Year: 2003
Type: review
Abstract: adenosine deaminase acting on RNA glutamate receptor α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid 5-hydroxytryptamine or serotonin serotonin receptor subtype 2C double-stranded RNA adenosine deaminase acting on tRNA small nucleolar RNA RNA interference Adenosine to inosine modification in pre-mRNA, with inosine acting as guanosine during translation, was the most recent type of RNA editing to be discovered (1Sommer B. Kohler M. Sprengel R. Seeburg P.H. Cell. 1991; 67: 11-19Abstract Full Text PDF PubMed Scopus (1226) Google Scholar). At present, it appears to be the most widespread type of nuclear pre-mRNA editing in higher eukaryotes (6Bass B.L. Annu. Rev. Biochem. 2002; 71: 817-846Crossref PubMed Scopus (998) Google Scholar, 14Gerber A.P. Keller W. Trends Biochem. Sci. 2001; 26: 376-384Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar, 25Palladino M.J. Keegan L.P. O'Connell M.A. Reenan R.A. Cell. 2000; 102: 437-449Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar). Adenosine deaminases acting on RNA (ADARs),1 the enzymes responsible for conversion of A-to-I in double-stranded (ds) RNA, were first noticed as cellular RNA unwinding activity (2Bass B.L. Weintraub H. Cell. 1988; 55: 1089-1098Abstract Full Text PDF PubMed Scopus (562) Google Scholar, 3Wagner R.W. Smith J.E. Cooperman B.S. Nishikura K. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 2647-2651Crossref PubMed Scopus (263) Google Scholar), as they lead to destabilization of RNA duplexes by introducing I·U mismatches. Since the initial cloning of the first RNA-specific adenosine deaminase, ADAR1 (4O'Connell M.A. Krause S. Higuchi M. Hsuan J.J. Totty N.F. Jenny A. Keller W. Mol. Cell. Biol. 1995; 15: 1389-1397Crossref PubMed Google Scholar, 5Kim U. Wang Y. Sanford T. Zeng Y. Nishikura K. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 11457-11461Crossref PubMed Scopus (383) Google Scholar), a family of A-to-I editing enzymes (ADAR1–3) has emerged (Fig. 1) (6Bass B.L. Annu. Rev. Biochem. 2002; 71: 817-846Crossref PubMed Scopus (998) Google Scholar, 7Melcher T. Maas S. Herb A. Sprengel R. Seeburg P.H. Higuchi M. Nature. 1996; 379: 460-464Crossref PubMed Scopus (443) Google Scholar, 8Lai F. Chen C.X. Carter K.C. Nishikura K. Mol. Cell. Biol. 1997; 17: 2413-2424Crossref PubMed Scopus (163) Google Scholar, 9Melcher T. Maas S. Herb A. Sprengel R. Higuchi M. Seeburg P.H. J. Biol. Chem. 1996; 271: 31795-31798Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 10Chen C.X. Cho D.S. Wang Q. Lai F. Carter K.C. Nishikura K. RNA. 2000; 6: 755-767Crossref PubMed Scopus (393) Google Scholar). Both ADAR1 and ADAR2 are detected in many tissues, whereas ADAR3 is expressed only in restricted regions of the brain (4O'Connell M.A. Krause S. Higuchi M. Hsuan J.J. Totty N.F. Jenny A. Keller W. Mol. Cell. Biol. 1995; 15: 1389-1397Crossref PubMed Google Scholar, 5Kim U. Wang Y. Sanford T. Zeng Y. Nishikura K. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 11457-11461Crossref PubMed Scopus (383) Google Scholar, 7Melcher T. Maas S. Herb A. Sprengel R. Seeburg P.H. Higuchi M. Nature. 1996; 379: 460-464Crossref PubMed Scopus (443) Google Scholar, 8Lai F. Chen C.X. Carter K.C. Nishikura K. Mol. Cell. Biol. 1997; 17: 2413-2424Crossref PubMed Scopus (163) Google Scholar, 9Melcher T. Maas S. Herb A. Sprengel R. Higuchi M. Seeburg P.H. J. Biol. Chem. 1996; 271: 31795-31798Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 10Chen C.X. Cho D.S. Wang Q. Lai F. Carter K.C. Nishikura K. RNA. 2000; 6: 755-767Crossref PubMed Scopus (393) Google Scholar). Members of the ADAR gene family share common structural features such as two or three repeats of a dsRNA binding motif and a separate deaminase or catalytic domain (4O'Connell M.A. Krause S. Higuchi M. Hsuan J.J. Totty N.F. Jenny A. Keller W. Mol. Cell. Biol. 1995; 15: 1389-1397Crossref PubMed Google Scholar, 5Kim U. Wang Y. Sanford T. Zeng Y. Nishikura K. