, Jia G, Ren B, Pan T, He C | display-authors = 6 | title = N6-methyladenosine-dependent regulation of messenger RNA stability | journal = Nature | volume = 505 | issue = 7481 | pages = 117–120 | date = January 2014 | pmid = 24284625 | pmc = 3877715 | doi = 10.1038/nature12730 | bibcode = 2014Natur.505..117W }}</ref> alternative polyA choice <ref name="ke2015" /> and stem cell pluripotency.<ref>{{cite journal | vauthors = Geula S, Moshitch-Moshkovitz S, Dominissini D, Mansour AA, Kol N, Salmon-Divon M, Hershkovitz V, Peer E, Mor N, Manor YS, Ben-Haim MS, Eyal E, Yunger S, Pinto Y, Jaitin DA, Viukov S, Rais Y, Krupalnik V, Chomsky E, Zerbib M, Maza I, Rechavi Y, Massarwa R, Hanna S, Amit I, Levanon EY, Amariglio N, Stern-Ginossar N, Novershtern N, Rechavi G, Hanna JH | display-authors = 6 | title = Stem cells. m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation | journal = Science | volume = 347 | issue = 6225 | pages = 1002–1006 | date = February 2015 | pmid = 25569111 | doi = 10.1126/science.1261417 | s2cid = 206562941 | doi-access = free }}</ref> [[Pseudouridine|Pseudouridylation]] of nonsense codons suppresses translation termination both ''in vitro'' and ''in vivo'', suggesting that RNA modification may provide a new way to expand the genetic code.<ref>{{cite journal | vauthors = Karijolich J, Yu YT | title = Converting nonsense codons into sense codons by targeted pseudouridylation | journal = Nature | volume = 474 | issue = 7351 | pages = 395–398 | date = June 2011 | pmid = 21677757 | pmc = 3381908 | doi = 10.1038/nature10165 }}</ref> 5-methylcytosine on the other hand has been associated with mRNA transport from the nucleus to the cytoplasm and enhancement of translation. These functions of m<sup>5</sup>C are not fully known and proven but one strong argument towards these functions in the cell is the observed localization of m<sup>5</sup>C to translation initiation site.<ref>{{cite journal | vauthors = Yang X, Yang Y, Sun BF, Chen YS, Xu JW, Lai WY, Li A, Wang X, Bhattarai DP, Xiao W, Sun HY, Zhu Q, Ma HL, Adhikari S, Sun M, Hao YJ, Zhang B, Huang CM, Huang N, Jiang GB, Zhao YL, Wang HL, Sun YP, Yang YG | display-authors = 6 | title = 5-methylcytosine promotes mRNA export - NSUN2 as the methyltransferase and ALYREF as an m<sup>5</sup>C reader | journal = Cell Research | volume = 27 | issue = 5 | pages = 606–625 | date = May 2017 | pmid = 28418038 | pmc = 5594206 | doi = 10.1038/cr.2017.55 }}</ref> Importantly, many modification enzymes are dysregulated and genetically mutated in many disease types.<ref name="li2013" /> For example, genetic mutations in pseudouridine synthases cause mitochondrial myopathy, sideroblastic anemia (MLASA) <ref>{{cite journal | vauthors = Bykhovskaya Y, Casas K, Mengesha E, Inbal A, Fischel-Ghodsian N | title = Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA) | journal = American Journal of Human Genetics | volume = 74 | issue = 6 | pages = 1303–1308 | date = June 2004 | pmid = 15108122 | pmc = 1182096 | doi = 10.1086/421530 }}</ref> and dyskeratosis congenital.<ref>{{cite journal | vauthors = Heiss NS, Knight SW, Vulliamy TJ, Klauck SM, Wiemann S, Mason PJ, Poustka A, Dokal I | display-authors = 6 | title = X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions | journal = Nature Genetics | volume = 19 | issue = 1 | pages = 32–38 | date = May 1998 | pmid = 9590285 | doi = 10.1038/ng0598-32 | s2cid = 205342127 }}</ref>
-Compared to the modifications identified from other RNA species like tRNA and rRNA, the amount of identified modifications on mRNA is very small. One of the biggest reasons why mRNA modifications are not so well known is missing research techniques. In addition to the lack of identified modifications, the knowledge of associated proteins is also behind other RNA species. Modifications are results of specific enzyme interactions with the RNA molecule.<ref name="McCown"/> Considering mRNA modifications most of the known related enzymes are the writer enzymes that add the modification on the mRNA. The additional groups of enzymes readers and erasers are for most of the modifications either poorly known of not known at all.<ref>{{Cite journal|last1=Gilbert|first1=W. V.|last2=Bell|first2=T. A.|last3=Schaening|first3=C.|date=2016-06-17|title=Messenger RNA modifications: Form, distribution, and function|url= |journal=Science|language=en|volume=352|issue=6292|pages=1408–1412|doi=10.1126/science.aad8711|issn=0036-8075|pmc=5094196|pmid=27313037|bibcode=2016Sci...352.1408G}}</ref> For these reasons there has been during the past decade huge interest in studying these modifications and their function.<ref name=":2" />
+Compared to the modifications identified from other RNA species like tRNA and rRNA, the amount of identified modifications on mRNA is very small. One of the biggest reasons why mRNA modifications are not so well known is missing research techniques. In addition to the lack of identified modifications, the knowledge of associated proteins is also behind other RNA species. Modifications are results of specific enzyme interactions with the RNA molecule.<ref name="McCown"/> Considering mRNA modifications most of the known related enzymes are the writer enzymes that add the modification on the mRNA. The additional groups of enzymes readers and erasers are for most of the modifications either poorly known of not known at all.<ref>{{cite journal | vauthors = Gilbert WV, Bell TA, Schaening C | title = Messenger RNA modifications: Form, distribution, and function | journal = Science | volume = 352 | issue = 6292 | pages = 1408–1412 | date = June 2016 | pmid = 27313037 | pmc = 5094196 | doi = 10.1126/science.aad8711 | bibcode = 2016Sci...352.1408G }}</ref> For these reasons there has been during the past decade huge interest in studying these modifications and their function.<ref name="Chen_2020" />
 === Transfer RNA modifications ===
-[[Transfer RNA]] or tRNA is the most abundantly modified type of RNA.<ref>{{cite journal | vauthors = Kirchner S, Ignatova Z | s2cid = 6727707 | title = Emerging roles of tRNA in adaptive translation, signalling dynamics and disease | journal = Nature Reviews. Genetics | volume = 16 | issue = 2 | pages = 98–112 | date = February 2015 | pmid = 25534324 | doi = 10.1038/nrg3861 }}</ref> Modifications in tRNA play crucial roles in maintaining translation efficiency through supporting structure, anticodon-codon interactions, and interactions with enzymes.<ref>{{cite journal | vauthors = Lorenz C, Lünse CE, Mörl M | title = tRNA Modifications: Impact on Structure and Thermal Adaptation | journal = Biomolecules | volume = 7 | issue = 2 | pages = 35 | date = April 2017 | pmid = 28375166 | pmc = 5485724 | doi = 10.3390/biom7020035 | doi-access = free }}</ref>
+[[Transfer RNA]] or tRNA is the most abundantly modified type of RNA.<ref>{{cite journal | vauthors = Kirchner S, Ignatova Z | title = Emerging roles of tRNA in adaptive translation, signalling dynamics and disease | journal = Nature Reviews. Genetics | volume = 16 | issue = 2 | pages = 98–112 | date = February 2015 | pmid = 25534324 | doi = 10.1038/nrg3861 | s2cid = 6727707 }}</ref> Modifications in tRNA play crucial roles in maintaining translation efficiency through supporting structure, anticodon-codon interactions, and interactions with enzymes.<ref>{{cite journal | vauthors = Lorenz C, Lünse CE, Mörl M | title = tRNA Modifications: Impact on Structure and Thermal Adaptation | journal = Biomolecules | volume = 7 | issue = 2 | pages = 35 | date = April 2017 | pmid = 28375166 | pmc = 5485724 | doi = 10.3390/biom7020035 | doi-access = free }}</ref>
 Anticodon modifications are important for proper decoding of mRNA. Since the genetic code is degenerate, anticodon modifications are necessary to properly decode mRNA. Particularly, the [[Wobble base pair|wobble position]] of the anticodon determines how the codons are read. For example, in eukaryotes an adenosine at position 34 of the anticodon can be converted to inosine. Inosine is a modification that is able to base-pair with cytosine, adenine, and uridine.<ref name="tRNA's wobble decoding of the genom">{{cite journal | vauthors = Agris PF, Vendeix FA, Graham WD | title = tRNA's wobble decoding of the genome: 40 years of modification | journal = Journal of Molecular Biology | volume = 366 | issue = 1 | pages = 1–13 | date = February 2007 | pmid = 17187822 | doi = 10.1016/j.jmb.2006.11.046 }}</ref>
@@ Line 28: / Line 30: @@
 === Ribosomal RNA modification ===
-Ribosomal RNA modifications are made throughout the ribosome synthesis. Modifications primarily play a role in the structure of the rRNA in order to protect translational efficiency.<ref>{{cite journal | vauthors = Sloan KE, Warda AS, Sharma S, Entian KD, Lafontaine DL, Bohnsack MT | title = Tuning the ribosome: The influence of rRNA modification on eukaryotic ribosome biogenesis and function | journal = RNA Biology | volume = 14 | issue = 9 | pages = 1138–1152 | date = September 2017 | pmid = 27911188 | pmc = 5699541 | doi = 10.1080/15476286.2016.1259781 }}</ref>
+Ribosomal RNA (rRNA) is essential to the makeup of ribosomes and peptide transfer during translation processes.<ref name=":0" /> Ribosomal RNA modifications are made throughout ribosome synthesis, and often occur during and/or after translation. Modifications primarily play a role in the structure of the rRNA in order to protect translational efficiency.<ref name=":0">{{cite journal | vauthors = Sloan KE, Warda AS, Sharma S, Entian KD, Lafontaine DL, Bohnsack MT | title = Tuning the ribosome: The influence of rRNA modification on eukaryotic ribosome biogenesis and function | journal = RNA Biology | volume = 14 | issue = 9 | pages = 1138–1152 | date = September 2017 | pmid = 27911188 | pmc = 5699541 | doi = 10.1080/15476286.2016.1259781 }}</ref> Chemical modification in rRNA consists of [[methylation]] of [[Ribose|ribose sugars]], [[isomerization]] of uridines, and methylation and [[acetylation]] of individual bases.<ref name=":1">{{Citation |last1=Sharma |first1=Sunny |title=Chemical Modifications of Ribosomal RNA |date=2022 |work=Ribosome Biogenesis: Methods and Protocols |pages=149–166 |editor-last=Entian |editor-first=Karl-Dieter |url=https://doi.org/10.1007/978-1-0716-2501-9_9 |access-date=2024-02-29 |series=Methods in Molecular Biology |place=New York, NY |publisher=Springer US |language=en |doi=10.1007/978-1-0716-2501-9_9 |isbn=978-1-0716-2501-9 |pmc=9761533 |pmid=35796987 |last2=Entian |first2=Karl-Dieter|volume=2533 }}</ref>
