ADAR RNA editing enzymes (adenosine deaminases acting on RNA) that convert adenosine bases to inosines were first identified biochemically 30 years ago. Since then, studies on ADARs in genetic model organisms, and evolutionary comparisons between them, continue to reveal a surprising range of pleiotropic biological effects of ADARs. This review focuses on Drosophila melanogaster, which has a single Adar gene encoding a homolog of vertebrate ADAR2 that site-specifically edits hundreds of transcripts to change individual codons in ion channel subunits and membrane and cytoskeletal proteins. Drosophila ADAR is involved in the control of neuronal excitability and neurodegeneration and, intriguingly, in the control of neuronal plasticity and sleep. Drosophila ADAR also interacts strongly with RNA interference, a key antiviral defense mechanism in invertebrates. Recent crystal structures of human ADAR2 deaminase domain-RNA complexes help to interpret available information on Drosophila ADAR isoforms and on the evolution of ADARs from tRNA deaminase ADAT proteins. ADAR RNA editing is a paradigm for the now rapidly expanding range of RNA modifications in mRNAs and ncRNAs. Even with recent progress, much remains to be understood about these groundbreaking ADAR RNA modification systems.

CEITEC at Masaryk University Brno Pavilion A35 Brno CZ 62500 Czech Republic

Zobrazit více v PubMed

Aguinaldo AMA, Turbeville JM, Linford LS, Rivera MC, Garey JR, Raff RA, Lake JA. 1997. Evidence for a clade of nematodes, arthropods and other moulting animals. Nature 387: 489–493. PubMed

Bass BL, Weintraub H. 1988. An unwinding activity that covalently modifies its double-strand RNA substrate. Cell 55: 1089–1098. PubMed

Bhogal B, Jepson JE, Savva YA, Pepper ASR, Reenan RA, Jongens TA. 2011. Modulation of dADAR-dependent RNA editing by the Drosophila fragile X mental retardation protein. Nat Neurosci 14: 1517–1524. PubMed PMC

Carpenter JA, Obbard DJ, Maside X, Jiggins FM. 2007. The recent spread of a vertically transmitted virus through populations of Drosophila melanogaster. Mol Ecol 16: 3947–3954. PubMed

Carpenter JA, Keegan LP, Wilfert L, O'Connell MA, Jiggins FM. 2009. Evidence for ADAR-induced hypermutation of the Drosophila sigma virus (Rhabdoviridae). BMC Genet 10: 75. PubMed PMC

Catanese DJ Jr, Matthews KS. 2011. Disconnected Interacting Protein 1 binds with high affinity to pre-tRNA and ADAT. Biochem Biophys Res Commun 414: 506–511. PubMed PMC

Chen CX, Cho DS, Wang Q, Lai F, Carter KC, Nishikura K. 2000. 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. PubMed PMC

Connolly CM, Dearth AT, Braun RE. 2005. Disruption of murine Tenr results in teratospermia and male infertility. Dev Biol 278: 13–21. PubMed

DeSousa D, Mukhopadhyay M, Pelka P, Zhao X, Dey BK, Robert V, Pélisson A, Bucheton A, Campos AR. 2003. A novel double-stranded RNA-binding protein, disco interacting protein 1 (DIP1), contributes to cell fate decisions during Drosophila development. J Biol Chem 278: 38040–38050. PubMed

Diegelmann S, Nieratschker V, Werner U, Hoppe J, Zars T, Buchner E. 2006. The conserved protein kinase-A target motif in synapsin of Drosophila is effectively modified by pre-mRNA editing. BMC Neurosci 7: 76. PubMed PMC

Donnelly CJ, Zhang PW, Pham JT, Haeusler AR, Mistry NA, Vidensky S, Daley EL, Poth EM, Hoover B, Fines DM. 2013. RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron 80: 415–428. PubMed PMC

Eifler T, Pokharel S, Beal PA. 2013. RNA-Seq analysis identifies a novel set of editing substrates for human ADAR2 present in Saccharomyces cerevisiae. Biochemistry 52: 7857–7869. PubMed PMC

Fumagalli D, Gacquer D, Rothé F, Lefort A, Libert F, Brown D, Kheddoumi N, Shlien A, Konopka T, Salgado R, et al. 2015. Principles governing A-to-I RNA editing in the breast cancer transcriptome. Cell Rep 13: 277–289. PubMed PMC

