Abstract
Transcriptome-wide mapping of posttranscriptional modifications in eukaryotic RNA revealed tens of thousands of modification sites. Modified nucleotides include 6-methyladenosine, 5-methylcytidine, pseudouridine, inosine, etc. Many modification sites are conserved, and many are regulated. The function is known for a minor subset of modified nucleotides, while the role of their majority is still obscure. In view of the global character of mRNA modification, RNA epigenetics arose as a new field of molecular biology. The review considers posttranscriptional modification of eukaryotic mRNA, focusing on the major modified nucleotides, the role they play in the cell, the methods to detect them, and the enzymes responsible for modification.
Keywords: 6-methyladenosine, 5-methylcytidine, pseuouridine, inosine
Footnotes
Original Russian Text © I.G. Laptev, A.Ya. Golovina, P.V. Sergiev, O.A. Dontsova, 2015, published in Molekulyarnaya Biologiya, 2015, Vol. 49, No. 6, pp. 923–936.
References
- 1.Dominissini D., Moshitch-Moshkovitz S., Schwartz S., et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature. 2012;485:201–206. doi: 10.1038/nature11112. [DOI] [PubMed] [Google Scholar]
- 2.Meyer K.D., Saletore Y., Zumbo P., et al. Comprehensive analysis of mRNA methylation reveals enrichment in 3' UTRs and near stop codons. Cell. 2012;149:1635–1646. doi: 10.1016/j.cell.2012.05.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Squires J.E., Patel H.R., Nousch M., et al. Widespread occurrence of 5-methylcytosine in human coding and non-coding RNA. Nucleic Acids Res. 2012;40:5023–5033. doi: 10.1093/nar/gks144. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Carlile T.M., Rojas-Duran M.F., Zinshteyn B., et al. Pseudouridine profiling reveals regulated mRNA pseudouridylation in yeast and human cells. Nature. 2014;515:143–146. doi: 10.1038/nature13802. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Schwartz S., Bernstein D.A., Mumbach M.R., et al. Transcriptome-wide mapping reveals widespread dynamic-regulated pseudouridylation of ncRNA and mRNA. Cell. 2014;159:148–162. doi: 10.1016/j.cell.2014.08.028. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Lovejoy A.F., Riordan D.P., Brown P.O. 2014. Transcriptome-wide mapping of pseudouridines: pseudouridine synthases modify specific mRNAs in S. cerevisiae. PLOS ONE. 9, e110799. [DOI] [PMC free article] [PubMed]
- 7.Muthukrishnan S., Both G.W., Furuichi Y., et al. 5'-Terminal 7-methylguanosine in eukaryotic mRNA is required for translation. Nature. 1975;255:33–37. doi: 10.1038/255033a0. [DOI] [PubMed] [Google Scholar]
- 8.Wei C.M., Gershowitz A., Moss B. Methylated nucleotides block 5' terminus of HeLa cell messenger RNA. Cell. 1975;4:379–386. doi: 10.1016/0092-8674(75)90158-0. [DOI] [PubMed] [Google Scholar]
- 9.Murthy M.R. Blocked and methylated 5'-terminal cap structures of rat brain messenger ribonucleic acids. J. Neurochem. 1982;38:28–40. doi: 10.1111/j.1471-4159.1982.tb10850.x. [DOI] [PubMed] [Google Scholar]
- 10.Langberg S.R., Moss B. Post-transcriptional modifications of mRNA. Purification and characterization of cap I and cap II RNA (nucleoside-2'-)methyltransferases from HeLa cells. J. Biol. Chem. 1981;256:10054–10060. [PubMed] [Google Scholar]