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 11457-11461Crossref PubMed Scopus (383) Google Scholar). Certain structural features are unique to particular ADAR members. For instance, ADAR1 contains two Z-DNA binding motifs (11Herbert A. Alfken J. Kim Y.G. Mian I.S. Nishikura K. Rich A. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 8421-8426Crossref PubMed Scopus (277) Google Scholar), whereas ADAR3 includes an arginine-rich single-stranded RNA binding domain at the N terminus (9Melcher T. Maas S. Herb A. Sprengel R. Higuchi M. Seeburg P.H. J. Biol. Chem. 1996; 271: 31795-31798Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 10Chen C.X. Cho D.S. Wang Q. Lai F. Carter K.C. Nishikura K. RNA. 2000; 6: 755-767Crossref PubMed Scopus (393) Google Scholar) (Fig. 1). In vitroRNA editing studies have revealed a significant difference in site selectivity displayed by ADAR1 and ADAR2 (7Melcher T. Maas S. Herb A. Sprengel R. Seeburg P.H. Higuchi M. Nature. 1996; 379: 460-464Crossref PubMed Scopus (443) Google Scholar, 8Lai F. Chen C.X. Carter K.C. Nishikura K. Mol. Cell. Biol. 1997; 17: 2413-2424Crossref PubMed Scopus (163) Google Scholar), whereas no RNA editing activity has been demonstrated yet for ADAR3 (9Melcher T. Maas S. Herb A. Sprengel R. Higuchi M. Seeburg P.H. J. Biol. Chem. 1996; 271: 31795-31798Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 10Chen C.X. Cho D.S. Wang Q. Lai F. Carter K.C. Nishikura K. RNA. 2000; 6: 755-767Crossref PubMed Scopus (393) Google Scholar). Orthologues of the mammalian ADARs have also been characterized and cloned from fruit fly (12Palladino M.J. Keegan L.P. O'Connell M.A. Reenan R.A. RNA. 2000; 6: 1004-1018Crossref PubMed Scopus (147) Google Scholar) and worms (6Bass B.L. Annu. Rev. Biochem. 2002; 71: 817-846Crossref PubMed Scopus (998) Google Scholar) (Fig. 1), and related genes have been identified in fish genomes (13Slavov D. Crnogorac-Jurcevic T. Clark M. Gardiner K. Gene (Amst.). 2000; 250: 53-60Crossref PubMed Scopus (38) Google Scholar). Subsequently, the subfamily of tRNA-specific A-to-I editing enzymes (ADAT1–3) was uncovered based on their sequence homologies to ADARs. ADAT3 is an adenosine deaminase in yeast shown to form an enzymatically active heterodimer with ADAT2 (14Gerber A.P. Keller W. Trends Biochem. Sci. 2001; 26: 376-384Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar). ADAT1 and ADAT2 are conserved from yeast to humans (15Maas S. Gerber A.P. Rich A. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 8895-8900Crossref PubMed Scopus (73) Google Scholar), and it is believed that an ADAT1-like adenosine deaminase is the ancestor of the current A-to-I editing enzymes (14Gerber A.P. Keller W. Trends Biochem. Sci. 2001; 26: 376-384Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar). A partially double-stranded RNA structure involving exonic and intronic sequences seems essential for editing to take place (16Burns C.M. Chu H. Rueter S.M. Hutchinson L.K. Canton H. Sanders-Bush E. Emeson R.B. Nature. 1997; 387: 303-308Crossref PubMed Scopus (873) Google Scholar, 17Higuchi M. Single F.N. Kohler M. Sommer B. Sprengel R. Seeburg P.H. Cell. 1993; 75: 1361-1370Abstract Full Text PDF PubMed Scopus (534) Google Scholar, 18Lomeli H. Mosbacher J. Melcher T. Hoger T. Geiger J.R. Kuner T. Monyer H. Higuchi M. Bach A. Seeburg P.H. Science. 1994; 266: 1709-1713Crossref PubMed Scopus (650) Google Scholar). By far, most of the genes found to undergo A-to-I RNA editing in mammals, Drosophila melanogaster, Caenorhabditis elegans, and squid, are expressed in the nervous system. Prominent examples are transcripts of the mammalian glutamate receptors (GluRs) and the serotonin receptor subunit 2C (5-HT2CR), where deamination of exonic adenosines leads to single amino acid changes in the resulting proteins often with profound consequences for receptor function (see Fig. 2). A-to-I editing was also found to occur in non-coding regions of pre-mRNAs (17Higuchi M. Single F.N. Kohler M. Sommer B. Sprengel R. Seeburg P.H. Cell. 1993; 75: 1361-1370Abstract Full Text PDF PubMed Scopus (534) Google Scholar, 19Rueter S.M. Dawson T.R. Emeson R.B. Nature. 