-== Types of changes ==
+==== Methylation ====
+Methylation of rRNA upholds structural rigidity by blocking base pair stacking and surrounds the 2’-OH group to block hydrolysis. It occurs at specific parts of eukaryotic rRNA. The template for methylation consists of 10-21 nucleotides.<ref name=":0" /> 2'-O-methylation of the ribose sugar is one of the most common rRNA modifications.<ref name=":2">{{Cite journal |last1=Borchardt |first1=Erin K. |last2=Martinez |first2=Nicole M. |last3=Gilbert |first3=Wendy V. |date=2020-11-23 |title=Regulation and Function of RNA Pseudouridylation in Human Cells |journal=Annual Review of Genetics |volume=54 |pages=309–336 |doi=10.1146/annurev-genet-112618-043830 |issn=0066-4197 |pmc=8007080 |pmid=32870730}}</ref> Methylation is primarily introduced by small nucleolar RNA's, referred to as snoRNPs. There are two classes of snoRNPs that target methylation sites, and they are referred to box C/D and box H/ACA.<ref name=":1" /><ref name=":2" /> One type of methylation, 2′-O-methylation, contributes to helical stabilization.<ref name=":0" />
-===Editing by insertion or deletion===
+==== Isomerization ====
+The isomerization of uridine to pseudouridine is the second most common rRNA modification. These pseudouridines are also introduced by the same classes of snoRNPs that participate in methylation. Pseudouridine synthases are the major participating enzymes in the reaction.<ref name=":3">{{Cite journal |last1=Borchardt |first1=Erin K. |last2=Martinez |first2=Nicole M. |last3=Gilbert |first3=Wendy V. |date=2020-11-23 |title=Regulation and Function of RNA Pseudouridylation in Human Cells |journal=Annual Review of Genetics |language=en |volume=54 |issue=1 |pages=309–336 |doi=10.1146/annurev-genet-112618-043830 |pmid=32870730 |issn=0066-4197|pmc=8007080 }}</ref> The H/ACA box snoRNPs introduce guide sequences that are about 14-15 nucleotides long.<ref name=":1" /> Pseudouridylation is triggered in numerous places of rRNAs at once to preserve the thermal stability of RNA.<ref name=":1" /> Pseudouridine allows for increased hydrogen bonding and alters translation in rRNA and tRNA.<ref name=":2" /><ref name=":3" /> It alters translation by increasing the affinity of the ribosome subunit to specific mRNAs.<ref name=":0" />
+'''Base Editing:'''
+Base editing is the third major class of rRNA modification, specifically in eukaryotes. There are 8 categories of base edits that can occur at the gap between the small and large ribosomal subunits.<ref name=":0" /> RNA methyltransferases are the enzymes that introduce base methylation.<ref name=":0" /> Acetyltransferases are the enzymes responsible for acetylation of cytosine in rRNA. Base methylation plays a role in translation. These base modifications all work in conjunction with the two other main classes of modification to contribute to RNA structural stability. An example of this occurs in N7-methylation, which increases the nucleotide's charge to increase ionic interactions of proteins attaching to the RNA before translation.
+=== Editing by insertion or deletion ===
 [[File:insertion.PNG|300px|thumb|The effect of uracil insertion in pre-mRNA transcripts]]
-RNA editing through the addition and deletion of uracil has been found in [[kinetoplast|kinetoplasts]] from the mitochondria of ''[[Trypanosoma brucei]].''<ref name=Benne_2>{{cite journal |vauthors= Benne R |title= RNA editing in trypanosomes |journal= European Journal of Biochemistry |volume= 221 |issue=1 |pages= 9–23 |date= April 1994 |pmid= 7513284 |doi= 10.1111/j.1432-1033.1994.tb18710.x }}</ref>
+RNA editing through the addition and deletion of uracil has been found in [[kinetoplast]]s from the mitochondria of ''[[Trypanosoma brucei]].''<ref name=Benne_2>{{cite journal | vauthors = Benne R | title = RNA editing in trypanosomes | journal = European Journal of Biochemistry | volume = 221 | issue = 1 | pages = 9–23 | date = April 1994 | pmid = 7513284 | doi = 10.1111/j.1432-1033.1994.tb18710.x | doi-access = free }}</ref>
 Because this may involve a large fraction of the sites in a gene, it is sometimes called "pan-editing" to distinguish it from topical editing of one or a few sites.
-Pan-editing starts with the base-pairing of the unedited primary transcript with a [[guide RNA]] (gRNA), which contains complementary sequences to the regions around the insertion/deletion points. The newly formed double-stranded region is then enveloped by an editosome, a large multi-protein complex that catalyzes the editing.<ref name=Arts_3>{{cite journal |vauthors= Arts GJ, Benne R |title= Mechanism and evolution of RNA editing in kinetoplastida |journal= Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression |volume= 1307 |issue=1 |pages= 39–54 |date= June 1996 |pmid= 8652667 |doi= 10.1016/0167-4781(96)00021-8 }}</ref><ref name =Alfonzo_4>{{cite journal |vauthors= Alfonzo JD, Thiemann O, Simpson L |title=The mechanism of U insertion/deletion RNA editing in kinetoplastid mitochondria |journal= Nucleic Acids Research |volume= 25 |issue= 19 |pages= 3751–9 |date= October 1997 |pmid= 9380494 |pmc= 146959 |doi= 10.1093/nar/25.19.3751 }}</ref> The editosome opens the transcript at the first mismatched nucleotide and starts inserting uridines. The inserted uridines will base-pair with the guide RNA, and insertion will continue as long as A or G is present in the guide RNA and will stop when a C or U is encountered.<ref name=Blum_5>{{cite journal |vauthors= Blum B, Bakalara N, Simpson L |title= A model for RNA editing in kinetoplastid mitochondria: "guide" RNA molecules transcribed from maxicircle DNA provide the edited information |journal= Cell |volume= 60 |issue=2 |pages= 189–98 |date= January 1990 |pmid= 1688737 |doi= 10.1016/0092-8674(90)90735-W |s2cid= 19656609 }}</ref><ref name=Kable_6>{{cite journal |vauthors= Kable ML, Heidmann S, Stuart KD |title= RNA editing: getting U into RNA |journal= Trends in Biochemical Sciences |volume= 22 |issue= 5 |pages= 162–6 |date= May 1997 |pmid= 9175474 |doi= 10.1016/S0968-0004(97)01041-4 }}</ref> The inserted nucleotides cause a [[frameshift]], and result in a translated protein that differs from its gene.
+Pan-editing starts with the base-pairing of the unedited primary transcript with a [[guide RNA]] (gRNA), which contains complementary sequences to the regions around the insertion/deletion points. The newly formed double-stranded region is then enveloped by an editosome, a large multi-protein complex that catalyzes the editing.<ref name=Arts_3>{{cite journal | vauthors = Arts GJ, Benne R | title = Mechanism and evolution of RNA editing in kinetoplastida | journal = Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression | volume = 1307 | issue = 1 | pages = 39–54 | date = June 1996 | pmid = 8652667 | doi = 10.1016/0167-4781(96)00021-8 }}</ref><ref name =Alfonzo_4>{{cite journal | vauthors = Alfonzo JD, Thiemann O, Simpson L | title = The mechanism of U insertion/deletion RNA editing in kinetoplastid mitochondria | journal = Nucleic Acids Research | volume = 25 | issue = 19 | pages = 3751–3759 | date = October 1997 | pmid = 9380494 | pmc = 146959 | doi = 10.1093/nar/25.19.3751 | doi-broken-date = 2024-02-22 }}</ref> The editosome opens the transcript at the first mismatched nucleotide and starts inserting uridines. The inserted uridines will base-pair with the guide RNA, and insertion will continue as long as A or G is present in the guide RNA and will stop when a C or U is encountered.<ref name=Blum_5>{{cite journal | vauthors = Blum B, Bakalara N, Simpson L | title = A model for RNA editing in kinetoplastid mitochondria: "guide" RNA molecules transcribed from maxicircle DNA provide the edited information | journal = Cell | volume = 60 | issue = 2 | pages = 189–198 | date = January 1990 | pmid = 1688737 | doi = 10.1016/0092-8674(90)90735-W | s2cid = 19656609 }}</ref><ref name=Kable_6>{{cite journal | vauthors = Kable ML, Heidmann S, Stuart KD | title = RNA editing: getting U into RNA | journal = Trends in Biochemical Sciences | volume = 22 | issue = 5 | pages = 162–166 | date = May 1997 | pmid = 9175474 | doi = 10.1016/S0968-0004(97)01041-4 }}</ref> The inserted nucleotides cause a [[frameshift]], and result in a translated protein that differs from its gene.
-The mechanism of the [[editosome]] involves an [[Endonuclease|endonucleolytic]] cut at the mismatch point between the guide RNA and the unedited transcript. The next step is catalyzed by one of the enzymes in the complex, a terminal U-transferase, which adds Us from UTP at the 3' end of the mRNA.<ref name=Simpson_7>{{cite journal |vauthors= Simpson L, Thiemann OH |title= Sense from nonsense: RNA editing in mitochondria of kinetoplastid protozoa and slime molds |journal= Cell |volume= 81 |issue= 6 |pages= 837–40 |date= June 1995 |pmid= 7781060 |doi= 10.1016/0092-8674(95)90003-9 |s2cid= 4634304 |doi-access= free }}</ref> The opened ends are held in place by other proteins in the complex. Another enzyme, a U-specific exoribonuclease, removes the unpaired Us. After editing has made mRNA complementary to gRNA, an RNA ligase rejoins the ends of the edited mRNA transcript.<ref name=Stuart_8>{{cite journal |vauthors= Stuart K |title= RNA editing in mitochondrial mRNA of trypanosomatids |journal= Trends in Biochemical Sciences |volume= 16 |issue=2 |pages= 68–72 |date= February 1991 |pmid= 1713359 |doi= 10.1016/0968-0004(91)90027-S }}</ref><ref name=Hajduk_10>{{cite book |vauthors= Hajduk SL, Sabatini RS |year=1998 |chapter= Mitochondrial mRNA editing in kinetoplastid protozoa |publisher= ASM Press |location= Washington, DC. |pages=377–394 |title= Modification and Editing of RNA |veditors= Grosjean H, Benne R }}</ref> As a consequence, the editosome can edit only in a 3' to 5' direction along the primary RNA transcript. The complex can act on only a single guide RNA at a time. Therefore, a RNA transcript requiring extensive editing will need more than one guide RNA and editosome complex.