Galeano F, Tomaselli S, Locatelli F, Gallo A. 2012. A-to-I RNA editing: the “ADAR” side of human cancer. Semin Cell Dev Biol 23: 244–250. PubMed

Gallo A, Locatelli F. 2012. ADARs: allies or enemies? The importance of A-to-I RNA editing in human disease: from cancer to HIV-1. Biol Rev Camb Philos Soc 87: 95–110. PubMed

Garrett S, Rosenthal JJ. 2012. RNA editing underlies temperature adaptation in K+ channels from polar octopuses. Science 335: 848–851. PubMed PMC

Gerber AP, Keller W. 2001. RNA editing by base deamination: more enzymes, more targets, new mysteries. Trends Biochem Sci 26: 376–384. PubMed

Graveley BR, Brooks AN, Carlson JW, Duff MO, Landolin JM, Yang L, Artieri CG, van Baren MJ, Boley N, Booth BW, et al. 2011. The developmental transcriptome of Drosophila melanogaster. Nature 471: 473–479. PubMed PMC

Grice LF, Degnan BM. 2015. The origin of the ADAR gene family and animal RNA editing. BMC Evol Biol 15: 4. PubMed PMC

Han L, Diao L, Yu S, Xu X, Li J, Zhang R, Yang Y, Werner HM, Eterovic AK, Yuan Y, et al. 2015. The genomic landscape and clinical relevance of A-to-I RNA editing in human cancers. Cancer Cell 28: 515–528. PubMed PMC

Hartner JC, Schmittwolf C, Kispert A, Müller AM, Higuchi M, Seeburg PH. 2004. Liver disintegration in the mouse embryo caused by deficiency in the RNA-editing enzyme ADAR1. J Biol Chem 279: 4894–4902. PubMed

Haussmann IU, Bodi Z, Sanchez-Moran E, Mongan NP, Archer N, Fray RG, Soller M. 2016. m6A potentiates Sxl alternative pre-mRNA splicing for robust Drosophila sex determination. Nature 540: 301–304. PubMed

Heale BS, Keegan LP, McGurk L, Michlewski G, Brindle J, Stanton CM, Caceres JF, O'Connell MA. 2009. Editing independent effects of ADARs on the miRNA/siRNA pathways. EMBO J 28: 3145–3156. PubMed PMC

Hideyama T, Yamashita T, Suzuki T, Tsuji S, Higuchi M, Seeburg PH, Takahashi R, Misawa H, Kwak S. 2010. Induced loss of ADAR2 engenders slow death of motor neurons from Q/R site-unedited GluR2. J Neurosci 30: 11917–11925. PubMed PMC

Higuchi M, Single FN, Köhler M, Sommer B, Sprengel R, Seeburg PH. 1993. RNA editing of AMPA receptor subunit GluR-B: a base-paired intron-exon structure determines position and efficiency. Cell 75: 1361–1370. PubMed

Higuchi M, Maas S, Single F, Hartner J, Rozov A, Burnashev N, Feldmeyer D, Sprengel R, Seeburg P. 2000. Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2. Nature 406: 78–81. PubMed

Hogg M, Paro S, Keegan LP, O'Connell MA. 2011. RNA editing by mammalian ADARs. Adv Genet 73: 87–120. PubMed

Irvine RF. 2005. Inositide evolution - towards turtle domination? J Physiol 566: 295–300. PubMed PMC

Jepson JE, Savva YA, Yokose C, Sugden AU, Sahin A, Reenan RA. 2011. Engineered alterations in RNA editing modulate complex behavior in Drosophila: regulatory diversity of adenosine deaminase acting on RNA (ADAR) targets. J Biol Chem 286: 8325–8337. PubMed PMC

Kawamura Y, Saito K, Kin T, Ono Y, Asai K, Sunohara T, Okada TN, Siomi MC, Siomi H. 2008. Drosophila endogenous small RNAs bind to Argonaute 2 in somatic cells. Nature 453: 793–797. PubMed

Keegan LP, Gallo A, O'Connell MA. 2001. The many roles of an RNA editor. Nat Rev Genet 2: 869–878. PubMed

