Key Points
-
A-to-I RNA editing is catalysed by adenosine deaminases acting on RNA (ADARs).
-
Three mammalian ADAR genes (ADAR1, ADAR2 and ADAR3) with common functional domains have been identified.
-
Protein-coding sequences of a limited number of genes, such as glutamate receptor GRIA2 and serotonin receptor HTR2C, are edited, resulting in dramatic alterations of protein functions.
-
Deficiencies in A-to-I RNA editing cause human diseases and pathophysiology.
-
Genome-wide screening has identified numerous A-to-I editing sites in inverted Alu repeats located in non-coding regions of mRNAs. Alu editing in these transcripts is likely to affect many cellular processes.
-
The biogenesis and function of certain miRNAs is regulated by editing of the primary miRNAs (pri-miRNAs).
-
ADAR1 forms a complex with Dicer to promote the efficacy of miRNA processing and RNA interference (RNAi) in developing embryos.
Abstract
Adenosine deaminases acting on RNA (ADARs) convert adenosine to inosine in double-stranded RNA. This A-to-I editing occurs not only in protein-coding regions of mRNAs, but also frequently in non-coding regions that contain inverted Alu repeats. Editing of coding sequences can result in the expression of functionally altered proteins that are not encoded in the genome, whereas the significance of Alu editing remains largely unknown. Certain microRNA (miRNA) precursors are also edited, leading to reduced expression or altered function of mature miRNAs. Conversely, recent studies indicate that ADAR1 forms a complex with Dicer to promote miRNA processing, revealing a new function of ADAR1 in the regulation of RNA interference.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Bass, B. L. & Weintraub, H. A developmentally regulated activity that unwinds RNA duplexes. Cell 48, 607–613 (1987).
Bass, B. L. & Weintraub, H. An unwinding activity that covalently modifies its double-stranded RNA substrate. Cell 55, 1089–1098 (1988).
Wagner, R. W., Smith, J. E., Cooperman, B. S. & Nishikura, K. A double-stranded RNA unwinding activity introduces structural alterations by means of adenosine to inosine conversions in mammalian cells and Xenopus eggs. Proc. Natl Acad. Sci. USA 86, 2647–2651 (1989).
Hogg, M., Paro, S., Keegan, L. P. & O'Connell, M. A. RNA editing by mammalian ADARs. Adv. Genet. 73, 87–120 (2011).
Nishikura, K. Functions and regulation of RNA editing by ADAR deaminases. Annu. Rev. Biochem. 79, 321–349 (2010).
Athanasiadis, A., Rich, A. & Maas, S. Widespread A-to-I RNA editing of Alu-containing mRNAs in the human transcriptome. PLoS Biol. 2, e391 (2004).
Bazak, L. et al. A-to-I RNA editing occurs at over a hundred million genomic sites, located in a majority of human genes. Genome Res. 24, 365–376 (2014).
Blow, M., Futreal, P. A., Wooster, R. & Stratton, M. R. A survey of RNA editing in human brain. Genome Res. 14, 2379–2387 (2004).
Fumagalli, D. et al. Principles governing A-to-I RNA editing in the breast cancer transcriptome. Cell Rep. 13, 277–289 (2015).
Han, L. et al. The genomic landscape and clinical relevance of A-to-I RNA editing in human cancers. Cancer Cell 28, 515–528 (2015).
Kim, D. D. et al. Widespread RNA editing of embedded Alu elements in the human transcriptome. Genome Res. 14, 1719–1725 (2004).
Levanon, E. Y. et al. Systematic identification of abundant A-to-I editing sites in the human transcriptome. Nat. Biotechnol. 22, 1001–1005 (2004).
Li, J. B. et al. Genome-wide identification of human RNA editing sites by parallel DNA capturing and sequencing. Science 324, 1210–1213 (2009).
Paz-Yaacov, N. et al. Elevated RNA editing activity is a major contributor to transcriptomic diversity in tumors. Cell Rep. 13, 267–276 (2015).
Peng, Z. et al. Comprehensive analysis of RNA-Seq data reveals extensive RNA editing in a human transcriptome. Nat. Biotechnol. 30, 253–260 (2012).