+The mechanism of the [[editosome]] involves an [[Endonuclease|endonucleolytic]] cut at the mismatch point between the guide RNA and the unedited transcript. The next step is catalyzed by one of the enzymes in the complex, a terminal U-transferase, which adds Us from UTP at the 3' end of the mRNA.<ref name=Simpson_7>{{cite journal | vauthors = Simpson L, Thiemann OH | title = Sense from nonsense: RNA editing in mitochondria of kinetoplastid protozoa and slime molds | journal = Cell | volume = 81 | issue = 6 | pages = 837–840 | date = June 1995 | pmid = 7781060 | doi = 10.1016/0092-8674(95)90003-9 | s2cid = 4634304 | doi-access = free }}</ref> The opened ends are held in place by other proteins in the complex. Another enzyme, a U-specific exoribonuclease, removes the unpaired Us. After editing has made mRNA complementary to gRNA, an RNA ligase rejoins the ends of the edited mRNA transcript.<ref name=Stuart_8>{{cite journal | vauthors = Stuart K | title = RNA editing in mitochondrial mRNA of trypanosomatids | journal = Trends in Biochemical Sciences | volume = 16 | issue = 2 | pages = 68–72 | date = February 1991 | pmid = 1713359 | doi = 10.1016/0968-0004(91)90027-S }}</ref><ref name=Hajduk_10>{{cite book |vauthors= Hajduk SL, Sabatini RS |year=1998 |chapter= Mitochondrial mRNA editing in kinetoplastid protozoa |publisher= ASM Press |location= Washington, DC. |pages=377–394 |title= Modification and Editing of RNA |veditors= Grosjean H, Benne R }}</ref> As a consequence, the editosome can edit only in a 3' to 5' direction along the primary RNA transcript. The complex can act on only a single guide RNA at a time. Therefore, a RNA transcript requiring extensive editing will need more than one guide RNA and editosome complex.
 ===Editing by deamination===
@@ Line 44: / Line 55: @@
 [[File:Apobgene.PNG|300px|thumb|The effect of C-to-U RNA editing on the human ApoB gene]]
 The editing involves cytidine deaminase that deaminates a cytidine base into a uridine base. An example of C-to-U editing is with the [[apolipoprotein B]] gene in humans. [[ApoB100|Apo B100]] is expressed in the liver and apo B48 is expressed in the intestines. In the intestines, the mRNA has a CAA sequence edited to be UAA, a stop codon, thus producing the shorter B48 form.
-C-to-U editing often occurs in the [[mitochondrial RNA]] of flowering plants. Different plants have different degrees of C-to-U editing; for example, eight editing events occur in mitochondria of the moss ''[[Funaria hygrometrica]]'', whereas over 1,700 editing events occur in the lycophytes ''[[Isoetes engelmannii|Isoetes engelmanii]]''.<ref>{{cite journal |vauthors= Takenaka M, Verbitskiy D, Zehrmann A, Härtel B, Bayer-Császár E, Glass F, Brennicke A |title= RNA editing in plant mitochondria—connecting RNA target sequences and acting proteins |journal= Mitochondrion |volume=  19 Pt B |pages= 191–7 |date= November 2014 |pmid= 24732437 |doi= 10.1016/j.mito.2014.04.005 | series = Plant Mitochondria in Mitochondrion }}</ref> C-to-U editing is performed by members of the pentatricopeptide repeat (PPR) protein family. Angiosperms have large PPR families, acting as ''trans'' -factors for ''cis'' -elements lacking a consensus sequence; [[Arabidopsis]] has around 450 members in its PPR family. There have been a number of discoveries of PPR proteins in both plastids and mitochondria.<ref>{{cite journal |vauthors= Shikanai T |title= RNA editing in plants: Machinery and flexibility of site recognition |journal= Biochimica et Biophysica Acta (BBA) - Bioenergetics |volume = 1847 |issue= 9 |pages= 779–85 |date= September 2015 |pmid= 25585161 |doi= 10.1016/j.bbabio.2014.12.010 |series= SI: Chloroplast Biogenesis |doi-access= free }}</ref>
+C-to-U editing often occurs in the [[mitochondrial RNA]] of flowering plants. Different plants have different degrees of C-to-U editing; for example, eight editing events occur in mitochondria of the moss ''[[Funaria hygrometrica]]'', whereas over 1,700 editing events occur in the lycophytes ''[[Isoetes engelmannii|Isoetes engelmanii]]''.<ref>{{cite journal | vauthors = Takenaka M, Verbitskiy D, Zehrmann A, Härtel B, Bayer-Császár E, Glass F, Brennicke A | title = RNA editing in plant mitochondria—connecting RNA target sequences and acting proteins | journal = Mitochondrion | volume = 19 | issue = Pt B | pages = 191–197 | date = November 2014 | pmid = 24732437 | doi = 10.1016/j.mito.2014.04.005 | series = Plant Mitochondria in Mitochondrion }}</ref> C-to-U editing is performed by members of the pentatricopeptide repeat (PPR) protein family. Angiosperms have large PPR families, acting as ''trans'' -factors for ''cis'' -elements lacking a consensus sequence; [[Arabidopsis]] has around 450 members in its PPR family. There have been a number of discoveries of PPR proteins in both plastids and mitochondria.<ref>{{cite journal | vauthors = Shikanai T | title = RNA editing in plants: Machinery and flexibility of site recognition | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1847 | issue = 9 | pages = 779–785 | date = September 2015 | pmid = 25585161 | doi = 10.1016/j.bbabio.2014.12.010 | series = SI: Chloroplast Biogenesis | doi-access = free }}</ref>
 ====A-to-I editing====
+{{See also|Deamination#Adenine|l1=Adenine deamination}}
 Adenosine-to-inosine (A-to-I) modifications contribute to nearly 90% of all editing events in RNA. The deamination of adenosine is catalyzed by the double-stranded RNA-specific adenosine deaminase ([[ADAR]]), which typically acts on pre-mRNAs. The deamination of adenosine to inosine disrupts and destabilizes the dsRNA base pairing, therefore rendering that particular dsRNA less able to produce [[Small interfering RNA|siRNA]], which interferes with the [[RNA interference|RNAi]] pathway.
-The [[wobble base pair]]ing causes deaminated RNA to have a unique but different structure, which may be related to the inhibition of the initiation step of RNA translation. Studies have shown that I-RNA (RNA with many repeats of the I-U base pair) recruits methylases that are involved in the formation of [[heterochromatin]] and that this chemical modification heavily interferes with miRNA target sites.<ref>{{cite journal | vauthors = Nishikura K | title = Functions and regulation of RNA editing by ADAR deaminases | journal = Annual Review of Biochemistry | volume = 79 | issue = 1 | pages = 321–49 | date = 2010 | pmid = 20192758 | pmc = 2953425 | doi = 10.1146/annurev-biochem-060208-105251 }}</ref> There is active research into the importance of A-to-I modifications and their purpose in the novel concept of [[epitranscriptomics]], in which modifications are made to RNA that alter their function.<ref>{{cite journal | vauthors = Tajaddod M, Jantsch MF, Licht K | title = The dynamic epitranscriptome: A to I editing modulates genetic information | journal = Chromosoma | volume = 125 | issue = 1 | pages = 51–63 | date = March 2016 | pmid = 26148686 | pmc = 4761006 | doi = 10.1007/s00412-015-0526-9 }}</ref><ref>{{cite journal | vauthors = Licht K, Jantsch MF | title = Rapid and dynamic transcriptome regulation by RNA editing and RNA modifications | journal = The Journal of Cell Biology | volume = 213 | issue = 1 | pages = 15–22 | date = April 2016 | pmid = 27044895 | pmc = 4828693 | doi = 10.1083/jcb.201511041 }}</ref> A long established consequence of A-to-I in mRNA is the interpretation of I as a G, therefore leading to functional A-to-G substitution, e.g. in the interpretation of the genetic code by ribosomes. Newer studies however, have weakened this correlation by showing that I's can also be decoded by the ribosome (although in a lesser extent) as A's and U's. Furthermore it was shown that I's lead to the stalling of ribosomes on the I-rich mRNA.<ref>{{cite journal | vauthors = Licht K, et al. | title = Inosine induces context-dependent recoding and translational stalling | journal = Nucleic Acids Research | volume = 47 | issue = 1 | pages = 3–14 | doi = 10.1093/nar/gky1163 | pmid = 30462291 | pmc = 6326813 | year = 2019 }}</ref>
+The [[wobble base pair]]ing causes deaminated RNA to have a unique but different structure, which may be related to the inhibition of the initiation step of RNA translation. Studies have shown that I-RNA (RNA with many repeats of the I-U base pair) recruits methylases that are involved in the formation of [[heterochromatin]] and that this chemical modification heavily interferes with miRNA target sites.<ref>{{cite journal | vauthors = Nishikura K | title = Functions and regulation of RNA editing by ADAR deaminases | journal = Annual Review of Biochemistry | volume = 79 | issue = 1 | pages = 321–349 | date = 2010 | pmid = 20192758 | pmc = 2953425 | doi = 10.1146/annurev-biochem-060208-105251 }}</ref> There is active research into the importance of A-to-I modifications and their purpose in the novel concept of [[epitranscriptomics]], in which modifications are made to RNA that alter their function.<ref>{{cite journal | vauthors = Tajaddod M, Jantsch MF, Licht K | title = The dynamic epitranscriptome: A to I editing modulates genetic information | journal = Chromosoma | volume = 125 | issue = 1 | pages = 51–63 | date = March 2016 | pmid = 26148686 | pmc = 4761006 | doi = 10.1007/s00412-015-0526-9 }}</ref><ref>{{cite journal | vauthors = Licht K, Jantsch MF | title = Rapid and dynamic transcriptome regulation by RNA editing and RNA modifications | journal = The Journal of Cell Biology | volume = 213 | issue = 1 | pages = 15–22 | date = April 2016 | pmid = 27044895 | pmc = 4828693 | doi = 10.1083/jcb.201511041 }}</ref> A long established consequence of A-to-I in mRNA is the interpretation of I as a G, therefore leading to functional A-to-G substitution, e.g. in the interpretation of the genetic code by ribosomes. Newer studies, however, have weakened this correlation by showing that inosines can also be decoded by the ribosome (although in a lesser extent) as adenosines or uracils. Furthermore, it was shown that I's lead to the stalling of ribosomes on the I-rich mRNA.<ref>{{cite journal | vauthors = Licht K, Hartl M, Amman F, Anrather D, Janisiw MP, Jantsch MF | title = Inosine induces context-dependent recoding and translational stalling | journal = Nucleic Acids Research | volume = 47 | issue = 1 | pages = 3–14 | date = January 2019 | pmid = 30462291 | pmc = 6326813 | doi = 10.1093/nar/gky1163 }}</ref>