- 11.Werner M., Purta E., Kaminska K.H., et al. 2'-O-ribose methylation of cap2 in human: Function and evolution in a horizontally mobile family. Nucleic Acids Res. 2011;39:4756–4768. doi: 10.1093/nar/gkr038. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Daffis S., Szretter K.J., Schriewer J., et al. 2'-O-methylation of the viral mRNA cap evades host restriction by IFIT family members. Nature. 2010;468:452–456. doi: 10.1038/nature09489. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Züst R., Cervantes-Barragan L., Habjan M., et al. Ribose 2'-O-methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5. Nat. Immunol. 2011;12:137–143. doi: 10.1038/ni.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Desrosiers R., Friderici K., Rottman F. Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells. Proc. Natl. Acad. Sci. U. S. A. 1974;71:3971–3975. doi: 10.1073/pnas.71.10.3971. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Horowitz S., Horowitz A., Nilsen T.W., et al. Mapping of N6-methyladenosine residues in bovine prolactin mRNA. Proc. Natl. Acad. Sci. U. S. A. 1984;81:5667–5671. doi: 10.1073/pnas.81.18.5667. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Narayan P., Ludwiczak R.L., Goodwin E.C., et al. Context effects on N6-adenosine methylation sites in prolactin mRNA. Nucleic Acids Res. 1994;22:419–426. doi: 10.1093/nar/22.3.419. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Kane S.E., Beemon K. Precise localization of m6A in Rous sarcoma virus RNA reveals clustering of methylation sites: Implications for RNA processing. Mol. Cell. Biol. 1985;5:2298–2306. doi: 10.1128/MCB.5.9.2298. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Shibler U., Kelley D.E., Perry R.P. Comparison of methylated sequences in messenger RNA and heterogeneous nuclear RNA from mouse L cells. J. Mol. Biol. 1997;115:695–714. doi: 10.1016/0022-2836(77)90110-3. [DOI] [PubMed] [Google Scholar]
- 19.Schwartz S., Agarwala S.D., Mumbach M.R., et al. High-resolution mapping reveals a conserved, widespread, dynamic mRNA methylation program in yeast meiosis. Cell. 2013;155:1409–1421. doi: 10.1016/j.cell.2013.10.047. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Vilfan I.D., Tsai Y.-C., Clark T.A., et al. Analysis of RNA base modification and structural rearrangement by single-molecule real-time detection of reverse transcription. J. Nanobiotechnol. 2013;11:8. doi: 10.1186/1477-3155-11-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Harcourt E.M., Ehrenschwender T., Batista P.J., et al. Identification of a selective polymerase enables detection of N6-methyladenosine in RNA. J. Am. Chem. Soc. 2013;135:19079–19082. doi: 10.1021/ja4105792. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Golovina A.Y., Dzama M.M., Petriukov K.S., et al. Method for site-specific detection of m6A nucleoside presence in RNA based on high-resolution melting (HRM) analysis. Nucleic Acids Res. 2014;42:e27. doi: 10.1093/nar/gkt1160. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Liu N., Parisien M., Dai Q., et al. Probing N6methyladenosine RNA modification status at single nucleotide resolution in mRNA and long noncoding RNA. RNA. 2013;19:1848–1856. doi: 10.1261/rna.041178.113. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Bokar J.A., Shambaugh M.E., Polayes D., et al. Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenisine)methyltransferase. RNA. 1997;3(11):1233–1247. [PMC free article] [PubMed] [Google Scholar]
- 25.Liu N., Pan T. RNA epigenetics. Transl. Res. 2015;165:28–35. doi: 10.1016/j.trsl.2014.04.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Liu J., Yue Y., Han D., et al. A METTL3–METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat. Chem. Biol. 2013;10:93–95. doi: 10.1038/nchembio.1432. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Ping X.-L., Sun B.-F., Wang L., et al. Mammalian WTAP is a regulatory subunit of the RNA N6methyladenosine methyltransferase. Cell Res. 2014;24:177–189. doi: 10.1038/cr.2014.3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Horiuchi K., Umetani M., Minami T., et al. Wilms’ tumor 1-associating protein regulates G2/M transition through stabilization of cyclin A2 mRNA. Proc. Natl. Acad. Sci. U. S. A. 2006;103:17278–17283. doi: 10.1073/pnas.0608357103. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Gerken T., Girard C.A., Tung Y.-C.L., et al. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science. 2007;318:1469–1472. doi: 10.1126/science.1151710. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Jia G., Yang C.-G., Yang S., et al. Oxidative demethylation of 3-methylthymine and 3-methyluracil in single-stranded DNA and RNA by mouse and human FTO. FEBS Lett. 2008;582:3313–3319. doi: 10.1016/j.febslet.2008.08.019. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Jia G., Fu Y., Zhao X., et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesityassociated FTO. Nat. Chem. Biol. 2011;7:885–887. doi: 10.1038/nchembio.687. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Boissel S., Reish O., Proulx K., et al. Loss-offunction mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations. Am. J. Hum. Genet. 2009;85:106–111. doi: 10.1016/j.ajhg.2009.06.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Han Z., Niu T., Chang J., et al. Crystal structure of the FTO protein reveals basis for its substrate specificity. Nature. 2010;464:1205–1209. doi: 10.1038/nature08921. [DOI] [PubMed] [Google Scholar]
- 34.Ratel D., Ravanat J.-L., Charles M.-P., et al. Undetectable levels of N6-methyl adenine in mouse DNA: cloning and analysis of PRED28, a gene coding for a putative mammalian DNA adenine methyltransferase. FEBS Lett. 2006;580:3179–3184. doi: 10.1016/j.febslet.2006.04.074. [DOI] [PubMed] [Google Scholar]
- 35.Fu Y., Jia G., Pang X., et al. FTO-mediated formation of N6-hydroxymethyladenosine and N6formyladenosine in mammalian RNA. Nat. Commun. 2013;4:1798. doi: 10.1038/ncomms2822. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Zheng G., Dahl J.A., Niu Y., et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol. Cell. 2013;49:18–29. doi: 10.1016/j.molcel.2012.10.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Ma W.-J., Cheng S., Campbell C., et al. Cloning and characterization of HuR, a ubiquitously expressed Elav-like protein. J. Biol. Chem. 1996;271:8144–8151. doi: 10.1074/jbc.271.14.8144. [DOI] [PubMed] [Google Scholar]
- 38.Kedde M., Agami R. Interplay between microRNAs and RNA-binding proteins determines developmental processes. Cell Cycle. 2008;7:899–903. doi: 10.4161/cc.7.7.5644. [DOI] [PubMed] [Google Scholar]
- 39.Kundu P., Fabian M.R., Sonenberg N., et al. HuR protein attenuates miRNA-mediated repression by promoting miRISC dissociation from the target RNA. Nucleic Acids Res. 2012;40:5088–5100. doi: 10.1093/nar/gks148. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Wang Y., Li Y., Toth J.I., et al. N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells. Nat. Cell Biol. 2014;16:191–198. doi: 10.1038/ncb2902. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Stoilov P., Rafalska I., Stamm S. YTH: A new domain in nuclear proteins. Trends Biochem. Sci. 2002;27:495–497. doi: 10.1016/S0968-0004(02)02189-8. [DOI] [PubMed] [Google Scholar]
- 42.Wang X., Lu Z., Gomez A., et al. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature. 2013;505:117–120. doi: 10.1038/nature12730. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Batista P.J., Molinie B., Wang J., et al. m6A RNA modification controls cell fate transition in mammalian embryonic stem cells. Cell Stem Cell. 2014;15:707–719. doi: 10.1016/j.stem.2014.09.019. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Geula S., Moshitch-Moshkovitz S., Dominissini D., et al. m6A mRNA methylation facilitates resolution of naive pluripotency toward differentiation. Science. 2015;347:1002–1006. doi: 10.1126/science.1261417. [DOI] [PubMed] [Google Scholar]