1999; 399: 75-80Crossref PubMed Scopus (519) Google Scholar), most notably in the transcripts of the editing enzyme ADAR2 (19Rueter S.M. Dawson T.R. Emeson R.B. Nature. 1999; 399: 75-80Crossref PubMed Scopus (519) Google Scholar). By editing its own transcripts, an alternative splice acceptor site is created in intron 1, leading to alternative splicing resulting in a nonfunctional protein (19Rueter S.M. Dawson T.R. Emeson R.B. Nature. 1999; 399: 75-80Crossref PubMed Scopus (519) Google Scholar). Interestingly, the only ADAR-like gene inDrosophila, DADAR, which is most closely related to the mammalian ADAR2 protein, is also self-edited but within the coding region (12Palladino M.J. Keegan L.P. O'Connell M.A. Reenan R.A. RNA. 2000; 6: 1004-1018Crossref PubMed Scopus (147) Google Scholar). A-to-I RNA editing of the antigenome RNA of hepatitis delta virus, which replaces a translational stop signal with a tryptophan codon (UAG to UGG) (20Polson A.G. Bass B.L. Casey J.L. Nature. 1996; 380: 454-456Crossref PubMed Scopus (286) Google Scholar) is an obligatory step in the hepatitis delta virus life cycle. In addition, an intronic branch site adenosine of SH-PTP1 tyrosine phosphatase has been proposed to be edited by ADAR (21Beghini A. Ripamonti C.B. Peterlongo P. Roversi G. Cairoli R. Morra E. Larizza L. Hum. Mol. Genet. 2000; 9: 2297-2304Crossref PubMed Scopus (128) Google Scholar). No examples have yet been identified of A-to-I editing creating a translational start codon (ATA to ATG) or changing a consensus polyadenylation signal (AAUAAA). However, such discoveries are likely. In contrast to its exquisite selectivity for adenosine residues deaminated in a natural RNA substrate with a characteristic hairpin structure including loops and bulges, ADARs almost randomly modify many adenosines (∼50%) within a long completely complementary dsRNA. One source of such extended dsRNA molecules is viral RNAs that are synthesized during replication and also transcription of viral genomes. These viruses, such as measles, seem to encounter ADARs and under certain circumstances are converted to hypermodified dsRNAs with many I·U mismatched base pairs, denoted I-dsRNAs (6Bass B.L. Annu. Rev. Biochem. 2002; 71: 817-846Crossref PubMed Scopus (998) Google Scholar, 22Zhang Z. Carmichael G.G. Cell. 2001; 106: 465-475Abstract Full Text Full Text PDF PubMed Scopus (391) Google Scholar). The physiological importance of A-to-I RNA editing has been confirmed by analysis of ADAR null mutation phenotypes. For instance,ADAR2 −/− mice died young after repeated episodes of epileptic seizures caused by underediting of GluR-B RNA at the Q/R site, which controls Ca2+ permeability of the resulting ion channel (23Higuchi M. Maas S. Single F.N. Hartner J. Rozov A. Burnashev N. Feldmeyer D. Sprengel R. Seeburg P.H. Nature. 2000; 406: 78-81Crossref PubMed Scopus (771) Google Scholar). Lethal phenotypes including dyserythropoietic defects were observed in chimeric mouse embryos derived from ADAR1+/− embryonic stem cells. However, the possibility that antisense transcripts derived from theADAR1 targeted allele may contribute to the observed phenotypes has not been ruled out (24Wang Q. Khillan J. Gadue P. Nishikura K. Science. 