-The development of high-throughput sequencing in recent years has allowed for the development of extensive databases for different modifications and edits of RNA. RADAR (Rigorously Annotated Database of A-to-I RNA editing) was developed in 2013 to catalog the vast variety of A-to-I sites and tissue-specific levels present in humans, pigs, <ref>{{cite journal | vauthors = Huang J, Lin L, Dong Z, et al. | title = A porcine brain-wide RNA editing landscape | journal = Communications Biology | volume = 4 | pages = 717 | date = June 2021 | issue = 1 | doi = 10.1038/s42003-021-02238-3 | pmid = 34112917 | pmc = 8192503 }}</ref> [[Mouse|mice]], and [[Fly|flies]]. The addition of novel sites and overall edits to the database are ongoing.<ref>{{cite journal | vauthors = Ramaswami G, Li JB | title = RADAR: a rigorously annotated database of A-to-I RNA editing | journal = Nucleic Acids Research | volume = 42 | issue = Database issue | pages = D109–13 | date = January 2014 | pmid = 24163250 | pmc = 3965033 | doi = 10.1093/nar/gkt996 }}</ref> The level of editing for specific editing sites, e.g. in the filamin A transcript, is tissue-specific.<ref>{{cite journal | vauthors = Stulić M, Jantsch MF | title = Spatio-temporal profiling of Filamin A RNA-editing reveals ADAR preferences and high editing levels outside neuronal tissues | journal = RNA Biology | volume = 10 | issue = 10 | pages = 1611–7 | date = October 2013 | pmid = 24025532 | pmc = 3866242 | doi = 10.4161/rna.26216 }}</ref> The efficiency of mRNA-splicing is a major factor controlling the level of A-to-I RNA editing.<ref>{{cite journal | vauthors = Licht K, Kapoor U, Mayrhofer E, Jantsch MF | title = Adenosine to Inosine editing frequency controlled by splicing efficiency | journal = Nucleic Acids Research | volume = 44 | issue = 13 | pages = 6398–408 | date = July 2016 | pmid = 27112566 | pmc = 5291252 | doi = 10.1093/nar/gkw325 }}</ref><ref>{{cite journal | vauthors = Licht K, Kapoor U, Amman F, Picardi E, Martin D, Bajad P, Jantsch MF | title = A high resolution A-to-I editing map in the mouse identifies editing events controlled by pre-mRNA splicing | journal = Genome Research | volume = 29 | issue = 9 | pages = 1453–1463 | date = September 2019 | pmid = 31427386 | pmc = 6724681 | doi = 10.1101/gr.242636.118 }}</ref> Interestingly, ADAR1 and ADAR2 also affect alternative splicing via both A-to-I editing ability and dsRNA binding ability.<ref>{{cite journal | vauthors = Kapoor U, Licht K, Amman F, Jakobi T, Martin D, Dieterich C, Jantsch MF | title = ADAR-deficiency perturbs the global splicing landscape in mouse tissues | journal = Genome Res | volume = 30 | issue = 8 | pages = 1107–1118 | date = August 2020 | pmid = 32727871 | pmc = 7462079 | doi = 10.1101/gr.256933.119 }}</ref><ref>{{cite journal | vauthors = Tang SJ, Shen H, An O, etal | title = Cis-and trans-regulations of pre-mRNA splicing by RNA editing enzymes influence cancer development | journal = Nature Communications | volume = 11 | issue = 1 | date = February 2020 | page = 799 | pmid = 32034135 | pmc = 7005744 | doi = 10.1038/s41467-020-14621-5 | bibcode = 2020NatCo..11..799T }}</ref>
+The development of high-throughput sequencing in recent years has allowed for the development of extensive databases for different modifications and edits of RNA. RADAR (Rigorously Annotated Database of A-to-I RNA editing) was developed in 2013 to catalog the vast variety of A-to-I sites and tissue-specific levels present in humans, [[Mouse|mice]], and [[Fly|flies]]. The addition of novel sites and overall edits to the database are ongoing.<ref>{{cite journal | vauthors = Ramaswami G, Li JB | title = RADAR: a rigorously annotated database of A-to-I RNA editing | journal = Nucleic Acids Research | volume = 42 | issue = Database issue | pages = D109–D113 | date = January 2014 | pmid = 24163250 | pmc = 3965033 | doi = 10.1093/nar/gkt996 }}</ref> The level of editing for specific editing sites, e.g. in the filamin A transcript, is tissue-specific.<ref>{{cite journal | vauthors = Stulić M, Jantsch MF | title = Spatio-temporal profiling of Filamin A RNA-editing reveals ADAR preferences and high editing levels outside neuronal tissues | journal = RNA Biology | volume = 10 | issue = 10 | pages = 1611–1617 | date = October 2013 | pmid = 24025532 | pmc = 3866242 | doi = 10.4161/rna.26216 }}</ref> The efficiency of mRNA-splicing is a major factor controlling the level of A-to-I RNA editing.<ref>{{cite journal | vauthors = Licht K, Kapoor U, Mayrhofer E, Jantsch MF | title = Adenosine to Inosine editing frequency controlled by splicing efficiency | journal = Nucleic Acids Research | volume = 44 | issue = 13 | pages = 6398–6408 | date = July 2016 | pmid = 27112566 | pmc = 5291252 | doi = 10.1093/nar/gkw325 }}</ref><ref>{{cite journal | vauthors = Licht K, Kapoor U, Amman F, Picardi E, Martin D, Bajad P, Jantsch MF | title = A high resolution A-to-I editing map in the mouse identifies editing events controlled by pre-mRNA splicing | journal = Genome Research | volume = 29 | issue = 9 | pages = 1453–1463 | date = September 2019 | pmid = 31427386 | pmc = 6724681 | doi = 10.1101/gr.242636.118 }}</ref> Interestingly, ADAR1 and ADAR2 also affect alternative splicing via both A-to-I editing ability and dsRNA binding ability.<ref>{{cite journal | vauthors = Kapoor U, Licht K, Amman F, Jakobi T, Martin D, Dieterich C, Jantsch MF | title = ADAR-deficiency perturbs the global splicing landscape in mouse tissues | journal = Genome Research | volume = 30 | issue = 8 | pages = 1107–1118 | date = August 2020 | pmid = 32727871 | pmc = 7462079 | doi = 10.1101/gr.256933.119 }}</ref><ref>{{cite journal | vauthors = Tang SJ, Shen H, An O, Hong H, Li J, Song Y, Han J, Tay DJ, Ng VH, Bellido Molias F, Leong KW, Pitcheshwar P, Yang H, Chen L | display-authors = 6 | title = Cis- and trans-regulations of pre-mRNA splicing by RNA editing enzymes influence cancer development | journal = Nature Communications | volume = 11 | issue = 1 | pages = 799 | date = February 2020 | pmid = 32034135 | pmc = 7005744 | doi = 10.1038/s41467-020-14621-5 | bibcode = 2020NatCo..11..799T }}</ref>
 ====Alternative mRNA editing====
-Alternative U-to-C mRNA editing was first reported in [[WT1]] (Wilms Tumor-1) transcripts,<ref>{{cite journal |vauthors= Sharma PM, Bowman M, Madden SL, Rauscher FJ, Sukumar S |title= RNA editing in the Wilms' tumor susceptibility gene, WT1 |journal= Genes & Development |volume= 8 |issue= 6 |pages= 720–31 |date= March 1994 |pmid= 7926762 |doi= 10.1101/gad.8.6.720 |doi-access= free }}</ref> and non-classic G-A mRNA changes were first observed in [[HNRNPK]] (heterogeneous nuclear ribonucleoprotein K) transcripts in both malignant and normal colorectal samples.<ref>{{cite journal | vauthors= Klimek-Tomczak K, Mikula M, Dzwonek A, Paziewska A, Karczmarski J, Hennig E, Bujnicki JM, Bragoszewski P, Denisenko O, Bomsztyk K, Ostrowski J |title= Editing of hnRNP K protein mRNA in colorectal adenocarcinoma and surrounding mucosa | journal= British Journal of Cancer |volume= 94 |issue= 4 |pages= 586–92 |date= February 2006 |pmid= 16404425 |pmc= 2361188 |doi= 10.1038/sj.bjc.6602938 }}</ref> The latter changes were also later seen alongside non-classic U-to-C alterations in brain cell [[TPH2]] (tryptophan hydroxylase 2) transcripts.<ref>{{cite journal | vauthors = Grohmann M, Hammer P, Walther M, Paulmann N, Büttner A, Eisenmenger W, Baghai TC, Schüle C, Rupprecht R, Bader M, Bondy B, Zill P, Priller J, Walther DJ |title = Alternative splicing and extensive RNA editing of human TPH2 transcripts |journal= PLOS ONE |volume= 5 |issue=1 |pages= e8956 |date= Jan 2010 |pmid= 20126463 |pmc= 2813293 |doi= 10.1371/journal.pone.0008956 |bibcode = 2010PLoSO...5.8956G |doi-access = free }}</ref> Although the reverse amination might be the simplest explanation for U-to-C changes, transamination and transglycosylation mechanisms have been proposed for plant U-to-C editing events in mitochondrial transcripts.<ref>{{cite journal |vauthors= Castandet B, Araya A |title= RNA editing in plant organelles. Why make it easy? |journal= Biochemistry. Biokhimiia |volume= 76 |issue=8 |pages= 924–31 |date= Aug 2011 |pmid= 22022966 |doi= 10.1134/S0006297911080086 |s2cid= 2174535 }}</ref> A recent study reported novel G-to-A mRNA changes in WT1 transcripts at two hotspots, proposing the [[APOBEC3A]] (apolipoprotein B mRNA editing enzyme, catalytic polypeptide 3A) as the enzyme implicated in this class of alternative mRNA editing.<ref>{{cite journal |vauthors = Niavarani A, Currie E, Reyal Y, Anjos-Afonso F, Horswell S, Griessinger E, Luis Sardina J, Bonnet D |title= APOBEC3A is implicated in a novel class of G-to-A mRNA editing in WT1 transcripts |journal= PLOS ONE |volume= 10 |issue=3 |pages= e0120089 |year= 2015 |pmid= 25807502 |pmc= 4373805 |doi= 10.1371/journal.pone.0120089 |bibcode= 2015PLoSO..1020089N |doi-access= free }}</ref> It was also shown that alternative mRNA changes were associated with canonical WT1 [[RNA splicing|splicing]] variants, indicating their functional significance.