- 45.Dubin D.T., Taylor R.H. The methylation state of poly A-containing-messenger RNA from cultured hamster cells. Nucleic Acids Res. 1975;2:1653–1668. doi: 10.1093/nar/2.10.1653. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Dubin D.T., Stollar V. Methylation of Sindbis virus “26S” messenger RNA. Biochem. Biophys. Res. Commun. 1975;66:1373–1379. doi: 10.1016/0006-291X(75)90511-2. [DOI] [PubMed] [Google Scholar]
- 47.Sommer R., Salditt-Georgieff M., Bachenheimer S., et al. The methylation of adenovirus-specific nuclear and cytoplasmic RNA. Nucleic Acids Res. 1976;3:749–765. doi: 10.1093/nar/3.3.749. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48.Furuichi Y., Morgan M., Shatkin A.J., et al. Methylated, blocked 5 termini in HeLa cell mRNA. Proc. Natl. Acad. Sci. U. S. A. 1975;72:1904–1908. doi: 10.1073/pnas.72.5.1904. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.Hussain S., Sajini A.A., Blanco S., et al. NSun2mediated cytosine-5 methylation of vault noncoding RNA determines its processing into regulatory small RNAs. Cell Rep. 2013;4:255–261. doi: 10.1016/j.celrep.2013.06.029. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50.Frye M., Watt F.M. The RNA methyltransferase Misu (NSun2) mediates Myc-induced proliferation and is upregulated in tumors. Curr. Biol. 2006;16:971–981. doi: 10.1016/j.cub.2006.04.027. [DOI] [PubMed] [Google Scholar]
- 51.Brzezicha B., Schmidt M., Makalowska I., et al. Identification of human tRNA:m5C methyltransferase catalysing intron-dependent m5C formation in the first position of the anticodon of the Formula. Nucleic Acids Res. 2006;34:6034–6043. doi: 10.1093/nar/gkl765. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52.Hussain S., Tuorto F., Menon S., et al. The mouse cytosine-5 RNA methyltransferase NSun2 is a component of the chromatoid body and required for testis differentiation. Mol. Cell. Biol. 2013;33:1561–1570. doi: 10.1128/MCB.01523-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 53.Blanco S., Kurowski A., Nichols J., et al. The RNA-methyltransferase Misu (NSun2) poises epidermal stem cells to differentiate. PLoS Genet. 2011;7:1–14. doi: 10.1371/journal.pgen.1002403. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 54.Khoddami V., Cairns B.R. Identification of direct targets and modified bases of RNA cytosine methyltransferases. Nat. Biotechnol. 2013;31:458–464. doi: 10.1038/nbt.2566. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55.Gu W., Hurto R.L., Hopper A.K., et al. Depletion of Saccharomyces cerevisiae tRNAHis guanylyltransferase Thg1p leads to uncharged tRNAHis with additional m5C. Mol. Cell. Biol. 2005;25:8191–8201. doi: 10.1128/MCB.25.18.8191-8201.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56.Eckhardt F., Lewin J., Cortese R., et al. DNA methylation profiling of human chromosomes 6, 20, and 22. Nat. Genet. 2006;38:1378–1385. doi: 10.1038/ng1909. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57.King M.Y., Redman K.L. RNA methyltransferases utilize two cysteine residues in the formation of 5-methylcytosine. Biochemistry. 2002;41:11218–11225. doi: 10.1021/bi026055q. [DOI] [PubMed] [Google Scholar]
- 58.Jackson-Grusby L., Laird P.W., Magge S.N., et al. Mutagenicity of 5-aza-2'-deoxycytidine is mediated by the mammalian DNA methyltransferase. Proc. Natl. Acad. Sci. U. S. A. 1997;94:4681–4685. doi: 10.1073/pnas.94.9.4681. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 59.Hussain S., Benavente S.B., Nascimento E., et al. The nucleolar RNA methyltransferase Misu (NSun2) is required for mitotic spindle stability. J. Cell Biol. 2009;186:27–40. doi: 10.1083/jcb.200810180. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 60.Agris P.F. Bringing order to translation: The contributions of transfer RNA anticodon-domain modifications. EMBO Rep. 2008;9:629–635. doi: 10.1038/embor.2008.104. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61.Basti M.M., Stuart J.W., Lam A.T., et al. Design, biological activity and NMR-solution structure of a DNA analogue of yeast tRNAPhe anticodon domain. Nat. Struct. Biol. 1996;3:38–44. doi: 10.1038/nsb0196-38. [DOI] [PubMed] [Google Scholar]