Porath, H. T., Carmi, S. & Levanon, E. Y. A genome-wide map of hyper-edited RNA reveals numerous new sites. Nat. Commun. 5, 4726 (2014).
Ramaswami, G. et al. Accurate identification of human Alu and non-Alu RNA editing sites. Nat. Methods 9, 579–581 (2012).
Ramaswami, G. et al. Identifying RNA editing sites using RNA sequencing data alone. Nat. Methods 10, 128–132 (2013).
Sakurai, M., Yano, T., Kawabata, H., Ueda, H. & Suzuki, T. Inosine cyanoethylation identifies A-to-I RNA editing sites in the human transcriptome. Nat. Chem. Biol. 6, 733–740 (2010). References 6–19 describe the global identification of numerous A-to-I editing sites in Alu repeats.
Iizasa, H. et al. Editing of Epstein–Barr virus-encoded BART6 microRNAs controls their Dicer targeting and consequently affects viral latency. J. Biol. Chem. 285, 33358–33370 (2010).
Kawahara, Y. et al. Frequency and fate of microRNA editing in human brain. Nucleic Acids Res. 36, 5270–5280 (2008).
Kawahara, Y., Zinshteyn, B., Chendrimada, T. P., Shiekhattar, R. & Nishikura, K. RNA editing of the microRNA-151 precursor blocks cleavage by the Dicer–TRBP complex. EMBO Rep. 8, 763–769 (2007).
Kawahara, Y. et al. Redirection of silencing targets by adenosine-to-inosine editing of miRNAs. Science 315, 1137–1140 (2007). This article shows that A-to-I editing of a miRNA-376a precursor results in alteration of the target genes of the miRNA.
Yang, W. et al. Modulation of microRNA processing and expression through RNA editing by ADAR deaminases. Nat. Struct. Mol. Biol. 13, 13–21 (2006).
Nishikura, K., Sakurai, M., Ariyoshi, K. & Ota, H. Antagonistic and stimulative roles of ADAR1 in RNA silencing. RNA Biol. 10, 1240–1247 (2013).
Ota, H. et al. ADAR1 forms a complex with Dicer to promote microRNA processing and RNA-induced gene silencing. Cell 153, 575–589 (2013). The authors demonstrate that ADAR1 forms a complex with Dicer to promote miRNA processing and RNAi efficacy.
Galeano, F., Tomaselli, S., Locatelli, F. & Gallo, A. A-to-I RNA editing: the “ADAR” side of human cancer. Semin. Cell Dev. Biol. 23, 244–250 (2012).
Hood, J. L. & Emeson, R. B. Editing of neurotransmitter receptor and ion channel RNAs in the nervous system. Curr. Top. Microbiol. Immunol. 353, 61–90 (2012).
Jepson, J. E. & Reenan, R. A. RNA editing in regulating gene expression in the brain. Biochim. Biophys. Acta 1779, 459–470 (2008).
Rosenthal, J. J. & Seeburg, P. H. A-to-I RNA editing: effects on proteins key to neural excitability. Neuron 74, 432–439 (2012).
Samuel, C. E. ADARs: viruses and innate immunity. Curr. Top. Microbiol. Immunol. 353, 163–195 (2012).
Slotkin, W. & Nishikura, K. Adenosine-to-inosine RNA editing and human disease. Genome Med. 5, 105 (2013).
Tariq, A. & Jantsch, M. F. Transcript diversification in the nervous system: A to I RNA editing in CNS function and disease development. Front. Neurosci. 6, 99 (2012).
Tomaselli, S., Galeano, F., Locatelli, F. & Gallo, A. ADARs and the balance game between virus infection and innate immune cell response. Curr. Issues Mol. Biol. 17, 37–52 (2014).
Rosenthal, J. J. The emerging role of RNA editing in plasticity. J. Exp. Biol. 218, 1812–1821 (2015).
Takenaka, M., Zehrmann, A., Verbitskiy, D., Hartel, B. & Brennicke, A. RNA editing in plants and its evolution. Annu. Rev. Genet. 47, 335–352 (2013).