+Alternative U-to-C mRNA editing was first reported in [[WT1]] (Wilms Tumor-1) transcripts,<ref>{{cite journal | vauthors = Sharma PM, Bowman M, Madden SL, Rauscher FJ, Sukumar S | title = RNA editing in the Wilms' tumor susceptibility gene, WT1 | journal = Genes & Development | volume = 8 | issue = 6 | pages = 720–731 | date = March 1994 | pmid = 7926762 | doi = 10.1101/gad.8.6.720 | doi-access = free }}</ref> and non-classic G-A mRNA changes were first observed in [[HNRNPK]] (heterogeneous nuclear ribonucleoprotein K) transcripts in both malignant and normal colorectal samples.<ref>{{cite journal | vauthors = Klimek-Tomczak K, Mikula M, Dzwonek A, Paziewska A, Karczmarski J, Hennig E, Bujnicki JM, Bragoszewski P, Denisenko O, Bomsztyk K, Ostrowski J | display-authors = 6 | title = Editing of hnRNP K protein mRNA in colorectal adenocarcinoma and surrounding mucosa | journal = British Journal of Cancer | volume = 94 | issue = 4 | pages = 586–592 | date = February 2006 | pmid = 16404425 | pmc = 2361188 | doi = 10.1038/sj.bjc.6602938 }}</ref> The latter changes were also later seen alongside non-classic U-to-C alterations in brain cell [[TPH2]] (tryptophan hydroxylase 2) transcripts.<ref>{{cite journal | vauthors = Grohmann M, Hammer P, Walther M, Paulmann N, Büttner A, Eisenmenger W, Baghai TC, Schüle C, Rupprecht R, Bader M, Bondy B, Zill P, Priller J, Walther DJ | display-authors = 6 | title = Alternative splicing and extensive RNA editing of human TPH2 transcripts | journal = PLOS ONE | volume = 5 | issue = 1 | pages = e8956 | date = January 2010 | pmid = 20126463 | pmc = 2813293 | doi = 10.1371/journal.pone.0008956 | doi-access = free | bibcode = 2010PLoSO...5.8956G }}</ref> Although the reverse amination might be the simplest explanation for U-to-C changes, transamination and transglycosylation mechanisms have been proposed for plant U-to-C editing events in mitochondrial transcripts.<ref>{{cite journal | vauthors = Castandet B, Araya A | title = RNA editing in plant organelles. Why make it easy? | journal = Biochemistry. Biokhimiia | volume = 76 | issue = 8 | pages = 924–931 | date = August 2011 | pmid = 22022966 | doi = 10.1134/S0006297911080086 | s2cid = 2174535 }}</ref> A recent study reported novel G-to-A mRNA changes in WT1 transcripts at two hotspots, proposing the [[APOBEC3A]] (apolipoprotein B mRNA editing enzyme, catalytic polypeptide 3A) as the enzyme implicated in this class of alternative mRNA editing.<ref>{{cite journal | vauthors = Niavarani A, Currie E, Reyal Y, Anjos-Afonso F, Horswell S, Griessinger E, Luis Sardina J, Bonnet D | display-authors = 6 | title = APOBEC3A is implicated in a novel class of G-to-A mRNA editing in WT1 transcripts | journal = PLOS ONE | volume = 10 | issue = 3 | pages = e0120089 | year = 2015 | pmid = 25807502 | pmc = 4373805 | doi = 10.1371/journal.pone.0120089 | doi-access = free | bibcode = 2015PLoSO..1020089N }}</ref> It was also shown that alternative mRNA changes were associated with canonical WT1 [[RNA splicing|splicing]] variants, indicating their functional significance.
 ===RNA editing in plant mitochondria and plastids===
-It has been shown in previous studies that the only types of RNA editing seen in the plants' mitochondria and plastids are conversion of C-to-U and U-to-C (very rare).<ref name= Covello_11>{{cite journal |vauthors = Covello PS, Gray MW |title= RNA editing in plant mitochondria |journal= Nature |volume= 341 |issue=6243 |pages= 662–6 |date= October 1989 |pmid= 2552326 |doi= 10.1038/341662a0 |bibcode= 1989Natur.341..662C |s2cid= 4373041 }}</ref><ref name=Gualberto_12>{{cite journal |vauthors= Gualberto JM, Lamattina L, Bonnard G, Weil JH, Grienenberger JM |title= RNA editing in wheat mitochondria results in the conservation of protein sequences |journal= Nature |volume= 341 |issue= 6243 |pages= 660–2 |date= October 1989 |pmid= 2552325 |doi= 10.1038/341660a0 |bibcode= 1989Natur.341..660G |s2cid= 19402913 }}</ref><ref name=Hiesel_13>{{cite journal |vauthors= Hiesel R, Wissinger B, Schuster W, Brennicke A |title= RNA editing in plant mitochondria |journal= Science |volume= 246 |issue= 4937 |pages= 1632–4 |date= December 1989 |pmid= 2480644 |doi= 10.1126/science.2480644 |bibcode= 1989Sci...246.1632H }}</ref><ref name=Hoch_14>{{cite journal |vauthors= Hoch B, Maier RM, Appel K, Igloi GL, Kössel H |title= Editing of a chloroplast mRNA by creation of an initiation codon |journal= Nature |volume= 353 |issue= 6340 |pages= 178–80 |date= Sep 1991 |pmid= 1653905 |doi= 10.1038/353178a0 |bibcode= 1991Natur.353..178H |s2cid= 4303733 }}</ref><ref name=Pring_15>{{cite journal |vauthors= Pring D, Brennicke A, Schuster W |title= RNA editing gives a new meaning to the genetic information in mitochondria and chloroplasts |journal= Plant Molecular Biology |volume= 21 |issue= 6 |pages= 1163–70 |date= March 1993 |pmid= 8490134 |doi= 10.1007/BF00023611 |s2cid= 30396182 }}</ref><ref name=Wissinger_16>{{cite journal |vauthors = Wissinger B, Brennicke A, Schuster W | title = Regenerating good sense: RNA editing and trans splicing in plant mitochondria |journal= Trends in Genetics |volume= 8 |issue=9 |pages= 322–8 |date= September 1992 |pmid= 1365399 |doi= 10.1016/0168-9525(92)90265-6 }}</ref><ref name=Grienenberger_17>{{cite journal |author=Grienenberger, J.M. |year=1993 |title= RNA editing in plant organelles |journal=RNA Editing (Benne, R., Ed.), Ellis Harwood, New York.}}</ref><ref name=Malek_18>{{cite journal |vauthors= Malek O, Lättig K, Hiesel R, Brennicke A, Knoop V |title= RNA editing in bryophytes and a molecular phylogeny of land plants |journal= The EMBO Journal |volume= 15 |issue=6 |pages= 1403–11 |date= March 1996 | pmid= 8635473 |pmc= 450045 |doi= 10.1002/j.1460-2075.1996.tb00482.x }}</ref><ref name=Freyer_19>{{cite journal |vauthors= Freyer R, Kiefer-Meyer MC, Kössel H |title= Occurrence of plastid RNA editing in all major lineages of land plants |journal= Proceedings of the National Academy of Sciences of the United States of America |volume= 94 |issue= 12 |pages= 6285–90 |date= June 1997 |pmid= 9177209 |pmc= 21041 |doi= 10.1073/pnas.94.12.6285 |bibcode= 1997PNAS...94.6285F |doi-access= free }}</ref><ref name=Dietrich_20>{{cite journal |vauthors= Dietrich A, Small I, Cosset A, Weil JH, Maréchal-Drouard L |title= Editing and import: strategies for providing plant mitochondria with a complete set of functional transfer RNAs |journal= Biochimie |volume= 78 |issue=6 |pages= 518–29 |year=1996 |pmid = 8915541 |doi= 10.1016/0300-9084(96)84758-4 }}</ref><ref name=Bock_21>{{cite journal |vauthors= Bock R, Hermann M, Fuchs M |title= Identification of critical nucleotide positions for plastid RNA editing site recognition |journal= RNA |volume= 3 |issue= 10 |pages= 1194–200 |date= October 1997 |pmid= 9326494 |pmc= 1369561 }}</ref><ref name= Gray_22>{{cite journal |vauthors = Gray MW, Covello PS |title = RNA editing in plant mitochondria and chloroplasts |journal= FASEB Journal |volume= 7 |issue= 1 |pages= 64–71 | date= January 1993 |pmid= 8422976 |doi = 10.1096/fasebj.7.1.8422976 |s2cid = 26005486 |url= http://www.fasebj.org/doi/pdf/10.1096/fasebj.7.1.8422976 }}</ref><ref name=Marchfelder_23>{{cite book |vauthors= Marchfelder A, Binder S, Brennicke A, Knoop V |year=1998 |chapter= Preface |title= Modification and Editing of RNA |veditors= Grosjean H, Benne R |pages=307–323 |publisher= ASM Press |location= Washington, DC}}</ref> RNA-editing sites are found mainly in the coding regions of mRNA, [[introns]], and other non-translated regions.<ref name=Hiesel_13/> In fact, RNA editing can restore the functionality of tRNA molecules.<ref name=Pring_15/><ref name=Wissinger_16/> The editing sites are found primarily upstream of mitochondrial or plastid RNAs. While the specific positions for C to U RNA editing events have been fairly well studied in both the mitochondrion and plastid,<ref>{{cite journal |vauthors = Takenaka M, Zehrmann A, Verbitskiy D, Härtel B, Brennicke A |title= RNA editing in plants and its evolution |journal= Annual Review of Genetics |volume= 47 |pages= 335–52 |date= 2013 |pmid= 24274753 |doi= 10.1146/annurev-genet-111212-133519 }}</ref> the identity and organization of all proteins comprising the editosome have yet to be established. Members of the expansive PPR protein family have been shown to function as ''trans''-acting factors for RNA sequence recognition.<ref>{{cite journal |vauthors= Barkan A, Small I |title= Pentatricopeptide repeat proteins in plants |journal= Annual Review of Plant Biology |volume= 65 |pages = 415–42 |date= 2014 |pmid= 24471833 | doi = 10.1146/annurev-arplant-050213-040159 }}</ref> Specific members of the MORF (Multiple Organellar RNA editing Factor) family are also required for proper editing at several sites. As some of these MORF proteins have been shown to interact with members of the PPR family, it is possible MORF proteins are components of the editosome complex.<ref>{{cite journal |vauthors= Bentolila S, Oh J, Hanson MR, Bukowski R |title= Comprehensive high-resolution analysis of the role of an Arabidopsis gene family in RNA editing |journal= PLOS Genetics |volume= 9 |issue= 6 |pages= e1003584 |date= June 2013 |pmid= 23818871 |pmc= 3688494 |doi= 10.1371/journal.pgen.1003584 }}</ref> An enzyme responsible for the trans- or deamination of the RNA transcript remains elusive, though it has been proposed that the PPR proteins may serve this function as well.
