Abstract
We review the structures and functions of ADARs and their involvements in human diseases. ADAR1 is widely expressed, particularly in the myeloid component of the blood system, and plays a prominent role in promiscuous editing of long dsRNA. Missense mutations that change ADAR1 residues and reduce RNA editing activity cause Aicardi–Goutières Syndrome, a childhood encephalitis and interferonopathy that mimics viral infection and resembles an extreme form of Systemic Lupus Erythmatosus (SLE). In Adar1 mouse mutant models aberrant interferon expression is prevented by eliminating interferon activation signaling from cytoplasmic dsRNA sensors, indicating that unedited cytoplasmic dsRNA drives the immune induction. On the other hand, upregulation of ADAR1 with widespread promiscuous RNA editing is a prominent feature of many cancers and particular site-specific RNA editing events are also affected. ADAR2 is most highly expressed in brain and is primarily required for site-specific editing of CNS transcripts; recent findings indicate that ADAR2 editing is regulated by neuronal excitation for synaptic scaling of glutamate receptors. ADAR2 is also linked to the circadian clock and to sleep. Mutations in ADAR2 could contribute to excitability syndromes such as epilepsy, to seizures, to diseases involving neuronal plasticity defects, such as autism and Fragile-X Syndrome, to neurodegenerations such as ALS, or to astrocytomas or glioblastomas in which reduced ADAR2 activity is required for oncogenic cell behavior. The range of human disease associated with ADAR1 mutations may extend further to include other inflammatory conditions while ADAR2 mutations may affect psychiatric conditions.
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Aizawa H, Hideyama T, Yamashita T, Kimura T, Suzuki N, Aoki M, Kwak S (2016) Deficient RNA-editing enzyme ADAR2 in an amyotrophic lateral sclerosis patient with a FUS(P525L) mutation. J Clin Neurosci 32:128–129. doi:10.1016/j.jocn.2015.12.039
Alon S, Vigneault F, Eminaga S, Christodoulou DC, Seidman JG, Church GM, Eisenberg E (2011) Barcoding bias in high-throughput multiplex sequencing of miRNA. Genome Res 21:1506–1511
Athanasiadis A, Rich A, Maas S (2004) Widespread A-to-I RNA editing of Alu-containing mRNAs in the human transcriptome. PLoS Biol 2:e391
Athanasiadis A, Placido D, Maas S, Brown BA 2nd, Lowenhaupt K, Rich A (2005) The crystal structure of the Zbeta domain of the RNA-editing enzyme ADAR1 reveals distinct conserved surfaces among Z-domains. J Mol Biol 351:496–507
Bahn JH, Ahn J, Lin X, Zhang Q, Lee JH, Civelek M, Xiao X (2015) Genomic analysis of ADAR1 binding and its involvement in multiple RNA processing pathways. Nat Commun 6:6355. doi:10.1038/ncomms7355
Basilio C, Wahba AJ, Lengyel P, Speyer JF, Ochoa S (1962) Synthetic polynucleotides and the amino acid code. Proc Natl Acad Sci USA 48:613–616
Bass BL, Weintraub H (1987) A developmental regulated activity that unwinds RNA duplexes. Cell 48:607–613
Bass BL, Weintraub H (1988) An unwinding activity that covalently modifies its double-strand RNA substrate. Cell 55:1089–1098
Bazak L, Haviv A, Barak M, Jacob-Hirsch J, Deng P, Zhang R, Isaacs FJ, Rechavi G, Li JB, Eisenberg E, Levanon EY (2014) 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. doi:10.1101/gr.164749.113
Beghini A, Ripamonti CB, Peterlongo P, Roversi G, Cairoli R, Morra E, Larizza L (2000) RNA hyperediting and alternative splicing of hematopoietic cell phosphatase (PTPN6) gene in acute myeloid leukemia. Hum Mol Genet 9:2297–2304