Smith, H. C., Bennett, R. P., Kizilyer, A., McDougall, W. M. & Prohaska, K. M. Functions and regulation of the APOBEC family of proteins. Semin. Cell Dev. Biol. 23, 258–268 (2012).
Aphasizhev, R. & Aphasizheva, I. Mitochondrial RNA processing in trypanosomes. Res. Microbiol. 162, 655–663 (2011).
Gott, J. M. & Emeson, R. B. Functions and mechanisms of RNA editing. Annu. Rev. Genet. 34, 499–531 (2000).
Jin, Y., Zhang, W. & Li, Q. Origins and evolution of ADAR-mediated RNA editing. IUBMB Life 61, 572–578 (2009).
Kim, U., Wang, Y., Sanford, T., Zeng, Y. & Nishikura, K. Molecular cloning of cDNA for double-stranded RNA adenosine deaminase, a candidate enzyme for nuclear RNA editing. Proc. Natl Acad. Sci. USA 91, 11457–11461 (1994).
Melcher, T. et al. A mammalian RNA editing enzyme. Nature 379, 460–464 (1996).
Chen, C. X. et al. A third member of the RNA-specific adenosine deaminase gene family, ADAR3, contains both single- and double-stranded RNA binding domains. RNA 6, 755–767 (2000).
Melcher, T. et al. RED2, a brain-specific member of the RNA-specific adenosine deaminase family. J. Biol. Chem. 271, 31795–31798 (1996).
Stefl, R., Xu, M., Skrisovska, L., Emeson, R. B. & Allain, F. H. Structure and specific RNA binding of ADAR2 double-stranded RNA binding motifs. Structure 14, 345–355 (2006).
Herbert, A. et al. A Z-DNA binding domain present in the human editing enzyme, double-stranded RNA adenosine deaminase. Proc. Natl Acad. Sci. USA 94, 8421–8426 (1997).
Schneider, M. F., Wettengel, J., Hoffmann, P. C. & Stafforst, T. Optimal guideRNAs for re-directing deaminase activity of hADAR1 and hADAR2 in trans. Nucleic Acids Res. 42, e87 (2014).
Schumacher, J. M., Lee, K., Edelhoff, S. & Braun, R. E. Distribution of Tenr, an RNA-binding protein, in a lattice-like network within the spermatid nucleus in the mouse. Biol. Reprod. 52, 1274–1283 (1995).
McKee, A. E. et al. A genome-wide in situ hybridization map of RNA-binding proteins reveals anatomically restricted expression in the developing mouse brain. BMC Dev. Biol. 5, 14 (2005).
Macbeth, M. R. et al. Inositol hexakisphosphate is bound in the ADAR2 core and required for RNA editing. Science 309, 1534–1539 (2005).
Nishikura, K. et al. Substrate specificity of the dsRNA unwinding/modifying activity. EMBO J. 10, 3523–3532 (1991).
Lehmann, K. A. & Bass, B. L. The importance of internal loops within RNA substrates of ADAR1. J. Mol. Biol. 291, 1–13 (1999).
Higuchi, M. et al. RNA editing of AMPA receptor subunit GluR-B: a base-paired intron–exon structure determines position and efficiency. Cell 75, 1361–1370 (1993).
Lehmann, K. A. & Bass, B. L. Double-stranded RNA adenosine deaminases ADAR1 and ADAR2 have overlapping specificities. Biochemistry 39, 12875–12884 (2000).
Hartner, J. C. et al. Liver disintegration in the mouse embryo caused by deficiency in the RNA-editing enzyme ADAR1. J. Biol. Chem. 279, 4894–4902 (2004).
Higuchi, M. et al. Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2. Nature 406, 78–81 (2000).
Wang, Q. et al. Stress-induced apoptosis associated with null mutation of ADAR1 RNA editing deaminase gene. J. Biol. Chem. 279, 4952–4961 (2004).
George, C. X. & Samuel, C. E. Human RNA-specific adenosine deaminase ADAR1 transcripts possess alternative exon 1 structures that initiate from different promoters, one constitutively active and the other interferon inducible. Proc. Natl Acad. Sci. USA 96, 4621–4626 (1999).