+It has been shown in previous studies that the only types of RNA editing seen in the plants' mitochondria and plastids are conversion of C-to-U and U-to-C (very rare).<ref name= Covello_11>{{cite journal | vauthors = Covello PS, Gray MW | title = RNA editing in plant mitochondria | journal = Nature | volume = 341 | issue = 6243 | pages = 662–666 | date = October 1989 | pmid = 2552326 | doi = 10.1038/341662a0 | s2cid = 4373041 | bibcode = 1989Natur.341..662C }}</ref><ref name=Gualberto_12>{{cite journal | vauthors = Gualberto JM, Lamattina L, Bonnard G, Weil JH, Grienenberger JM | title = RNA editing in wheat mitochondria results in the conservation of protein sequences | journal = Nature | volume = 341 | issue = 6243 | pages = 660–662 | date = October 1989 | pmid = 2552325 | doi = 10.1038/341660a0 | s2cid = 19402913 | bibcode = 1989Natur.341..660G }}</ref><ref name=Hiesel_13>{{cite journal | vauthors = Hiesel R, Wissinger B, Schuster W, Brennicke A | title = RNA editing in plant mitochondria | journal = Science | volume = 246 | issue = 4937 | pages = 1632–1634 | date = December 1989 | pmid = 2480644 | doi = 10.1126/science.2480644 | bibcode = 1989Sci...246.1632H }}</ref><ref name=Hoch_14>{{cite journal | vauthors = Hoch B, Maier RM, Appel K, Igloi GL, Kössel H | title = Editing of a chloroplast mRNA by creation of an initiation codon | journal = Nature | volume = 353 | issue = 6340 | pages = 178–180 | date = September 1991 | pmid = 1653905 | doi = 10.1038/353178a0 | s2cid = 4303733 | bibcode = 1991Natur.353..178H }}</ref><ref name=Pring_15>{{cite journal | vauthors = Pring D, Brennicke A, Schuster W | title = RNA editing gives a new meaning to the genetic information in mitochondria and chloroplasts | journal = Plant Molecular Biology | volume = 21 | issue = 6 | pages = 1163–1170 | date = March 1993 | pmid = 8490134 | doi = 10.1007/BF00023611 | s2cid = 30396182 }}</ref><ref name=Wissinger_16>{{cite journal | vauthors = Wissinger B, Brennicke A, Schuster W | title = Regenerating good sense: RNA editing and trans splicing in plant mitochondria | journal = Trends in Genetics | volume = 8 | issue = 9 | pages = 322–328 | date = September 1992 | pmid = 1365399 | doi = 10.1016/0168-9525(92)90265-6 }}</ref><ref name=Grienenberger_17>{{cite journal | vauthors = Grienenberger JM |year=1993 |title= RNA editing in plant organelles |journal=RNA Editing (Benne, R., Ed.), Ellis Harwood, New York.}}</ref><ref name=Malek_18>{{cite journal | vauthors = Malek O, Lättig K, Hiesel R, Brennicke A, Knoop V | title = RNA editing in bryophytes and a molecular phylogeny of land plants | journal = The EMBO Journal | volume = 15 | issue = 6 | pages = 1403–1411 | date = March 1996 | pmid = 8635473 | pmc = 450045 | doi = 10.1002/j.1460-2075.1996.tb00482.x }}</ref><ref name=Freyer_19>{{cite journal | vauthors = Freyer R, Kiefer-Meyer MC, Kössel H | title = Occurrence of plastid RNA editing in all major lineages of land plants | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 12 | pages = 6285–6290 | date = June 1997 | pmid = 9177209 | pmc = 21041 | doi = 10.1073/pnas.94.12.6285 | doi-access = free | bibcode = 1997PNAS...94.6285F }}</ref><ref name=Dietrich_20>{{cite journal | vauthors = Dietrich A, Small I, Cosset A, Weil JH, Maréchal-Drouard L | title = Editing and import: strategies for providing plant mitochondria with a complete set of functional transfer RNAs | journal = Biochimie | volume = 78 | issue = 6 | pages = 518–529 | year = 1996 | pmid = 8915541 | doi = 10.1016/0300-9084(96)84758-4 }}</ref><ref name=Bock_21>{{cite journal | vauthors = Bock R, Hermann M, Fuchs M | title = Identification of critical nucleotide positions for plastid RNA editing site recognition | journal = RNA | volume = 3 | issue = 10 | pages = 1194–1200 | date = October 1997 | pmid = 9326494 | pmc = 1369561 }}</ref><ref name= Gray_22>{{cite journal | vauthors = Gray MW, Covello PS | title = RNA editing in plant mitochondria and chloroplasts | journal = FASEB Journal | volume = 7 | issue = 1 | pages = 64–71 | date = January 1993 | pmid = 8422976 | doi = 10.1096/fasebj.7.1.8422976 | doi-access = free | s2cid = 26005486 }}</ref><ref name=Marchfelder_23>{{cite book |vauthors= Marchfelder A, Binder S, Brennicke A, Knoop V |year=1998 |chapter= Preface |title= Modification and Editing of RNA |veditors= Grosjean H, Benne R |pages=307–323 |publisher= ASM Press |location= Washington, DC}}</ref> RNA-editing sites are found mainly in the coding regions of mRNA, [[introns]], and other non-translated regions.<ref name=Hiesel_13/> In fact, RNA editing can restore the functionality of tRNA molecules.<ref name=Pring_15/><ref name=Wissinger_16/> The editing sites are found primarily upstream of mitochondrial or plastid RNAs. While the specific positions for C to U RNA editing events have been fairly well studied in both the mitochondrion and plastid,<ref>{{cite journal | vauthors = Takenaka M, Zehrmann A, Verbitskiy D, Härtel B, Brennicke A | title = RNA editing in plants and its evolution | journal = Annual Review of Genetics | volume = 47 | pages = 335–352 | date = 2013 | pmid = 24274753 | doi = 10.1146/annurev-genet-111212-133519 }}</ref> the identity and organization of all proteins comprising the editosome have yet to be established. Members of the expansive PPR protein family have been shown to function as ''trans''-acting factors for RNA sequence recognition.<ref>{{cite journal | vauthors = Barkan A, Small I | title = Pentatricopeptide repeat proteins in plants | journal = Annual Review of Plant Biology | volume = 65 | pages = 415–442 | date = 2014 | pmid = 24471833 | doi = 10.1146/annurev-arplant-050213-040159 | doi-access = free }}</ref> Specific members of the MORF (Multiple Organellar RNA editing Factor) family are also required for proper editing at several sites. As some of these MORF proteins have been shown to interact with members of the PPR family, it is possible MORF proteins are components of the editosome complex.<ref>{{cite journal | vauthors = Bentolila S, Oh J, Hanson MR, Bukowski R | title = Comprehensive high-resolution analysis of the role of an Arabidopsis gene family in RNA editing | journal = PLOS Genetics | volume = 9 | issue = 6 | pages = e1003584 | date = June 2013 | pmid = 23818871 | pmc = 3688494 | doi = 10.1371/journal.pgen.1003584 | doi-access = free }}</ref> An enzyme responsible for the trans- or deamination of the RNA transcript remains elusive, though it has been proposed that the PPR proteins may serve this function as well.
 RNA editing is essential for the normal functioning of the plant's translation and respiration activity. Editing can restore the essential base-pairing sequences of tRNAs, restoring functionality.<ref name=Price_24>{{cite book |vauthors = Price DH, Gray MW |year=1998 |chapter= Editing of tRNA |title=  Modification and Editing of RNA |veditors= Grosjean H, Benne R |pages=289–306 |publisher= ASM Press |location= Washington, DC}}</ref> It has also been linked to the production of RNA-edited proteins that are incorporated into the polypeptide complexes of the respiration pathway. Therefore, it is highly probable that polypeptides synthesized from unedited RNAs would not function properly and hinder the activity of both mitochondria and plastids.
@@ Line 66: / Line 78: @@
 ===RNA editing in viruses===
-Viruses (i.e., [[measles]], [[mumps]], or [[parainfluenza]]), especially viruses that have an RNA genome, have been shown to have evolved to utilize RNA modifications in many ways when taking over the host cell. Viruses are known to utilize the RNA modifications in different parts of their infection cycle from immune evasion to protein translation enhancement.<ref name=":3" /> RNA editing is used for stability and generation of protein variants.<ref name=Curran_26>{{cite journal |vauthors = Curran J, Boeck R, Kolakofsky D |title= The Sendai virus P gene expresses both an essential protein and an inhibitor of RNA synthesis by shuffling modules via mRNA editing |journal= The EMBO Journal |volume= 10 |issue=10 |pages= 3079–85 |date= October 1991 |pmid= 1655410 |pmc= 453024 |doi= 10.1002/j.1460-2075.1991.tb07860.x }}</ref><ref name=Zheng_27>{{cite journal |vauthors= Zheng H, Fu TB, Lazinski D, Taylor J |title= Editing on the genomic RNA of human hepatitis delta virus |journal= Journal of Virology |volume= 66 |issue=8 |pages= 4693–7 |date= August 1992 |pmid= 1629949 |pmc= 241294 |doi= 10.1128/jvi.66.8.4693-4697.1992 }}</ref> Viral RNAs are transcribed by a virus-encoded RNA-dependent [[RNA polymerase]], which is prone to pausing and "stuttering" at certain nucleotide combinations. In addition, up to several hundred non-templated A's are added by the polymerase at the 3' end of nascent mRNA.<ref name=Kolakofsky_28>{{cite book |vauthors= Kolakofsky D, Hausmann S |year=1998 |chapter= Chapter 23: Cotranscriptional Paramyxovirus mRNA Editing: a Contradiction in Terms? |title= Modification and Editing of RNA |veditors= Grosjean H, Benne R |pages= 413–420 |publisher= ASM Press |location= Washington, DC}}</ref> These As help stabilize the mRNA. Furthermore, the pausing and stuttering of the RNA polymerase allows the incorporation of one or two Gs or As upstream of the translational codon.<ref name=Kolakofsky_28/> The addition of the non-templated nucleotides shifts the reading frame, which generates a different protein.