Behm M, Wahlstedt H, Widmark A, Eriksson M, Ohman M (2017) Accumulation of nuclear ADAR2 regulates A-to-I RNA editing during neuronal development. J Cell Sci. doi:10.1242/jcs.200055
Brown BA 2nd, Lowenhaupt K, Wilbert CM, Hanlon EB, Rich A (2000) The zalpha domain of the editing enzyme dsRNA adenosine deaminase binds left-handed Z-RNA as well as Z-DNA. Proc Natl Acad Sci USA 97:13532–13536. doi:10.1073/pnas.240464097
Buckingham SD, Kwak S, Jones AK, Blackshaw SE, Sattelle DB (2008) Edited GluR2, a gatekeeper for motor neurone survival? BioEssays 30:1185–1192
Burns CM, Chu H, Rueter SM, Hutchinson LK, Canton H, Sanders-Bush E, Emeson RB (1997) Regulation of serotonin-2C receptor G-protein coupling by RNA editing. Nature 387:303–308
Bycroft M, Grunert S, Murzin AG, Proctor M, St Johnston D (1995) NMR solution structure of a dsRNA binding domain from Drosophila staufen protein reveals homology to the N-terminal domain of ribosomal protein S5. EMBO J 14:3563–3571
Cenci C, Barzotti R, Galeano F, Corbelli S, Rota R, Massimi L, Di Rocco C, O’Connell MA, Gallo A (2008) Down-regulation of RNA editing in pediatric astrocytomas: ADAR2 editing activity inhibits cell migration and proliferation. J Biol Chem 283:7251–7260
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
Chen L, Li Y, Lin CH, Chan TH, Chow RK, Song Y, Liu M, Yuan YF, Fu L, Kong KL, Qi L, Li Y, Zhang N, Tong AH, Kwong DL, Man K, Lo CM, Lok S, Tenen DG, Guan XY (2013) Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma. Nat Med 19:209–216. doi:10.1038/nm.3043
Chen YB, Liao XY, Zhang JB, Wang F, Qin HD, Zhang L, Shugart YY, Zeng YX, Jia WH (2017) ADAR2 functions as a tumor suppressor via editing IGFBP7 in esophageal squamous cell carcinoma. Int J Oncol 50:622–630. doi:10.3892/ijo.2016.3823
Choudhury Y, Tay FC, Lam DH, Sandanaraj E, Tang C, Ang BT, Wang S (2012) Attenuated adenosine-to-inosine editing of microRNA-376a* promotes invasiveness of glioblastoma cells. J Clin Invest 122:4059–4076. doi:10.1172/JCI62925
Collingridge GL, Olsen RW, Peters J, Spedding M (2009) A nomenclature for ligand-gated ion channels. Neuropharmacology 56:2–5
Crow YJ, Manel N (2015) Aicardi–Goutieres syndrome and the type I interferonopathies. Nat Rev Immunol 15:429–440
Desterro JMP, Keegan LP, Lafarga M, Berciano MT, O’Connell M, Carmo-Fonseca M (2003) Dynamic association of RNA-editing enzymes with the nucleolus. J Cell Sci 116:1805–1818. doi:10.1242/jcs.00371
Donnelly CJ, Zhang P-W, 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
Dracheva S, Patel N, Woo DA, Marcus SM, Siever LJ, Haroutunian V (2008) Increased serotonin 2C receptor mRNA editing: a possible risk factor for suicide. Mol Psychiatry 13:1001–1010. doi:10.1038/sj.mp.4002081
Eggington JM, Greene T, Bass BL (2011) Predicting sites of ADAR editing in double-stranded RNA. Nat Commun 2:319. doi:10.1038/ncomms1324
Evans AJ, Gurung S, Wilkinson KA, Stephens DJ, Henley JM (2017) Assembly, secretory pathway trafficking, and surface delivery of kainate receptors is regulated by neuronal activity. Cell Rep 19:2613–2626
Ferrick-Kiddie EA, Rosenthal JJ, Ayers GD, Emeson RB (2017) Mutations underlying Episodic Ataxia type-1 antagonize Kv1. 1 RNA editing. Sci Rep 7:41095. doi:10.1038/srep41095