Patterson, J. B. & Samuel, C. E. Expression and regulation by interferon of a double-stranded-RNA-specific adenosine deaminase from human cells: evidence for two forms of the deaminase. Mol. Cell. Biol. 15, 5376–5388 (1995).
Peng, P. L. et al. ADAR2-dependent RNA editing of AMPA receptor subunit GluR2 determines vulnerability of neurons in forebrain ischemia. Neuron 49, 719–733 (2006).
Yang, L. et al. c-Jun amino-terminal kinase-1 mediates glucose-responsive upregulation of the RNA editing enzyme ADAR2 in pancreatic beta-cells. PLoS ONE 7, e48611 (2012).
Shoshan, E. et al. Reduced adenosine-to-inosine miR-455-5p editing promotes melanoma growth and metastasis. Nat. Cell Biol. 17, 311–321 (2015).
Cho, D. S. et al. Requirement of dimerization for RNA editing activity of adenosine deaminases acting on RNA. J. Biol. Chem. 278, 17093–17102 (2003).
Poulsen, H. et al. Dimerization of ADAR2 is mediated by the double-stranded RNA binding domain. RNA 12, 1350–1360 (2006).
Valente, L. & Nishikura, K. RNA binding-independent dimerization of adenosine deaminases acting on RNA and dominant negative effects of nonfunctional subunits on dimer functions. J. Biol. Chem. 282, 16054–16061 (2007).
Desterro, J. M. et al. Dynamic association of RNA-editing enzymes with the nucleolus. J. Cell Sci. 116, 1805–1818 (2003).
Fritz, J. et al. RNA-regulated interaction of transportin-1 and exportin-5 with the double-stranded RNA-binding domain regulates nucleocytoplasmic shuttling of ADAR1. Mol. Cell. Biol. 29, 1487–1497 (2009).
Strehblow, A., Hallegger, M. & Jantsch, M. F. Nucleocytoplasmic distribution of human RNA-editing enzyme ADAR1 is modulated by double-stranded RNA-binding domains, a leucine-rich export signal, and a putative dimerization domain. Mol. Biol. Cell 13, 3822–3835 (2002).
Poulsen, H., Nilsson, J., Damgaard, C. K., Egebjerg, J. & Kjems, J. CRM1 mediates the export of ADAR1 through a nuclear export signal within the Z-DNA binding domain. Mol. Cell. Biol. 21, 7862–7871 (2001).
Barraud, P., Banerjee, S., Mohamed, W. I., Jantsch, M. F. & Allain, F. H. A bimodular nuclear localization signal assembled via an extended double-stranded RNA-binding domain acts as an RNA-sensing signal for transportin 1. Proc. Natl Acad. Sci. USA 111, E1852–E1861 (2014).
Maas, S. & Gommans, W. M. Identification of a selective nuclear import signal in adenosine deaminases acting on RNA. Nucleic Acids Res. 37, 5822–5829 (2009).
Sansam, C. L., Wells, K. S. & Emeson, R. B. Modulation of RNA editing by functional nucleolar sequestration of ADAR2. Proc. Natl Acad. Sci. USA 100, 14018–14023 (2003).
Marcucci, R. et al. Pin1 and WWP2 regulate GluR2 Q/R site RNA editing by ADAR2 with opposing effects. EMBO J. 30, 4211–4222 (2011).
Burns, C. M. et al. Regulation of serotonin-2C receptor G-protein coupling by RNA editing. Nature 387, 303–308 (1997).
Bhalla, T., Rosenthal, J. J., Holmgren, M. & Reenan, R. Control of human potassium channel inactivation by editing of a small mRNA hairpin. Nat. Struct. Mol. Biol. 11, 950–956 (2004).
Daniel, C., Wahlstedt, H., Ohlson, J., Bjork, P. & Ohman, M. Adenosine-to-inosine RNA editing affects trafficking of the γ-aminobutyric acid type A (GABAA) receptor. J. Biol. Chem. 286, 2031–2040 (2011).
Kawahara, Y. et al. Glutamate receptors: RNA editing and death of motor neurons. Nature 427, 801 (2004).
Hideyama, T. et al. Induced loss of ADAR2 engenders slow death of motor neurons from Q/R site-unedited GluR2. J. Neurosci. 30, 11917–11925 (2010).