+Viruses (i.e., [[measles]], [[mumps]], or [[parainfluenza]]), especially viruses that have an RNA genome, have been shown to have evolved to utilize RNA modifications in many ways when taking over the host cell. Viruses are known to utilize the RNA modifications in different parts of their infection cycle from immune evasion to protein translation enhancement.<ref name="Pereira-Montecinos_2017" /> RNA editing is used for stability and generation of protein variants.<ref name=Curran_26>{{cite journal | vauthors = Curran J, Boeck R, Kolakofsky D | title = The Sendai virus P gene expresses both an essential protein and an inhibitor of RNA synthesis by shuffling modules via mRNA editing | journal = The EMBO Journal | volume = 10 | issue = 10 | pages = 3079–3085 | date = October 1991 | pmid = 1655410 | pmc = 453024 | doi = 10.1002/j.1460-2075.1991.tb07860.x }}</ref><ref name=Zheng_27>{{cite journal | vauthors = Zheng H, Fu TB, Lazinski D, Taylor J | title = Editing on the genomic RNA of human hepatitis delta virus | journal = Journal of Virology | volume = 66 | issue = 8 | pages = 4693–4697 | date = August 1992 | pmid = 1629949 | pmc = 241294 | doi = 10.1128/jvi.66.8.4693-4697.1992 }}</ref> Viral RNAs are transcribed by a virus-encoded RNA-dependent [[RNA polymerase]], which is prone to pausing and "stuttering" at certain nucleotide combinations. In addition, up to several hundred non-templated A's are added by the polymerase at the 3' end of nascent mRNA.<ref name=Kolakofsky_28>{{cite book |vauthors= Kolakofsky D, Hausmann S |year=1998 |chapter= Chapter 23: Cotranscriptional Paramyxovirus mRNA Editing: a Contradiction in Terms? |title= Modification and Editing of RNA |veditors= Grosjean H, Benne R |pages= 413–420 |publisher= ASM Press |location= Washington, DC}}</ref> These As help stabilize the mRNA. Furthermore, the pausing and stuttering of the RNA polymerase allows the incorporation of one or two Gs or As upstream of the translational codon.<ref name=Kolakofsky_28/> The addition of the non-templated nucleotides shifts the reading frame, which generates a different protein.
-Additionally, the RNA modifications are shown to have both positive and negative effects on the replication and translation efficiency depending on the virus.  For example, Courtney et al.<ref name=":1" /> showed that an RNA modification called 5-methylcytosine is added to the viral mRNA in the cells to enhance the protein translation of HIV-1 virus. The inhibition of m<sup>5</sup>C modification on viral mRNA results in significant reduction in viral protein translation, but interestingly it has no effect on the expression of viral mRNAs in the cell. On the other hand, Lichinchi et al.<ref>{{Cite journal|last1=Lichinchi|first1=Gianluigi|last2=Zhao|first2=Boxuan Simen|last3=Wu|first3=Yinga|last4=Lu|first4=Zhike|last5=Qin|first5=Yue|last6=He|first6=Chuan|last7=Rana|first7=Tariq M.|date=November 2016|title=Dynamics of Human and Viral RNA Methylation during Zika Virus Infection|url= |journal=Cell Host & Microbe|language=en|volume=20|issue=5|pages=666–673|doi=10.1016/j.chom.2016.10.002|pmc=5155635|pmid=27773536}}</ref> showed that N6-methyladenosine modification on ZIKV mRNA inhibits the viral replication.
+Additionally, the RNA modifications are shown to have both positive and negative effects on the replication and translation efficiency depending on the virus.  For example, Courtney et al.<ref name="Courtney_2019" /> showed that an RNA modification called 5-methylcytosine is added to the viral mRNA in infected host cells in order to enhance the protein translation of HIV-1 virus. The inhibition of the m<sup>5</sup>C modification on viral mRNA results in significant reduction in viral protein translation, but interestingly it has no effect on the expression of viral mRNAs in the cell. On the other hand, Lichinchi et al.<ref>{{cite journal | vauthors = Lichinchi G, Zhao BS, Wu Y, Lu Z, Qin Y, He C, Rana TM | title = Dynamics of Human and Viral RNA Methylation during Zika Virus Infection | journal = Cell Host & Microbe | volume = 20 | issue = 5 | pages = 666–673 | date = November 2016 | pmid = 27773536 | pmc = 5155635 | doi = 10.1016/j.chom.2016.10.002 }}</ref> showed that the N6-methyladenosine modification on ZIKV mRNA inhibits the viral replication.
-==Origin and evolution of RNA editing==
+==Origin and Evolution of RNA editing==
-The RNA-editing system seen in the animal may have evolved from mononucleotide deaminases, which have led to larger gene families that include the apobec-1 and adar genes. These genes share close identity with the bacterial deaminases involved in nucleotide metabolism. The adenosine deaminase of ''E. coli'' cannot deaminate a nucleoside in the RNA; the enzyme's reaction pocket is too small for the RNA strand to bind to. However, this active site is widened by amino acid changes in the corresponding human analog genes, ''[[APOBEC1]]'' and ''[[ADAR]]'', allowing deamination.<ref name=Carter_29>{{cite book |vauthors= Carter CW |year=1998 |chapter= Nucleoside deaminases for cytidine and adenosine: comparisons with deaminases acting on RNA |title= Modification and Editing of RNA |veditors= Grosjean H, Benne R |pages= 363–376 |publisher= ASM Press |location= Washington, DC}}</ref><ref name=Navaratnam_30>{{cite journal |vauthors= Navaratnam N, Fujino T, Bayliss J, Jarmuz A, How A, Richardson N, Somasekaram A, Bhattacharya S, Carter C, Scott J |title= Escherichia coli cytidine deaminase provides a molecular model for ApoB RNA editing and a mechanism for RNA substrate recognition |journal= Journal of Molecular Biology |volume= 275 |issue= 4 |pages= 695–714 |date= January 1998 |pmid= 9466941 |doi= 10.1006/jmbi.1997.1506 }}</ref>
+The RNA-editing system seen in the animal may have evolved from mononucleotide deaminases, which have led to larger gene families that include the apobec-1 and adar genes. These genes share close identity with the bacterial deaminases involved in nucleotide metabolism. The adenosine deaminase of ''E. coli'' cannot deaminate a nucleoside in the RNA; the enzyme's reaction pocket is too small for the RNA strand to bind to. However, this active site is widened by amino acid changes in the corresponding human analog genes, ''[[APOBEC1]]'' and ''[[ADAR]]'', allowing deamination.<ref name=Carter_29>{{cite book |vauthors= Carter CW |year=1998 |chapter= Nucleoside deaminases for cytidine and adenosine: comparisons with deaminases acting on RNA |title= Modification and Editing of RNA |veditors= Grosjean H, Benne R |pages= 363–376 |publisher= ASM Press |location= Washington, DC}}</ref><ref name=Navaratnam_30>{{cite journal | vauthors = Navaratnam N, Fujino T, Bayliss J, Jarmuz A, How A, Richardson N, Somasekaram A, Bhattacharya S, Carter C, Scott J | display-authors = 6 | title = Escherichia coli cytidine deaminase provides a molecular model for ApoB RNA editing and a mechanism for RNA substrate recognition | journal = Journal of Molecular Biology | volume = 275 | issue = 4 | pages = 695–714 | date = January 1998 | pmid = 9466941 | doi = 10.1006/jmbi.1997.1506 }}</ref>
-The gRNA-mediated pan-editing in [[Trypanosomatid|trypanosome]] mitochondria, involving templated insertion of U residues, is an entirely different biochemical reaction. The enzymes involved have been shown in other studies to be recruited and adapted from different sources.<ref name=Arts_3/><ref name=Covello_31>{{cite journal |vauthors= Covello PS, Gray MW |title= On the evolution of RNA editing |journal= Trends in Genetics |volume= 9 |issue=8 |pages= 265–8 |date= Aug 1993 |pmid= 8379005 |doi= 10.1016/0168-9525(93)90011-6 }}</ref> But the specificity of nucleotide insertion via the interaction between the gRNA and mRNA is similar to the tRNA editing processes in the animal and [[Acanthamoeba]] mitochondria.<ref name=Lonergan_32>{{cite journal | vauthors = Lonergan KM, Gray MW |title= Predicted editing of additional transfer RNAs in Acanthamoeba castellanii mitochondria |journal= Nucleic Acids Research |volume= 21 |issue= 18 |pages = 4402 | date= September 1993 |pmid= 8415006 |pmc= 310088 |doi= 10.1093/nar/21.18.4402 }}</ref> Eukaryotic ribose methylation of rRNAs by guide RNA molecules is a similar form of modification.<ref name=Bachellerie_33>{{cite book |vauthors= Bachellerie JP, Cavaille J |year=1998 |chapter= Small nucleolar RNAs guide the ribose methylations of eukaryotic rRNAs |title= Modification and Editing of RNA |veditors= Grosjean H, Benne R |pages= 255–272 |publisher=ASM Press |location= Washington, DC}}</ref>
+The gRNA-mediated pan-editing in [[Trypanosomatid|trypanosome]] mitochondria, involving templated insertion of U residues, is an entirely different biochemical reaction. The enzymes involved have been shown in other studies to be recruited and adapted from different sources.<ref name=Arts_3/><ref name=Covello_31>{{cite journal | vauthors = Covello PS, Gray MW | title = On the evolution of RNA editing | journal = Trends in Genetics | volume = 9 | issue = 8 | pages = 265–268 | date = August 1993 | pmid = 8379005 | doi = 10.1016/0168-9525(93)90011-6 }}</ref> But the specificity of nucleotide insertion via the interaction between the gRNA and mRNA is similar to the tRNA editing processes in the animal and [[Acanthamoeba]] mitochondria.<ref name=Lonergan_32>{{cite journal | vauthors = Lonergan KM, Gray MW | title = Predicted editing of additional transfer RNAs in Acanthamoeba castellanii mitochondria | journal = Nucleic Acids Research | volume = 21 | issue = 18 | pages = 4402 | date = September 1993 | pmid = 8415006 | pmc = 310088 | doi = 10.1093/nar/21.18.4402 }}</ref> Eukaryotic ribose methylation of rRNAs by guide RNA molecules is a similar form of modification.<ref name=Bachellerie_33>{{cite book |vauthors= Bachellerie JP, Cavaille J |year=1998 |chapter= Small nucleolar RNAs guide the ribose methylations of eukaryotic rRNAs |title= Modification and Editing of RNA |veditors= Grosjean H, Benne R |pages= 255–272 |publisher=ASM Press |location= Washington, DC}}</ref>
-Thus, RNA editing evolved more than once. Several adaptive rationales for editing have been suggested.<ref name=Speijer_2011>{{cite journal |vauthors= Speijer D |title= Does constructive neutral evolution play an important role in the origin of cellular complexity? Making sense of the origins and uses of biological complexity |journal= BioEssays |volume= 33 |issue= 5 |pages= 344–9 |date= May 2011 |pmid= 21381061 |doi= 10.1002/bies.201100010 |s2cid= 205470421 }}</ref> Editing is often described as a mechanism of correction or repair to compensate for defects in gene sequences. However, in the case of gRNA-mediated editing, this explanation does not seem possible because if a defect happens first, there is no way to generate an error-free gRNA-encoding region, which presumably arises by duplication of the original gene region. This thinking leads to an evolutionary proposal called "constructive neutral evolution" in which the order of steps is reversed, with the gratuitous capacity for editing preceding the "defect".<ref name= Stoltzfus_1999>{{cite journal |vauthors= Stoltzfus A |title= On the possibility of constructive neutral evolution |journal= Journal of Molecular Evolution |volume= 49 |issue=2 |pages= 169–81 |date= August 1999 |pmid= 10441669 |doi= 10.1007/PL00006540 |bibcode= 1999JMolE..49..169S |citeseerx= 10.1.1.466.5042 |s2cid= 1743092 }}</ref> <sup>31</sup>
+Thus, RNA editing evolved more than once. Several adaptive rationales for editing have been suggested.<ref name=Speijer_2011>{{cite journal | vauthors = Speijer D | title = Does constructive neutral evolution play an important role in the origin of cellular complexity? Making sense of the origins and uses of biological complexity | journal = BioEssays | volume = 33 | issue = 5 | pages = 344–349 | date = May 2011 | pmid = 21381061 | doi = 10.1002/bies.201100010 | s2cid = 205470421 }}</ref> Editing is often described as a mechanism of correction or repair to compensate for defects in gene sequences. However, in the case of gRNA-mediated editing, this explanation does not seem possible because if a defect happens first, there is no way to generate an error-free gRNA-encoding region, which presumably arises by duplication of the original gene region. A more plausible alternative for the evolutionary origins of this system is through [[constructive neutral evolution]], where the order of steps is reversed, with the gratuitous capacity for editing preceding the "defect".<ref name= Stoltzfus_1999>{{cite journal | vauthors = Stoltzfus A | title = On the possibility of constructive neutral evolution | journal = Journal of Molecular Evolution | volume = 49 | issue = 2 | pages = 169–181 | date = August 1999 | pmid = 10441669 | doi = 10.1007/PL00006540 | s2cid = 1743092 | citeseerx = 10.1.1.466.5042 | bibcode = 1999JMolE..49..169S }}</ref>
-==RNA editing may be involved in RNA degradation==
-A study looked at the involvement of RNA editing in RNA degradation.<ref name=Agranat_34>{{cite journal |vauthors= Agranat L, Raitskin O, Sperling J, Sperling R | title = The editing enzyme ADAR1 and the mRNA surveillance protein hUpf1 interact in the cell nucleus |journal= Proceedings of the National Academy of Sciences of the United States of America |volume= 105 |issue= 13 |pages= 5028–33 |date= April 2008 |pmid= 18362360 |pmc= 2278206 |doi= 10.1073/pnas.0710576105 | bibcode = 2008PNAS..105.5028A | doi-access = free }}</ref> The researchers specifically looked at the interaction between ADAR and [[UPF1]], an enzyme involved in the [[nonsense-mediated mRNA decay]] pathway (NMD). They found that ADAR and UPF1 are found within the suprasliceosome and they form a complex that leads to the down-regulation of specific genes. The exact mechanism or the exact pathways that these two are involved in are unknown at this time. The only fact that this research has shown is that they form a complex and down-regulate specific genes.