Filippini A, Bonini D, Lacoux C, Pacini L, Zingariello M, Sancillo L, Bosisio D, Salvi V, Mingardi J, La Via L (2017) Absence of the Fragile X Mental Retardation Protein results in defects of RNA editing of neuronal mRNAs in mouse. RNA Biol 22:1–12. doi:10.1080/15476286.2017.1338232
Fisher AJ, Beal PA (2017) Effects of Aicardi–Goutieres syndrome mutations predicted from ADAR-RNA structures. RNA Biol 14:164–170. doi:10.1080/15476286.2016.1267097
Fitzgerald LW, Iyer G, Conklin DS, Krause CM, Marshall A, Patterson JP, Tran DP, Jonak GJ, Hartig PR (1999) Messenger RNA editing of the human serotonin 5-HT2C receptor. Neuropsychopharmacology 21:82S–90S. doi:10.1016/S0893-133X(99)00004-4
Fumagalli D, Gacquer D, Rothe F, Lefort A, Libert F, Brown D, Kheddoumi N, Shlien A, Konopka T, Salgado R, Larsimont D, Polyak K, Willard-Gallo K, Desmedt C, Piccart M, Abramowicz M, Campbell PJ, Sotiriou C, Detours V (2015) Principles governing A-to-I RNA editing in the breast cancer transcriptome. Cell Rep 13:277–289. doi:10.1016/j.celrep.2015.09.032
Galeano F, Rossetti C, Tomaselli S, Cifaldi L, Lezzerini M, Pezzullo M, Boldrini R, Massimi L, Di Rocco CM, Locatelli F, Gallo A (2013) ADAR2-editing activity inhibits glioblastoma growth through the modulation of the CDC14B/Skp2/p21/p27 axis. Oncogene 32:998–1009. doi:10.1038/onc.2012.125
Gan Z, Zhao L, Yang L, Huang P, Zhao F, Li W, Liu Y (2006) RNA editing by ADAR2 is metabolically regulated in pancreatic islets and beta-cells. J Biol Chem 281:33386–33394
Graveley BR, Brooks AN, Carlson JW, Duff MO, Landolin JM, Yang L, Artieri CG, van Baren MJ, Boley N, Booth BW, Brown JB, Cherbas L, Davis CA, Dobin A, Li R, Lin W, Malone JH, Mattiuzzo NR, Miller D, Sturgill D, Tuch BB, Zaleski C, Zhang D, Blanchette M, Dudoit S, Eads B, Green RE, Hammonds A, Jiang L, Kapranov P, Langton L, Perrimon N, Sandler JE, Wan KH, Willingham A, Zhang Y, Zou Y, Andrews J, Bickel PJ, Brenner SE, Brent MR, Cherbas P, Gingeras TR, Hoskins RA, Kaufman TC, Oliver B, Celniker SE (2011) The developmental transcriptome of Drosophila melanogaster. Nature 471:473–479
Greger IH, Esteban JA (2007) AMPA receptor biogenesis and trafficking. Curr Opin Neurobiol 17:289–297
Greger IH, Khatri L, Ziff EB (2002) RNA editing at arg607 controls AMPA receptor exit from the endoplasmic reticulum. Neuron 34:759–772
Greger IH, Watson JF, Cull-Candy SG (2017) Structural and functional architecture of AMPA-type glutamate receptors and their auxiliary proteins. Neuron 94:713–730
Gu T, Buaas FW, Simons AK, Ackert-Bicknell CL, Braun RE, Hibbs MA (2012) Canonical A-to-I and C-to-U RNA editing is enriched at 3′UTRs and microRNA target sites in multiple mouse tissues. PLoS One 7:e33720. doi:10.1371/journal.pone.0033720
Han SW, Kim HP, Shin JY, Jeong EG, Lee WC, Kim KY, Park SY, Lee DW, Won JK, Jeong SY, Park KJ, Park JG, Kang GH, Seo JS, Kim JI, Kim TY (2014) RNA editing in RHOQ promotes invasion potential in colorectal cancer. J Exp Med 211:613–621. doi:10.1084/jem.20132209
Han L, Diao L, Yu S, Xu X, Li J, Zhang R, Yang Y, Werner HM, Eterovic AK, Yuan Y, Li J, Nair N, Minelli R, Tsang YH, Cheung LW, Jeong KJ, Roszik J, Ju Z, Woodman SE, Lu Y, Scott KL, Li JB, Mills GB, Liang H (2015) The genomic landscape and clinical relevance of A-to-I RNA editing in human cancers. Cancer Cell 28:515–528. doi:10.1016/j.ccell.2015.08.013
Hartner JC, Schmittwolf C, Kispert A, Muller 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
Hartner JC, Walkley CR, Lu J, Orkin SH (2009) ADAR1 is essential for the maintenance of hematopoiesis and suppression of interferon signaling. Nat Immunol 10:109–115