Ishiuchi, S. et al. Ca2+-permeable AMPA receptors regulate growth of human glioblastoma via Akt activation. J. Neurosci. 27, 7987–8001 (2007).
Hartner, J. C., Walkley, C. R., Lu, J. & Orkin, S. H. ADAR1 is essential for the maintenance of hematopoiesis and suppression of interferon signaling. Nat. Immunol. 10, 109–115 (2009).
Liddicoat, B. J. et al. RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself. Science 349, 1115–1120 (2015). The authors show that A-to-I editing by ADAR1 is required for preventing sensing by MDA5 of long dsRNAs made from repetitive elements, with consequences for the embryonic lethality of Adar1 -null mice.
XuFeng, R. et al. ADAR1 is required for hematopoietic progenitor cell survival via RNA editing. Proc. Natl Acad. Sci. USA 106, 17763–17768 (2009).
Mannion, N. M. et al. The RNA-editing enzyme ADAR1 controls innate immune responses to RNA. Cell Rep. 9, 1482–1494 (2014).
Rice, G. I. et al. Mutations in ADAR1 cause Aicardi–Goutieres syndrome associated with a type I interferon signature. Nat. Genet. 44, 1243–1248 (2012).
Yang, S. et al. Adenosine deaminase acting on RNA 1 limits RIG-I RNA detection and suppresses IFN production responding to viral and endogenous RNAs. J. Immunol. 193, 3436–3445 (2014).
Suzuki, N. et al. Ten novel mutations of the ADAR1 gene in Japanese patients with dyschromatosis symmetrica hereditaria. J. Invest. Dermatol. 127, 309–311 (2007).
Kawahara, Y. et al. Dysregulated editing of serotonin 2C receptor mRNAs results in energy dissipation and loss of fat mass. J. Neurosci. 28, 12834–12844 (2008).
Morabito, M. V. et al. Mice with altered serotonin 2C receptor RNA editing display characteristics of Prader–Willi syndrome. Neurobiol. Dis. 39, 169–180 (2010).
Mombereau, C., Kawahara, Y., Gundersen, B. B., Nishikura, K. & Blendy, J. A. Functional relevance of serotonin 2C receptor mRNA editing in antidepressant- and anxiety-like behaviors. Neuropharmacology 59, 468–473 (2010).
Eran, A. et al. Comparative RNA editing in autistic and neurotypical cerebella. Mol. Psychiatry 18, 1041–1048 (2013).
Rueter, S. M., Dawson, T. R. & Emeson, R. B. Regulation of alternative splicing by RNA editing. Nature 399, 75–80 (1999).
Feng, Y., Sansam, C. L., Singh, M. & Emeson, R. B. Altered RNA editing in mice lacking ADAR2 autoregulation. Mol. Cell. Biol. 26, 480–488 (2006).
Lev-Maor, G. et al. RNA-editing-mediated exon evolution. Genome Biol. 8, R29 (2007).
Zhang, Z. & Carmichael, G. G. The fate of dsRNA in the nucleus: a p54nrb-containing complex mediates the nuclear retention of promiscuously A-to-I edited RNAs. Cell 106, 465–475 (2001).
Chen, L. L., DeCerbo, J. N. & Carmichael, G. G. Alu element-mediated gene silencing. EMBO J. 27, 1694–1705 (2008).
Prasanth, K. V. et al. Regulating gene expression through RNA nuclear retention. Cell 123, 249–263 (2005).
Chen, L. L. & Carmichael, G. G. Altered nuclear retention of mRNAs containing inverted repeats in human embryonic stem cells: functional role of a nuclear noncoding RNA. Mol. Cell 35, 467–478 (2009).
Scadden, A. D. & Smith, C. W. Specific cleavage of hyper-edited dsRNAs. EMBO J. 20, 4243–4252 (2001).
Morita, Y. et al. Human endonuclease V is a ribonuclease specific for inosine-containing RNA. Nat. Commun. 4, 2273 (2013). The authors show that EndoV is the ribonuclease specific to inosine-containing RNAs.