- 62.Chow C.S., Lamichhane T.N., Mahto S.K. Expanding the nucleotide repertoire of the ribosome with post-transcriptional modifications. ACS Chem. Biol. 2007;2:610–619. doi: 10.1021/cb7001494. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 63.Amort T., Soulière M.F., Wille A., et al. Long non-coding RNAs as targets for cytosine methylation. RNA Biol. 2013;10:1002–1008. doi: 10.4161/rna.24454. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 64.Davis F.F., Allen F.W. Ribonucleic acids from yeast which contain a fifth nucleotide. J. Biol. Chem. 1957;227:907–915. [PubMed] [Google Scholar]
- 65.Ge J., Yu Y.-T. RNA pseudouridylation: new insights into an old modification. Trends Biochem. Sci. 2013;38:210–218. doi: 10.1016/j.tibs.2013.01.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 66.Hoang C., Ferré-D’Amaré A.R. Cocrystal structure of a tRNA ψ55 pseudouridine synthase: Nucleotide flipping by an RNA-modifying enzyme. Cell. 2001;107:929–939. doi: 10.1016/S0092-8674(01)00618-3. [DOI] [PubMed] [Google Scholar]
- 67.Ni J., Tien A.L., Fournier M.J. Small nucleolar RNAs direct site-specific synthesis of pseudouridine in ribosomal RNA. Cell. 1997;89:565–573. doi: 10.1016/S0092-8674(00)80238-X. [DOI] [PubMed] [Google Scholar]
- 68.Baker D.L. RNA-guided RNA modification: functional organization of the archaeal H/ACA RNP. Genes Dev. 2005;19:1238–1248. doi: 10.1101/gad.1309605. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 69.Ma X., Yang C., Alexandrov A., et al. Pseudouridylation of yeast U2 snRNA is catalyzed by either an RNA-guided or RNA-independent mechanism. EMBO J. 2005;24:2403–2413. doi: 10.1038/sj.emboj.7600718. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 70.Xiao M., Yang C., Schattner P., et al. Functionality and substrate specificity of human box H/ACA guide RNAs. RNA. 2008;15:176–186. doi: 10.1261/rna.1361509. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 71.Massenet S., Motorin Y., Lafontaine D.L., et al. Pseudouridine mapping in the Saccharomyces cerevisiae spliceosomal U small nuclear RNAs (snRNAs) reveals that pseudouridine synthase pus1p exhibits a dual substrate specificity for U2 snRNA and tRNA. Mol. Cell. Biol. 1999;19:2142–2154. doi: 10.1128/MCB.19.3.2142. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 72.Ma X., Zhao X., Yu Y.-T. Pseudouridylation (ψ) of U2 snRNA in S.cerevisiae is catalyzed by an RNAindependent mechanism. EMBO J. 2003;22:1889–1897. doi: 10.1093/emboj/cdg191. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 73.Cavaillé J., Buiting K., Kiefmann M., et al. Identification of brain-specific and imprinted small nucleolar RNA genes exhibiting an unusual genomic organization. Proc. Natl. Acad. Sci. U. S. A. 2000;97:14311–14316. doi: 10.1073/pnas.250426397. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 74.Hüttenhofer A., Brosius J., Bachellerie J.-P. RNomics: Identification and function of small, nonmessenger RNAs. Curr. Opin. Chem. Biol. 2002;6:835–843. doi: 10.1016/S1367-5931(02)00397-6. [DOI] [PubMed] [Google Scholar]
- 75.Hunter S., Jones P., Mitchell A., et al. 2012. InterPro in 2011: New developments in the family and domain prediction database. Nucleic Acids Res. 40, D306–D312. [DOI] [PMC free article] [PubMed]