2000; 290: 1765-1768Crossref PubMed Scopus (353) Google Scholar). The genetic inactivation ofDADAR in Drosophila resulted in flies with extreme behavioral deficits and neurological symptoms such as paralysis, locomotor uncoordination, and tremors, which increased in severity with age (25Palladino M.J. Keegan L.P. O'Connell M.A. Reenan R.A. Cell. 2000; 102: 437-449Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar). The observed phenotype is likely to be the result of the total lack of A-to-I RNA editing in the brains of the mutant flies (25Palladino M.J. Keegan L.P. O'Connell M.A. Reenan R.A. Cell. 2000; 102: 437-449Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar). In light of these findings it can be speculated that dysfunction of A-to-I RNA editing in humans could be cause for or contribute to certain pathophysiological processes and diseases. The measured amount of inosine, especially in the brain, is substantial and suggests that many genes undergo A-to-I editing (26Paul M.S. Bass B.L. EMBO J. 1998; 17: 1120-1127Crossref PubMed Scopus (230) Google Scholar). However, since the initial discovery of A-to-I RNA editing (1Sommer B. Kohler M. Sprengel R. Seeburg P.H. Cell. 1991; 67: 11-19Abstract Full Text PDF PubMed Scopus (1226) Google Scholar), only a few edited genes have been identified from discrepancies between the mRNA (cDNA) and genomic sequences, and their discovery was entirely serendipitous. A recently devised method for the enrichment and cloning of inosine-containing RNAs provides the first comprehensive search tool and has lead to the isolation of new edited RNA sequences; 10 from C. elegans and 19 from human brain (27Morse D.P. Aruscavage P.J. Bass B.L. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 7906-7911Crossref PubMed Scopus (184) Google Scholar). They include transcripts from diverse genes such as tankyrase, NADH-ubiquinone oxidoreductase, and a snoRNA precursor (27Morse D.P. Aruscavage P.J. Bass B.L. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 7906-7911Crossref PubMed Scopus (184) Google Scholar). All of the identified RNAs have A-to-I conversions in non-coding regions, mainly in 3′-UTR and intronic sequences, often involving repetitive elements such as Alu and LINE1 repeats (27Morse D.P. Aruscavage P.J. Bass B.L. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 7906-7911Crossref PubMed Scopus (184) Google Scholar). Potentially, the modifications in 3′-UTR secondary structures could alter the stability, transport, or translation of the mRNA, and intronic editing might influence the kinetics or efficiency of splicing (Fig. 2). Because no novel or known genes with editing sites in coding regions were isolated during the unbiased screening (27Morse D.P. Aruscavage P.J. Bass B.L. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 7906-7911Crossref PubMed Scopus (184) Google Scholar), it might be that the editing events that were discovered previously within the coding regions represent exceptional cases where, due to the beneficial function of the edited gene variant, positive selection has led to an increase in editing rates. It will be interesting to see if exhaustive screening of the enriched RNA pools will eventually lead to an accurate estimate of the total number of edited genes in the mammalian genome and the ratio of coding to non-coding editing sites. However, two dozen or so newly identified genes do not explain the discrepancy between significant amounts of inosine detectable within the poly(A) fraction of cellular RNA on one hand and the paucity of newly identified targets on the other. What could explain this seeming contradiction? One possibility is that there are a small number of genes that get edited extensively, contributing most of the measurable inosine. Such a mode of modification by ADARs, termed hyperediting, has previously been reported for the host-induced editing of viral RNAs (6Bass B.L. Annu. Rev. Biochem. 2002; 71: 817-846Crossref PubMed Scopus (998) Google Scholar). Indeed, some of the substrates in C. elegans and human are modified at multiple positions (27Morse D.P. Aruscavage P.J. Bass B.L. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 7906-7911Crossref PubMed Scopus (184) Google Scholar). At the same time, the observed amount of inosine in mRNA (up to 1 inosine in every 17,000 nucleotides (26Paul M.S. Bass B.L. EMBO J. 1998; 17: 1120-1127Crossref PubMed Scopus (230) Google Scholar)) could also be explained if many genes are edited at few positions but with low efficiency. This would make it much more difficult to identify individual editing events, because only a small fraction of the gene's transcripts carry the modification. Also, it is possible that the RNA editing machinery continuously probes nascent transcripts for new editing sites. In light of the few constraints on non-coding sequences (i.e. intronic, 5′-UTR, and 3′-UTR), novel, editable RNA structures could continue to appear at a significant rate within the pool of primary transcripts. Because such probing is a non-directional and initially low rate phenomenon, it would be difficult to detect these editing events and to distinguish them from reverse transcription or sequencing errors. One can imagine a scenario where opportunistic editing of newly formed RNA structures generates a constant “inosine background” that could account for most of the inosine measured. This is supported by the that the of repetitive sequences in the mammalian some active leads to a number of repeats within expressed The of repetitive elements in most of the newly identified editing substrates the It is to that ADARs might be in the of and repetitive elements or in the of gene and inactivation (Fig. sequences and transcription of and antisense RNA, with the to form have been proposed to a in these modification processes A.P. M.A. Science. 1999; PubMed Scopus Google Scholar). new A-to-I RNA editing sites within the coding regions of receptors and have been reported In D. melanogaster, transcripts for the receptor were found to be edited at positions within the binding region of the receptor channel M. Reenan R.A. E. 2002; PubMed Google Scholar). This receptor to the of genes targeted for A-to-I editing that in the nervous system. a novel of A-to-I editing characterized in also a gene for the channel J.J. F. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). editing sites have been which are in with influence on the In addition, one editing site in a domain for subunit was shown to of the J.J. F. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). the that residues are by editing is of the of in certain fish genes to their function at low a possible of editing J.J. F. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, P.H. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). function for channel subunit and has recently been to the same editing in which channel L. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar) and also is for of its pre-mRNA (23Higuchi M. Maas S. Single F.N. Hartner J. Rozov A. Burnashev N. Feldmeyer D. Sprengel R. Seeburg P.H. Nature. 2000; 406: 78-81Crossref PubMed Scopus (771) Google Scholar). The edited GluR-B an at the Q/R are within the of the protein receptors L. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). the Q/R site of GluR-B is the for a of receptor and of them on the of the codon by RNA editing P.H. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, L. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). or A-to-I editing activity be the cause of phenotypes that to known in in with to brain and of receptor pre-mRNA at a total of sites leads to of three amino acid residues in the resulting in in of the receptor (16Burns C.M. Chu H. Rueter S.M. Hutchinson L.K. Canton H. Sanders-Bush E. Emeson R.B. Nature. 1997; 387: 303-308Crossref PubMed Scopus (873) Google Scholar). RNA editing at displayed the most Q. P.J. Chen C.X. Cho D.S. Nishikura K. J. 2000; PubMed Scopus Google Scholar). Interestingly, substantial in the RNA editing and increase in the of the receptor at were observed in the of H. J.J. C. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). The measured changes in the of the receptor are to have resulted in of the of in these H. J.J. C. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). Interestingly, the of mice with an changes in editing that were to observed in H. J.J. C. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). These with two related C.M. K. Emeson R.B. Sanders-Bush E. 2001; PubMed Scopus Google Scholar, M.S. R.W. P.J. Mol. 2001; 6: PubMed Scopus Google Scholar), the possibility that changes in RNA editing of the may be in the of and also that changes in editing could be by and to the in editing within of the brain and RNA editing is will be to the of these findings for and to the between changes in serotonin and in editing P.H. 2002; Full Text Full Text PDF PubMed Scopus Google H. J.J. C. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). to the editing of glutamate receptors in the nervous to a between editing and seizures are the features of mice with underediting at the GluR-B Q/R site, mainly due to the increased in these mice (23Higuchi M. Maas S. Single F.N. Hartner J. Rozov A. Burnashev N. Feldmeyer D. Sprengel R. Seeburg P.H. Nature. 2000; 406: 78-81Crossref PubMed Scopus (771) Google Scholar, R. F. D.S. Feldmeyer D. P. Seeburg P.H. Sprengel R. Science. 1995; PubMed Scopus Google Scholar, D. K. R. R. Rozov A. Burnashev N. Sprengel R. Seeburg P.H. 1999; PubMed Scopus Google Scholar). Also, Q/R site editing in the receptor the mutant mice an increased to seizures B. A. T. R.A. J. T. S. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). of the GluR-B Q/R site also be an for the of epileptic seizures in with of S. S. M. Rich A. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google Scholar). This is from findings that in these the RNA editing activity of the enzyme for GluR-B Q/R site editing (23Higuchi M. Maas S. Single F.N. Hartner J. Rozov A. Burnashev N. Feldmeyer D. Sprengel R. Seeburg P.H. Nature. 2000; 406: 78-81Crossref PubMed Scopus (771) Google Scholar), is S. S. M. Rich A. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google Scholar). Q/R site editing was to with measured in the mouse in the cases it will be to the observed changes in RNA editing are consequences of the or are in In the symptoms of or might be more if account is of the in RNA What are the that could cause a significant in the rate of editing at a can that from known ADAR substrates a RNA sequence will be edited in from the for double-stranded regions and certain and that for the of editing (6Bass B.L. Annu. Rev. Biochem. 2002; 71: 817-846Crossref PubMed Scopus (998) Google Scholar), features of the substrates and protein appear to be in A for in will be the RNAs are for binding and modification by these Because of the of intronic sequences in the dsRNA structures essential for editing of and pre-mRNA, A-to-I RNA editing occur or with it is likely that RNA editing and splicing with (Fig. In the brains of mice the almost of GluR-B RNA editing at the Q/R site due to the total of the editing enzyme ADAR2 the kinetics of splicing (23Higuchi M. Maas S. Single F.N. Hartner J. Rozov A. Burnashev N. Feldmeyer D. Sprengel R. Seeburg P.H. Nature. 2000; 406: 78-81Crossref PubMed Scopus (771) Google Scholar), the between the processes of RNA editing and In the amounts of edited GluR-B primary transcripts undergo splicing as from the of editing measured in GluR-B mRNA with in GluR-B pre-mRNA (23Higuchi M. Maas S. Single F.N. Hartner J. Rozov A. Burnashev N. Feldmeyer D. Sprengel R. Seeburg P.H. Nature. 2000; 406: 78-81Crossref PubMed Scopus (771) Google splicing of edited transcripts has also been observed in the of ADAR2 S. S. M. Rich A. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google Scholar). A number of are found that the and of and the of a RNA with their sequences in W. Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar). One such mammalian expressed in the brain and a sequence for mRNA J. K. M. M. B. J. A. Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar). it is to the of the adenosine which also A-to-I editing The modification is to with the ADAR deamination (Fig. the of the and editing may be the most in the and rate of modifications The of a dsRNA especially one with many mismatched base and bulges, may be to of P.H. 2002; Full Text Full Text PDF PubMed Scopus Google a of particular importance for of the dsRNA structure in A-to-I RNA by dsRNA and appears to be step (Fig. in RNA a dsRNA of the dsRNA structure and in the of a or splicing and of of channel transcripts at the region the editing sites R.A. G. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). This that the editing efficiency of a substrate RNA may on the of the dsRNA structure its splicing rate R.A. G. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). it has been reported recently that ADAR1 and ADAR2 proteins are with nuclear that known for pre-mRNA splicing Cho D.S. J. Nishikura K. R. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google Scholar). This suggests an interesting possibility that certain physiological or or may or the and of RNA A or splicing as as ADAR which in RNA editing Q. P.J. Chen C.X. Cho D.S. Nishikura K. J. 2000; PubMed Scopus Google Scholar, R.A. G. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) (Fig. A number of unique structural and features ADAR1 from the known ADAR gene family (Fig. 1). ADAR1 has been shown to be of out editing of certain sites such as the A and sites in transcripts C.X. Cho D.S. Wang Q. Lai F. Carter K.C. Nishikura K. RNA. 2000; 6: 755-767Crossref PubMed Scopus (393) Google Scholar, Y. Emeson R.B. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar) and the intronic in GluR-B (7Melcher T. Maas S. Herb A. Sprengel R. Seeburg P.H. Higuchi M. Nature. 1996; 379: 460-464Crossref PubMed Scopus (443) Google Scholar, M. Maas S. Single F.N. Hartner J. Rozov A. Burnashev N. Feldmeyer D. Sprengel R. Seeburg P.H. Nature. 2000; 406: 78-81Crossref PubMed Scopus (771) Google Scholar), its in in editing of nuclear pre-mRNA has not yet been unique domain and that ADAR1 might in have in nuclear pre-mRNA ADAR1 in the of their are expressed due to the of The ADAR1 protein is in the and whereas the expressed is nuclear Rev. 2001; PubMed Scopus Google Scholar) (Fig. A for the ADAR1 in the has been (6Bass B.L. Annu. Rev. Biochem. 2002; 71: 817-846Crossref PubMed Scopus (998) Google Scholar, Rev. 2001; PubMed Scopus Google Scholar). The ADAR1 includes a unique domain that has been shown to in the with One has been that Z-DNA binding to ADAR1 to genes (11Herbert A. Alfken J. Kim Y.G. Mian I.S. Nishikura K. Rich A. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 8421-8426Crossref PubMed Scopus (277) Google Scholar), and proteins have recently been in the of R. H. Chen M. K. 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RNA that is at partially double-stranded a substrate for A-to-I This the of cellular processes that on double-stranded RNA molecules as such as will be by A-to-I RNA editing (Fig. is a dsRNA the of mRNA in the may be in processes such as in the For the in the the most significant of the ADAR gene family is the form of The of the dsRNAs has been reported to be A-to-I editing in by ADAR proteins Smith EMBO 2001; PubMed Scopus Google Scholar). it is possible that ADAR1 may with of the recently identified of RNAs such as and small RNAs and their (Fig. The studies may the of a to or with viral or after by ADARs. cellular that on inosine-containing RNA or have been identified (Fig. A activity that has been reported at sites with dsRNA of I·U and base pairs, by ADAR1 Smith EMBO J. 2001; PubMed Scopus Google Scholar). In addition, a protein of binding to hypermodified has also been reported Z. Carmichael G.G. 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Source: Journal of Biological Chemistry
Authors: Stefan Maas, Alexander Rich, Kazuko Nishikura
Institutions: Massachusetts Institute of Technology, The Wistar Institute
Language: English
Topic: RNA regulation and disease
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
OpenAlex ID: W2061934519