Scadden, A. D. The RISC subunit Tudor-SN binds to hyper-edited double-stranded RNA and promotes its cleavage. Nat. Struct. Mol. Biol. 12, 489–496 (2005).
Scadden, A. D. Inosine-containing dsRNA binds a stress-granule-like complex and downregulates gene expression in trans. Mol. Cell 28, 491–500 (2007).
Weissbach, R. & Scadden, A. D. Tudor-SN and ADAR1 are components of cytoplasmic stress granules. RNA 18, 462–471 (2012).
Ng, S. K., Weissbach, R., Ronson, G. E. & Scadden, A. D. Proteins that contain a functional Z-DNA-binding domain localize to cytoplasmic stress granules. Nucleic Acids Res. 41, 9786–9799 (2013).
Vitali, P. & Scadden, A. D. Double-stranded RNAs containing multiple IU pairs are sufficient to suppress interferon induction and apoptosis. Nat. Struct. Mol. Biol. 17, 1043–1050 (2010). The authors show that I·U dsRNA resembling extensively edited RNA can suppress interferon signalling, which is activated by unedited long dsRNA.
Castel, S. E. & Martienssen, R. A. RNA interference in the nucleus: roles for small RNAs in transcription, epigenetics and beyond. Nat. Rev. Genet. 14, 100–112 (2013).
Wang, Q., Zhang, Z., Blackwell, K. & Carmichael, G. G. Vigilins bind to promiscuously A-to-I-edited RNAs and are involved in the formation of heterochromatin. Curr. Biol. 15, 384–391 (2005). The authors report that vigilin in complex with ADAR1 binds to inosine-containing RNAs, revealing a possible role for A-to-I editing in heterochromatic gene silencing in mammalian cells.
Zhou, J., Wang, Q., Chen, L. L. & Carmichael, G. G. On the mechanism of induction of heterochromatin by the RNA-binding protein vigilin. RNA 14, 1773–1781 (2008).
Kondo, Y. & Issa, J. P. Enrichment for histone H3 lysine 9 methylation at Alu repeats in human cells. J. Biol. Chem. 278, 27658–27662 (2003).
Savva, Y. A. et al. RNA editing regulates transposon-mediated heterochromatic gene silencing. Nat. Commun. 4, 2745 (2013). The authors report that A-to-I editing of dsRNAs derived from retrotransposons antagonizes silencing by RNAi of retrotransposons in flies, revealing a possible role for A-to-I editing in the suppression of heterochromatic gene silencing.
Ha, M. & Kim, V. N. Regulation of microRNA biogenesis. Nat. Rev. Mol. Cell Biol. 15, 509–524 (2014).
Mendell, J. T. & Olson, E. N. MicroRNAs in stress signaling and human disease. Cell 148, 1172–1187 (2012).
Croce, C. M. & Calin, G. A. miRNAs, cancer, and stem cell division. Cell 122, 6–7 (2005).
Lei, T. et al. Perturbation of biogenesis and targeting of Epstein–Barr virus-encoded miR-BART3 microRNA by adenosine-to-inosine editing. J. Gen. Virol. 94, 2739–2744 (2013).
Pfeffer, S. et al. Identification of microRNAs of the herpesvirus family. Nat. Methods 2, 269–276 (2005).
Alon, S. et al. Systematic identification of edited microRNAs in the human brain. Genome Res. 22, 1533–1540 (2012).
Chiang, H. R. et al. Mammalian microRNAs: experimental evaluation of novel and previously annotated genes. Genes Dev. 24, 992–1009 (2010).
Chawla, G. & Sokol, N. S. ADAR mediates differential expression of polycistronic microRNAs. Nucleic Acids Res. 42, 5245–5255 (2014).
Heale, B. S. et al. Editing independent effects of ADARs on the miRNA/siRNA pathways. EMBO J. 28, 3145–3156 (2009).
Tomaselli, S. et al. Modulation of microRNA editing, expression and processing by ADAR2 deaminase in glioblastoma. Genome Biol. 16, 5 (2015).
Vesely, C., Tauber, S., Sedlazeck, F. J., von Haeseler, A. & Jantsch, M. F. Adenosine deaminases that act on RNA induce reproducible changes in abundance and sequence of embryonic miRNAs. Genome Res. 22, 1468–1476 (2012).