Keegan LP, Leroy A, Sproul D, O'Connell MA. 2004. Adenosine deaminases acting on RNA (ADARs): RNA-editing enzymes. Genome Biol 5: 209. PubMed PMC

Keegan LP, Brindle J, Gallo A, Leroy A, Reenan RA, O'Connell MA. 2005. Tuning of RNA editing by ADAR is required in Drosophila. EMBO J 24: 2183–2193. PubMed PMC

Keegan LP, McGurk L, Palavicini JP, Brindle J, Paro S, Li X, Rosenthal JJ, O'Connell MA. 2011. Functional conservation in human and Drosophila of Metazoan ADAR2 involved in RNA editing: loss of ADAR1 in insects. Nucleic Acids Res 39: 7249–7262. PubMed PMC

Kohn AB, Sanford RS, Yoshida MA, Moroz LL. 2015. Parallel evolution and lineage-specific expansion of RNA editing in ctenophores. Integr comp Biol 55: 1111–1120. PubMed PMC

Lence T, Akhtar J, Bayer M, Schmid K, Spindler L, Ho CH, Kreim N, Andrade-Navarro MA, Poeck B, Helm M. 2016. m6A modulates neuronal functions and sex determination in Drosophila. Nature 540: 242–247. PubMed

Levanon EY, Eisenberg E, Yelin R, Nemzer S, Hallegger M, Shemesh R, Fligelman ZY, Shoshan A, Pollock SR, Sztybel D, et al. 2004. Systematic identification of abundant A-to-I editing sites in the human transcriptome. Nat Biotechnol 22: 1001–1005. PubMed

Li X, Overton IM, Baines RA, Keegan LP, O'Connell MA. 2014. The ADAR RNA editing enzyme controls neuronal excitability in Drosophila melanogaster. Nucleic Acids Res 42: 1139–1151. PubMed PMC

Liscovitch-Brauer N, Alon S, Porath HT, Elstein B, Unger R, Ziv T, Admon A, Levanon EY, Rosenthal JJ, Eisenberg E. 2017. Trade-off between transcriptome plasticity and genome evolution in cephalopods. Cell 169: 191–202.e111. PubMed PMC

Liu Y, Samuel CE. 1996. Mechanism of interferon action: functionally distinct RNA-binding and catalytic domains in the interferon-inducible, double-stranded RNA-specific adenosine deaminase. J Virol 70: 1961–1968. PubMed PMC

Liu Y, Lei M, Samuel CE. 2000. Chimeric double-stranded RNA-specific adenosine deaminase ADAR1 proteins reveal functional selectivity of double-stranded RNA-binding domains from ADAR1 and protein kinase PKR. Proc Natl Acad Sci 97: 12541–12546. PubMed PMC

Macbeth MR, Schubert HL, Vandemark AP, Lingam AT, Hill CP, Bass BL. 2005. Inositol hexakisphosphate is bound in the ADAR2 core and required for RNA editing. Science 309: 1534–1539. PubMed PMC

Maldonado C, Alicea D, Gonzalez M, Bykhovskaia M, Marie B. 2013. Adar is essential for optimal presynaptic function. Mol Cell Neurosci 52: 173–180. PubMed PMC

Mannion NM, Greenwood SM, Young R, Cox S, Brindle J, Read D, Nellåker C, Vesely C, Ponting CP, McLaughlin PJ. 2014. The RNA-editing enzyme ADAR1 controls innate immune responses to RNA. Cell Rep 9: 1482–1494. PubMed PMC

Marlow H, Arendt D. 2014. Evolution: ctenophore genomes and the origin of neurons. Curr Biol 24: R757–R761. PubMed

Matthews MM, Thomas JM, Zheng Y, Tran K, Phelps KJ, Scott AI, Havel J, Fisher AJ, Beal PA. 2016. Structures of human ADAR2 bound to dsRNA reveal base-flipping mechanism and basis for site selectivity. Nat Struct Mol Biol 23: 426–433. PubMed PMC

Melcher T, Maas S, Herb A, Sprengel R, Higuchi M, Seeburg PH. 1996. RED2, a brain specific member of the RNA-specific adenosine deaminase family. J Biol Chem 271: 31795–31798. PubMed