- 76.Wu G., Xiao M., Yang C., et al. U2 snRNA is inducibly pseudouridylated at novel sites by Pus7p and snR81 RNP. EMBO J. 2011;30:79–89. doi: 10.1038/emboj.2010.316. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 77.Courtes F.C., Gu C., Wong N.S.C., et al. 28S rRNA is inducibly pseudouridylated by the mTOR pathway translational control in CHO cell cultures. J. Biotechnol. 2014;174:16–21. doi: 10.1016/j.jbiotec.2014.01.024. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 78.Bakin A., Ofengand J. Four newly located pseudouridylate residues in Escherichia coli 23S ribosomal RNA are all at the peptidyltransferase center: Analysis by the application of a new sequencing technique. Biochemistry. 1993;32:9754–9762. doi: 10.1021/bi00088a030. [DOI] [PubMed] [Google Scholar]
- 79.Karikó K., Muramatsu H., Welsh F.A., et al. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol. Ther. 2008;16:1833–1840. doi: 10.1038/mt.2008.200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 80.Karijolich J., Yu Y.-T. Converting nonsense codons into sense codons by targeted pseudouridylation. Nature. 2011;474:395–398. doi: 10.1038/nature10165. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 81.Nishikura K. Functions and regulation of RNA editing by ADAR deaminases. Annu. Rev. Biochem. 2010;79:321–349. doi: 10.1146/annurev-biochem-060208-105251. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 82.Rueter S.M., Dawson T.R., Emeson R.B. Regulation of alternative splicing by RNA editing. Nature. 1999;399:75–80. doi: 10.1038/19992. [DOI] [PubMed] [Google Scholar]
- 83.Bass B.L. RNA editing by adenosine deaminases that act on RNA. Annu. Rev. Biochem. 2002;71:817. doi: 10.1146/annurev.biochem.71.110601.135501. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 84.Jepson J.E.C., Reenan R.A. RNA editing in regulating gene expression in the brain. Biochim. Biophys. Acta—Gene Regul. Mech. 2008;1779:459–470. doi: 10.1016/j.bbagrm.2007.11.009. [DOI] [PubMed] [Google Scholar]
- 85.Kim U., Wang Y., Sanford T., et al. Molecular cloning of cDNA for double-stranded RNA adenosine deaminase, a candidate enzyme for nuclear RNA editing. Proc. Natl. Acad. Sci. U. S. A. 1994;91:11457–11461. doi: 10.1073/pnas.91.24.11457. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 86.Lai F., Chen C.-X., Carter K.C., et al. Editing of glutamate receptor B subunit ion channel RNAs by four alternatively spliced DRADA2 double-stranded RNA adenosine deaminases. Mol. Cell. Biol. 1997;17:2413–2424. doi: 10.1128/MCB.17.5.2413. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 87.Chen C.X., Cho D.S., Wang Q., et al. A third member of the RNA-specific adenosine deaminase gene family, ADAR3, contains both singleand doublestranded RNA binding domains. RNA. 2000;6:755–767. doi: 10.1017/S1355838200000170. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 88.Slavov D., Crnogorac-Jurevi T., Clark M., et al. Comparative analysis of the DRADA A-to-I RNA editing gene from mammals, pufferfish and zebrafish. Gene. 2000;250:53–60. doi: 10.1016/S0378-1119(00)00175-X. [DOI] [PubMed] [Google Scholar]
- 89.Cho D.-S.C., Yang W., Lee J.T., et al. Requirement of dimerization for RNA editing activity of adenosine deaminases acting on RNA. J. Biol. Chem. 2003;278:17093–17102. doi: 10.1074/jbc.M213127200. [DOI] [PubMed] [Google Scholar]
- 90.Slotkin W., Nishikura K. Adenosine-to-inosine RNA editing and human disease. Genome Med. 2013;5:105. doi: 10.1186/gm508. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 91.Nigita G., Veneziano D., Ferro A. A-to-I RNA editing: Current knowledge sources and computational approaches with special emphasis on non-coding RNA molecules. Front. Bioeng. Biotechnol. 2015;3:37. doi: 10.3389/fbioe.2015.00037. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 92.Li J.B., Levanon E.Y., Yoon J.-K., et al. Genome-wide identification of human RNA editing sites by parallel DNA capturing and sequencing. Science. 2009;324:1210–1213. doi: 10.1126/science.1170995. [DOI] [PubMed] [Google Scholar]