Chen, T. et al. ADAR1 is required for differentiation and neural induction by regulating microRNA processing in a catalytically independent manner. Cell Res. 25, 459–476 (2015).
Galore-Haskel, G. et al. A novel immune resistance mechanism of melanoma cells controlled by the ADAR1 enzyme. Oncotarget 6, 28999–29015 (2015).
Bahn, J. H. et al. Genomic analysis of ADAR1 binding and its involvement in multiple RNA processing pathways. Nat. Commun. 6, 6355 (2015).
Ekdahl, Y., Farahani, H. S., Behm, M., Lagergren, J. & Ohman, M. A-to-I editing of microRNAs in the mammalian brain increases during development. Genome Res. 22, 1477–1487 (2012).
Choudhury, Y. et al. Attenuated adenosine-to-inosine editing of microRNA-376a* promotes invasiveness of glioblastoma cells. J. Clin. Invest. 122, 4059–4076 (2012).
Bass, B. L. Double-stranded RNA as a template for gene silencing. Cell 101, 235–238 (2000).
Tonkin, L. A. & Bass, B. L. Mutations in RNAi rescue aberrant chemotaxis of ADAR mutants. Science 302, 1725 (2003). This article shows the interaction between RNAi and RNA-editing pathways in vivo in mutant worm strains.
Tonkin, L. A. et al. RNA editing by ADARs is important for normal behavior in Caenorhabditis elegans. EMBO J. 21, 6025–6035 (2002).
Wu, D., Lamm, A. T. & Fire, A. Z. Competition between ADAR and RNAi pathways for an extensive class of RNA targets. Nat. Struct. Mol. Biol. 18, 1094–1101 (2011). The authors report that A-to-I editing of dsRNAs derived from transposons and pseudogenes suppresses the generation of endo-siRNAs from these loci and their entry into the RNAi pathway.
Warf, M. B., Shepherd, B. A., Johnson, W. E. & Bass, B. L. Effects of ADARs on small RNA processing pathways in C. elegans . Genome Res. 22, 1488–1498 (2012).
Ma, E., MacRae, I. J., Kirsch, J. F. & Doudna, J. A. Autoinhibition of human dicer by its internal helicase domain. J. Mol. Biol. 380, 237–243 (2008).
Sommer, B., Kohler, M., Sprengel, R. & Seeburg, P. H. RNA editing in brain controls a determinant of ion flow in glutamate-gated channels. Cell 67, 11–19 (1991).
Lomeli, H. et al. Control of kinetic properties of AMPA receptor channels by nuclear RNA editing. Science 266, 1709–1713 (1994).
Sailer, A. et al. Generation and analysis of GluR5(Q636R) kainate receptor mutant mice. J. Neurosci. 19, 8757–8764 (1999).
Egebjerg, J. & Heinemann, S. F. Ca2+ permeability of unedited and edited versions of the kainate selective glutamate receptor GluR6. Proc. Natl Acad. Sci. USA 90, 755–759 (1993).
Kohler, M., Burnashev, N., Sakmann, B. & Seeburg, P. H. Determinants of Ca2+ permeability in both TM1 and TM2 of high affinity kainate receptor channels: diversity by RNA editing. Neuron 10, 491–500 (1993).
Levanon, E. Y. et al. Evolutionarily conserved human targets of adenosine to inosine RNA editing. Nucleic Acids Res. 33, 1162–1168 (2005).
Galeano, F. et al. Human BLCAP transcript: new editing events in normal and cancerous tissues. Int. J. Cancer 127, 127–137 (2010).
Chan, T. H. et al. A disrupted RNA editing balance mediated by ADARs (Adenosine DeAminases that act on RNA) in human hepatocellular carcinoma. Gut 63, 832–843 (2014).
Martinez, H. D. et al. RNA editing of androgen receptor gene transcripts in prostate cancer cells. J. Biol. Chem. 283, 29938–29949 (2008).
Chen, L. et al. Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma. Nat. Med. 19, 209–216 (2013).