O'Connell MA, Krause S, Higuchi M, Hsuan JJ, Totty NF, Jenny A, Keller W. 1995. Cloning of cDNAs encoding mammalian double-stranded RNA-specific adenosine deaminase. Mol Cell Biol 15: 1389–1397. PubMed PMC

O'Connell MA, Mannion NM, Keegan LP. 2015. The epitranscriptome and innate immunity. PLoS Genet 11: e1005687. PubMed PMC

Ota H, Sakurai M, Gupta R, Valente L, Wulff BE, Ariyoshi K, Iizasa H, Davuluri RV, Nishikura K. 2013. ADAR1 forms a complex with Dicer to promote microRNA processing and RNA-induced gene silencing. Cell 153: 575–589. PubMed PMC

Pal-Bhadra M, Leibovitch BA, Gandhi SG, Chikka MR, Bhadra U, Birchler JA, Elgin SC. 2004. Heterochromatic silencing and HP1 localization in Drosophila are dependent on the RNAi machinery. Science 303: 669–672. PubMed

Palladino MJ, Keegan LP, O'Connell MA, Reenan RA. 2000a. dADAR, a Drosophila double-stranded RNA-specific adenosine deaminase is highly developmentally regulated and is itself a target for RNA editing. RNA 6: 1004–1018. PubMed PMC

Palladino MJ, Keegan LP, O'Connell MA, Reenan RA. 2000b. A-to-I pre-mRNA editing in Drosophila is primarily involved in adult nervous system function and integrity. Cell 102: 437–449. PubMed

Pan B, Nath S, Sun L, Hart D, Sundaralingam M. 1998. Crystal structure of an RNA octamer duplex r (CCCIUGGG) 2 incorporating tandem I· U wobbles. Nucleic Acids Res 26: 5699–5706. PubMed PMC

Paz-Yaacov N, Bazak L, Buchumenski I, Porath HT, Danan-Gotthold M, Knisbacher BA, Eisenberg E, Levanon EY. 2015. Elevated RNA editing activity is a major contributor to transcriptomic diversity in tumors. Cell Rep 13: 267–276. PubMed

Pestal K, Funk CC, Snyder JM, Price ND, Treuting PM, Stetson DB. 2015. Isoforms of RNA-editing enzyme ADAR1 independently control nucleic acid sensor MDA5-driven autoimmunity and multi-organ development. Immunity 43: 933–944. PubMed PMC

Putnam NH, Srivastava M, Hellsten U, Dirks B, Chapman J, Salamov A, Terry A, Shapiro H, Lindquist E, Kapitonov VV, et al. 2007. Sea anemone genome reveals ancestral eumetazoan gene repertoire and genomic organization. Science 317: 86–94. PubMed

Reenan RA, Hanrahan CJ, Barry G. 2000. The mle(napts) RNA helicase mutation in Drosophila results in a splicing catastrophe of the para Na+ channel transcript in a region of RNA editing. Neuron 25: 139–149. PubMed

Rice GI, Kasher PR, Forte GM, Mannion NM, Greenwood SM, Szynkiewicz M, Dickerson JE, Bhaskar SS, Zampini M, Briggs TA, et al. 2012. Mutations in ADAR1 cause Aicardi-Goutieres syndrome associated with a type I interferon signature. Nat Genet 44: 1243–1248. PubMed PMC

Riedmann EM, Schopoff S, Hartner JC, Jantsch MF. 2008. Specificity of ADAR-mediated RNA editing in newly identified targets. RNA 14: 1110–1118. PubMed PMC

Robinson JE, Paluch J, Dickman DK, Joiner WJ. 2016. ADAR-mediated RNA editing suppresses sleep by acting as a brake on glutamatergic synaptic plasticity. Nat Commun 7: 10512. PubMed PMC

Roy S, Ernst J, Kharchenko PV, Kheradpour P, Negre N, Eaton ML, Landolin JM, Bristow CA, Ma L, Lin MF, et al. 2010. Identification of functional elements and regulatory circuits by Drosophila modENCODE. Science 330: 1787–1797. PubMed PMC

Ryan JF, Pang K, Schnitzler CE, Nguyen A-D, Moreland RT, Simmons DK, Koch BJ, Francis WR, Havlak P; NISC Comparative Sequencing Program. 2013. The genome of the ctenophore Mnemiopsis leidyi and its implications for cell type evolution. Science 342: 1242592. PubMed PMC