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. doi:10.1038/emboj.2009.244
Herbert A, Rich A (1999) Left-handed Z-DNA: structure and function. Genetica 106:37–47
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
Hideyama T, Yamashita T, Aizawa H, Tsuji S, Kakita A, Takahashi H, Kwak S (2012) Profound downregulation of the RNA editing enzyme ADAR2 in ALS spinal motor neurons. Neurobiol Dis 45:1121–1128. doi:10.1016/j.nbd.2011.12.033
Higuchi M, Single FN, Kohler 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
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
Hughes ME, Grant GR, Paquin C, Qian J, Nitabach MN (2012) Deep sequencing the circadian and diurnal transcriptome of Drosophila brain. Genome Res 22:1266–1281
Iwamoto K, Kato T (2003) RNA editing of serotonin 2C receptor in human postmortem brains of major mental disorders. Neurosci Lett 346:169–172
Jiang Q, Crews LA, Barrett CL, Chun HJ, Court AC, Isquith JM, Zipeto MA, Goff DJ, Minden M, Sadarangani A, Rusert JM, Dao KH, Morris SR, Goldstein LS, Marra MA, Frazer KA, Jamieson CH (2013) ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia. Proc Natl Acad Sci USA 110:1041–1046. doi:10.1073/pnas.1213021110
Kim U, Wang Y, Sanford T, Zeng Y, Nishikura K (1994) Molecular cloning of cDNAs for double-stranded RNA adenosine deaminase, a candidate enzyme for nuclear RNA editing. Proc Natl Acad Sci USA 91:11457–11461
King AE, Woodhouse A, Kirkcaldie MT, Vickers JC (2016) Excitotoxicity in ALS: overstimulation, or overreaction? Exp Neurol 275(Pt 1):162–171. doi:10.1016/j.expneurol.2015.09.019
Kubota-Sakashita M, Iwamoto K, Bundo M, Kato T (2014) A role of ADAR2 and RNA editing of glutamate receptors in mood disorders and schizophrenia. Mol Brain 7:5. doi:10.1186/1756-6606-7-5
Lehmann KA, Bass BL (2000) Double-stranded RNA adenosine deaminases ADAR1 and ADAR2 have overlapping specificities. Biochemistry 39:12875–12884
Li L, Qian G, Zuo Y, Yuan Y, Cheng Q, Guo T, Liu J, Liu C, Zhang L, Zheng H (2016) Ubiquitin-dependent turnover of adenosine deaminase acting on RNA 1 (ADAR1) is required for efficient antiviral activity of type I interferon. J Biol Chem 291:24974–24985
Liddicoat BJ, Piskol R, Chalk AM, Ramaswami G, Higuchi M, Hartner JC, Li JB, Seeburg PH, Walkley CR (2015) RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself. Science 349(6252):1115–1120. doi:10.1126/science.aac7049
Livingston JH, Lin JP, Dale RC, Gill D, Brogan P, Munnich A, Kurian MA, Gonzalez-Martinez V, De Goede CG, Falconer A, Forte G, Jenkinson EM, Kasher PR, Szynkiewicz M, Rice GI, Crow YJ (2014) A type I interferon signature identifies bilateral striatal necrosis due to mutations in ADAR1. J Med Genet 51:76–82. doi:10.1136/jmedgenet-2013-102038
Lomeli H, Mosbacher J, Melcher T, Höger T, Geiger JR, Kuner T, Monyer H, Higuchi M, Bach A, Seeburg PH (1994) Control of kinetic properties of AMPA receptor channels by nuclear RNA editing. Science 266:1709–1713
Lyddon R, Dwork AJ, Keddache M, Siever LJ, Dracheva S (2013) Serotonin 2c receptor RNA editing in major depression and suicide. World J Biol Psychiatry 14:590–601. doi:10.3109/15622975.2011.630406
Maas S, Patt S, Schrey M, Rich A (2001) Underediting of glutamate receptor GluR-B mRNA in malignant gliomas. Proc Natl Acad Sci USA 98:14687–14692
Macbeth MR, Schubert HL, VanDemark AF, Lingam AT, Hill CP, Bass BL (2005) Structural biology: inositol hexakisphosphate is bound in the ADAR2 core and required for RNA editing. Science 309:1534–1539. doi:10.1126/science.1113150