Yeo, J., Goodman, R. A., Schirle, N. T., David, S. S. & Beal, P. A. RNA editing changes the lesion specificity for the DNA repair enzyme NEIL1. Proc. Natl Acad. Sci. USA 107, 20715–20719 (2010).
Shimokawa, T. et al. RNA editing of the GLI1 transcription factor modulates the output of Hedgehog signaling. RNA Biol. 10, 321–333 (2013).
Han, S. W. et al. RNA editing in RHOQ promotes invasion potential in colorectal cancer. J. Exp. Med. 211, 613–621 (2014).
Liu, W. H. et al. ADAR2-mediated editing of miR-214 and miR-122 precursor and antisense RNA transcripts in liver cancers. PLoS ONE 8, e81922 (2013).
Nishikura, K. Editor meets silencer: crosstalk between RNA editing and RNA interference. Nat. Rev. Mol. Cell Biol 7, 919–931 (2006).
Acknowledgements
The author thanks John M. Murray for critical reading of the manuscript. This work was supported in part by grants from the U.S. National Institutes of Health, Ellison Medical Foundation, Macula Vision Research Foundation and the Commonwealth Universal Research Enhancement Program of the Pennsylvania Department of Health.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The author declares no competing financial interests.
Glossary
- Alu
-
A type of retrotransposon of the short interspersed nuclear elements (SINE) family found in primate genomes. There are about 1.4 million copies of Alu in the human genome.
- Z-DNA
-
A left-handed form of DNA that is different from the common A and B structural isoforms of DNA. Its biological functions are largely unknown.
- Deamination
-
The chemical process that replaces a primary amino group by a hydroxyl group, resulting in conversion of one nucleoside to another.
- Inositol hexakisphosphate
-
(InsP6). An intracellular organic compound that is found throughout the animal kingdom and is affiliated with a wide range of important physiological activities such as modulation of haemoglobin structure and function.
- Retrotransposon
-
A class of genetic elements that includes endogenous retroviruses and transposable elements, which propagate in the genome through an intermediate RNA stage.
- Nuclear paraspeckles
-
Discrete, irregularly shaped nuclear compartments. Usually, approximately 10–30 paraspeckles are present in the interphase mammalian nucleus. Their function is not known, but they may trap certain proteins in the nucleus.
- Wobble base pairs
-
Pairs of nucleotides other than G:C and A:U, such as thermodynamically less stable I:U and G:U pairs. Wobble base pairs, like Watson–Crick base pairs, participate in RNA folding and the formation of secondary structures.
- Endogenous short interfering RNAs
-
(endo-siRNAs). siRNAs derived from endogenous double-stranded transcripts and repetitive elements such as Alu or other retrotransposons.
- RNase III protein
-
A double-stranded RNA (dsRNA)-specific endonuclease that cleaves dsRNA into short fragments with a 3′ overhang and a recessed 5′ phosphate. The RNA interference (RNAi) factors Drosha and Dicer are such proteins.
- RNA-induced silencing complex
-
(RISC). A complex containing short interfering RNAs (siRNAs) or microRNAs (miRNAs) and an Argonaute protein, which mediates the degradation or translation inhibition of target mRNAs that have high sequence complementarity to the small RNAs.
Rights and permissions
About this article
Cite this article
Nishikura, K. A-to-I editing of coding and non-coding RNAs by ADARs. Nat Rev Mol Cell Biol 17, 83–96 (2016). https://doi.org/10.1038/nrm.2015.4
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrm.2015.4
This article is cited by
-
Epitranscriptomic modifications in mesenchymal stem cell differentiation: advances, mechanistic insights, and beyond
Cell Death & Differentiation (2024)
-
Transcriptomic analysis reveals associations of blood-based A-to-I editing with Parkinson’s disease
Journal of Neurology (2024)
-
CREBZF mRNA nanoparticles suppress breast cancer progression through a positive feedback loop boosted by circPAPD4
Journal of Experimental & Clinical Cancer Research (2023)
-
Biological roles of A-to-I editing: implications in innate immunity, cell death, and cancer immunotherapy
Journal of Experimental & Clinical Cancer Research (2023)
-
Tissue-specific temperature dependence of RNA editing levels in zebrafish
BMC Biology (2023)