Ryter JM, Schultz SC. 1998. Molecular basis of double-stranded RNA-protein interactions: structure of a dsRNA-binding domain complexed with dsRNA. EMBO J 17: 7505–7513. PubMed PMC

Savva YA, Jepson JEC, Sahin A, Sugden AU, Dorsky JS, Alpert L, Lawrence C, Reenan RA. 2012. Auto-regulatory RNA editing fine-tunes mRNA re-coding and complex behaviour in Drosophila. Nat Commun 3: 790. PubMed PMC

Savva YA, Jepson JE, Chang Y-J, Whitaker R, Jones BC, St Laurent G, Tackett MR, Kapranov P, Jiang N, Du G. 2013. RNA editing regulates transposon-mediated heterochromatic gene silencing. Nat Commun 4: 2745. PubMed PMC

Scadden AD. 2005. The RISC subunit Tudor-SN binds to hyper-edited double-stranded RNA and promotes its cleavage. Nat Struct Mol Biol 12: 489–496. PubMed

Scadden AD, Smith CW. 2001. RNAi is antagonized by A-->I hyper-editing. EMBO Rep 2: 1107–1111. PubMed PMC

Serra MJ, Smolter PE, Westhof E. 2004. Pronounced instability of tandem IU base pairs in RNA. Nucleic Acids Res 32: 1824–1828. PubMed PMC

Stefl R, Oberstrass FC, Hood JL, Jourdan M, Zimmermann M, Skrisovska L, Maris C, Peng L, Hofr C, Emeson RB, et al. 2010. The solution structure of the ADAR2 dsRBM-RNA complex reveals a sequence-specific readout of the minor groove. Cell 143: 225–237. PubMed PMC

Thomas JM, Beal PA. 2017. How do ADARs bind RNA? New protein-RNA structures illuminate substrate recognition by the RNA editing ADARs. Bioessays 39 10.1002/bies.201600187. PubMed DOI PMC

Wagner RW, Smith JE, Cooperman BS, Nishikura K. 1989. 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 86: 2647–2651. PubMed PMC

Wang Q, Khillan J, Gadue P, Nishikura K. 2000. Requirement of the RNA editing deaminase ADAR1 gene for embryonic erythropoiesis. Science 290: 1765–1768. PubMed

Wang C, Xu JR, Liu H. 2016. A-to-I RNA editing independent of ADARs in filamentous fungi. RNA Biol 13: 940–945. PubMed PMC

Watson PJ, Millard CJ, Riley AM, Robertson NS, Wright LC, Godage HY, Cowley SM, Jamieson AG, Potter BV, Schwabe JW. 2016. Insights into the activation mechanism of class I HDAC complexes by inositol phosphates. Nat Commun 7: 11262. PubMed PMC

Wong SK, Sato S, Lazinski DW. 2001. Substrate recognition by ADAR1 and ADAR2. RNA 7: 846–858. PubMed PMC

Wood JG, Helfand SL. 2013. Chromatin structure and transposable elements in organismal aging. Front Genet 4: 274. PubMed PMC

Wood JG, Jones BC, Jiang N, Chang C, Hosier S, Wickremesinghe P, Garcia M, Hartnett DA, Burhenn L, Neretti N, et al. 2016. Chromatin-modifying genetic interventions suppress age-associated transposable element activation and extend life span in Drosophila. Proc Natl Acad Sci 113: 11277–11282. PubMed PMC

Wu C, Orozco C, Boyer J, Leglise M, Goodale J, Batalov S, Hodge CL, Haase J, Janes J, Huss JW III, et al. 2009. BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources. Genome Biol 10: R130. PubMed PMC

Zhang Q, Zhang L, Gao X, Qi S, Chang Z, Wu Q. 2015. DIP1 plays an antiviral role against DCV infection in Drosophila melanogaster. Biochem Biophys Res Commun 460: 222–226. PubMed

Adar RNA editing-dependent and -independent effects are required for brain and innate immune functions in Drosophila

Membrane and synaptic defects leading to neurodegeneration in Adar mutant Drosophila are rescued by increased autophagy