 == Therapeutic mRNA Editing ==
 {{See also|CRISPR#Cas13 (formerly C2c2)}}
-Directing edits to correct mutated sequences was first proposed and demonstrated in 1995.<ref name=":0">{{cite journal | vauthors = Woolf TM, Chase JM, Stinchcomb DT | title = Toward the therapeutic editing of mutated RNA sequences | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 18 | pages = 8298–302 | date = August 1995 | pmid = 7545300 | pmc = 41144 | doi = 10.1073/pnas.92.18.8298 | bibcode = 1995PNAS...92.8298W | doi-access = free }}</ref>  This initial work used synthetic RNA antisense oligonucleotides complementary to a pre-mature stop codon mutation in a dystrophin sequence to activate A-to-I editing of the stop codon to a read through codon in a model xenopus cell system.<ref name=":0" />  While this also led to nearby inadvertent A-to-I transitions, A to I (read as G) transitions can correct all three stop codons, but cannot create a stop codon.  Therefore, the changes led >25% correction of the targeted stop codon with read through to a downstream luciferase reporter sequence.  Follow on work by Rosenthal achieved editing of mutated mRNA sequence in mammalian cell culture by directing an oligonucleotide linked to a cytidine deaminase to correct a mutated cystic fibrosis sequence.<ref>{{cite journal | vauthors = Montiel-Gonzalez MF, Vallecillo-Viejo I, Yudowski GA, Rosenthal JJ | title = Correction of mutations within the cystic fibrosis transmembrane conductance regulator by site-directed RNA editing | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 45 | pages = 18285–90 | date = November 2013 | pmid = 24108353 | pmc = 3831439 | doi = 10.1073/pnas.1306243110 | bibcode = 2013PNAS..11018285M | doi-access = free }}</ref>  More recently, CRISPR-Cas13 fused to deaminases has been employed to direct mRNA editing.<ref>{{cite journal | vauthors = Cox DB, Gootenberg JS, Abudayyeh OO, Franklin B, Kellner MJ, Joung J, Zhang F | title = RNA editing with CRISPR-Cas13 | journal = Science | volume = 358 | issue = 6366 | pages = 1019–1027 | date = November 2017 | pmid = 29070703 | pmc = 5793859 | doi = 10.1126/science.aaq0180 | bibcode = 2017Sci...358.1019C }}</ref>
+Directing edits to correct mutated sequences was first proposed and demonstrated in 1995.<ref name="Woolf_1995">{{cite journal | vauthors = Woolf TM, Chase JM, Stinchcomb DT | title = Toward the therapeutic editing of mutated RNA sequences | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 18 | pages = 8298–8302 | date = August 1995 | pmid = 7545300 | pmc = 41144 | doi = 10.1073/pnas.92.18.8298 | doi-access = free | bibcode = 1995PNAS...92.8298W }}</ref>  This initial work used synthetic RNA antisense oligonucleotides complementary to a pre-mature stop codon mutation in a dystrophin sequence to activate A-to-I editing of the stop codon to a read through codon in a model xenopus cell system.<ref name="Woolf_1995" />  While this also led to nearby inadvertent A-to-I transitions, A to I (read as G) transitions can correct all three stop codons, but cannot create a stop codon.  Therefore, the changes led >25% correction of the targeted stop codon with read through to a downstream luciferase reporter sequence.  Follow on work by Rosenthal achieved editing of mutated mRNA sequence in mammalian cell culture by directing an oligonucleotide linked to a cytidine deaminase to correct a mutated cystic fibrosis sequence.<ref>{{cite journal | vauthors = Montiel-Gonzalez MF, Vallecillo-Viejo I, Yudowski GA, Rosenthal JJ | title = Correction of mutations within the cystic fibrosis transmembrane conductance regulator by site-directed RNA editing | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 45 | pages = 18285–18290 | date = November 2013 | pmid = 24108353 | pmc = 3831439 | doi = 10.1073/pnas.1306243110 | doi-access = free | bibcode = 2013PNAS..11018285M }}</ref>  More recently, CRISPR-Cas13 fused to deaminases has been employed to direct mRNA editing.<ref>{{cite journal | vauthors = Cox DB, Gootenberg JS, Abudayyeh OO, Franklin B, Kellner MJ, Joung J, Zhang F | title = RNA editing with CRISPR-Cas13 | journal = Science | volume = 358 | issue = 6366 | pages = 1019–1027 | date = November 2017 | pmid = 29070703 | pmc = 5793859 | doi = 10.1126/science.aaq0180 | bibcode = 2017Sci...358.1019C }}</ref>
+In 2022, therapeutic RNA editing for Cas7-11 was reported.<ref>{{cite news | vauthors = Williams S |title=Neuroscientists expand CRISPR toolkit with new, compact Cas7-11 enzyme |url=https://phys.org/news/2022-05-neuroscientists-crispr-toolkit-compact-cas7-.html |access-date=22 June 2022 |work=Massachusetts Institute of Technology |language=en}}</ref><ref>{{cite journal | vauthors = Kato K, Zhou W, Okazaki S, Isayama Y, Nishizawa T, Gootenberg JS, Abudayyeh OO, Nishimasu H | display-authors = 6 | title = Structure and engineering of the type III-E CRISPR-Cas7-11 effector complex | journal = Cell | volume = 185 | issue = 13 | pages = 2324–2337.e16 | date = June 2022 | pmid = 35643083 | doi = 10.1016/j.cell.2022.05.003 | s2cid = 249103058 | doi-access = free }}</ref> It enables sufficiently targeted cuts and an early version of it was used for ''[[in vitro]]'' editing in 2021.<ref>{{cite journal | vauthors = Özcan A, Krajeski R, Ioannidi E, Lee B, Gardner A, Makarova KS, Koonin EV, Abudayyeh OO, Gootenberg JS | display-authors = 6 | title = Programmable RNA targeting with the single-protein CRISPR effector Cas7-11 | journal = Nature | volume = 597 | issue = 7878 | pages = 720–725 | date = September 2021 | pmid = 34489594 | doi = 10.1038/s41586-021-03886-5 | s2cid = 237432753 | bibcode = 2021Natur.597..720O }}</ref>
 === Comparison to DNA editing ===
-Unlike DNA editing, which is permanent, the effects of RNA editing − including potential [[Off-target genome editing|off-target mutations]] in RNA − are transient and are not inherited. RNA editing is therefore considered to be less risky. Furthermore, it may only require a guide RNA by using the ADAR protein already found in humans and many other eukaryotes' cells instead of needing to introduce a foreign protein into the body.<ref>{{cite web |title=Watch out, CRISPR. The RNA editing race is on |url=https://cen.acs.org/business/start-ups/WatchCRISPR-RNA-editing-race/97/i12 |website=Chemical & Engineering News |access-date=30 September 2020 |language=en}}</ref>
+Unlike DNA editing, which is permanent, the effects of RNA editing − including potential [[Off-target genome editing|off-target mutations]] in RNA − are transient and are not inherited. RNA editing is therefore considered to be less risky. Furthermore, it may only require a guide RNA by using the ADAR protein already found in humans and many other eukaryotes' cells instead of needing to introduce a foreign protein into the body.<ref>{{cite journal | vauthors = Cross R | date = 25 March 2019 |title=Watch out, CRISPR. The RNA editing race is on |url=https://cen.acs.org/business/start-ups/WatchCRISPR-RNA-editing-race/97/i12 | journal = Chemical & Engineering News | volume = 97 | issue = 12 |access-date=30 September 2020 |language=en}}</ref>
+== See also ==
+* [[DNA editing]]
+* [[Epigenome editing]]
+* [[NcRNA therapy]]
 == References ==