- 93.Sakurai M., Yano T., Kawabata H., et al. Inosine cyanoethylation identifies A-to-I RNA editing sites in the human transcriptome. Nat. Chem. Biol. 2010;6:733–740. doi: 10.1038/nchembio.434. [DOI] [PubMed] [Google Scholar]
- 94.Sakurai M., Ueda H., Yano T., et al. A biochemical landscape of A-to-I RNA editing in the human brain transcriptome. Genome Res. 2014;24:522–534. doi: 10.1101/gr.162537.113. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 95.Lomeli H., Mosbacher J., Melcher T., et al. Control of kinetic properties of AMPA receptor channels by nuclear RNA editing. Science. 1994;266:1709–1713. doi: 10.1126/science.7992055. [DOI] [PubMed] [Google Scholar]
- 96.Verdoorn T.A., Burnashev N., Monyer H., et al. Structural determinants of ion flow through recombinant glutamate receptor channels. Science. 1991;252:1715–1718. doi: 10.1126/science.1710829. [DOI] [PubMed] [Google Scholar]
- 97.Hume R.I., Dingledine R., Heinemann S.F. Identification of a site in glutamate receptor subunits that controls calcium permeability. Science. 1991;253:1028–1031. doi: 10.1126/science.1653450. [DOI] [PubMed] [Google Scholar]
- 98.Higuchi M., Maas S., Single F.N., et al. Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2. Nature. 2000;406:78–81. doi: 10.1038/35017558. [DOI] [PubMed] [Google Scholar]
- 99.Kwak S., Kawahara Y. Deficient RNA editing of GluR2 and neuronal death in amyotropic lateral sclerosis. J. Mol. Med. 2005;83:110–120. doi: 10.1007/s00109-004-0599-z. [DOI] [PubMed] [Google Scholar]
- 100.Maas S., Patt S., Schrey M., et al. Underediting of glutamate receptor GluR-B mRNA in malignant gliomas. Proc. Natl. Acad. Sci. U. S. A. 2001;98:14687–14692. doi: 10.1073/pnas.251531398. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 101.Takuma H., Kwak S., Yoshizawa T., et al. Reduction of GluR2 RNA editing, a molecular change that increases calcium influx through AMPA receptors, selective in the spinal ventral gray of patients with amyotrophic lateral sclerosis. Ann. Neurol. 1999;46:806–815. doi: 10.1002/1531-8249(199912)46:6<806::AID-ANA2>3.0.CO;2-S. [DOI] [PubMed] [Google Scholar]
- 102.Kawahara Y., Ito K., Sun H., et al. Glutamate receptors: RNA editing and death of motor neurons. Nature. 2004;427:801. doi: 10.1038/427801a. [DOI] [PubMed] [Google Scholar]
- 103.Peng P.L., Zhong X., Tu W., et al. ADAR2dependent RNA editing of AMPA receptor subunit GluR2 determines vulnerability of neurons in forebrain ischemia. Neuron. 2006;49:719–733. doi: 10.1016/j.neuron.2006.01.025. [DOI] [PubMed] [Google Scholar]
- 104.Burns C.M., Chu H., Rueter S.M., et al. Regulation of serotonin-2C receptor G-protein coupling by RNA editing. Nature. 1997;387:303–308. doi: 10.1038/387303a0. [DOI] [PubMed] [Google Scholar]
- 105.Marion S., Weiner D.M., Caron M.G. RNA editing induces variation in desensitization and trafficking of 5-hydroxytryptamine 2c receptor isoforms. J. Biol. Chem. 2004;279:2945–2954. doi: 10.1074/jbc.M308742200. [DOI] [PubMed] [Google Scholar]
- 106.Kawahara Y., Grimberg A., Teegarden S., et al. Dysregulated editing of serotonin 2C receptor mRNAs results in energy dissipation and loss of fat mass. J. Neurosci. 2008;28:12834–12844. doi: 10.1523/JNEUROSCI.3896-08.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 107.Iwamoto K., Bundo M., Kato T. Serotonin receptor 2C and mental disorders: Genetic, expression, and RNA editing studies. RNA Biol. 2009;6:248–253. doi: 10.4161/rna.6.3.8370. [DOI] [PubMed] [Google Scholar]