Mahajan SS, Thai KH, Chen K, Ziff E (2011) Exposure of neurons to excitotoxic levels of glutamate induces cleavage of the rna editing enzyme, adenosine deaminase acting on RNA 2, and loss of glur2 editing. Neuroscience. doi:10.1016/j.neuroscience.2011.05.027
Mannion NM, Greenwood SM, Young R, Cox S, Brindle J, Read D, Nellaker C, Vesely C, Ponting CP, McLaughlin PJ, Jantsch MF, Dorin J, Adams IR, Scadden AD, Ohman M, Keegan LP, O’Connell MA (2014) The RNA-editing enzyme ADAR1 controls innate immune responses to RNA. Cell Rep 9:1482–1494. doi:10.1016/j.celrep.2014.10.041
Marcucci R, Brindle J, Paro S, Casadio A, Hempel S, Morrice N, Bisso A, Keegan LP, Del Sal G, O’Connell MA (2011) Pin1 and WWP2 regulate GluR2 Q/R site RNA editing by ADAR2 with opposing effects. EMBO J 30:4211–4222. doi:10.1038/emboj.2011.303
Masliah G, Barraud P, Allain FH (2013) RNA recognition by double-stranded RNA binding domains: a matter of shape and sequence. Cell Mol Life Sci 70:1875–1895. doi:10.1007/s00018-012-1119-x
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. doi:10.1038/nsmb.3203
Medzhitov R (2010) Inflammation 2010: new adventures of an old flame. Cell 140:771–776
Mittaz L, Antonarakis SE, Higuchi M, Scott HS (1997) Localization of a novel human RNA-editing deaminase (hRED2 or ADARB2) to chromosome 10p15. Hum Genet 100:398–400
Nemlich Y, Greenberg E, Ortenberg R, Besser MJ, Barshack I, Jacob-Hirsch J, Jacoby E, Eyal E, Rivkin L, Prieto VG, Chakravarti N, Duncan LM, Kallenberg DM, Galun E, Bennett DC, Amariglio N, Bar-Eli M, Schachter J, Rechavi G, Markel G (2013) MicroRNA-mediated loss of ADAR1 in metastatic melanoma promotes tumor growth. J Clin Investig 123:2703–2718. doi:10.1172/JCI62980
Ng SK, Weissbach R, Ronson GE, Scadden AD (2013) Proteins that contain a functional Z-DNA-binding domain localize to cytoplasmic stress granules. Nucleic Acids Res 41:9786–9799. doi:10.1093/nar/gkt750
Niswender CM, Copeland SC, Herrick-Davis K, Emeson RB, Sanders-Bush E (1999) RNA editing of the human serotonin 5-hydroxytryptamine 2C receptor silences constitutive activity. J Biol Chem 274:9472–9478
Niswender CM, Herrick-Davis K, Dilley GE, Meltzer HY, Overholser JC, Stockmeier CA, Emeson RB, Sanders-Bush E (2001) RNA editing of the human serotonin 5-HT2C receptor. Alterations in suicide and implications for serotonergic pharmacotherapy. Neuropsychopharmacology 24:478–491
Oakes E, Anderson A, Cohen-Gadol A, Hundley HA (2017) Adenosine deaminase that acts on RNA 3 (ADAR3) binding to glutamate receptor subunit B pre-mRNA inhibits RNA editing in glioblastoma. J Biol Chem 292:4326–4335
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
Ohman M, Kallman AM, Bass BL (2000) In vitro analysis of the binding of ADAR2 to the pre-mRNA encoding the GluR-B R/G site. RNA 6:687–697
Okin D, Medzhitov R (2012) Evolution of inflammatory diseases. Curr Biol 22:R733–R740
Orlandi C, La Via L, Bonini D, Mora C, Russo I, Barbon A, Barlati S (2011) AMPA receptor regulation at the mRNA and protein level in rat primary cortical cultures. PLoS One 6:e25350
Park E, Guo J, Shen S, Demirdjian L, Wu YN, Lin L, Xing Y (2017) Population and allelic variation of A-to-I RNA editing in human transcriptomes. Genome Biol 18:143
Patterson JB, Samuel CE (1995) 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
Paupard MC, O’Connell MA, Gerber AP, Zukin RS (2000) Patterns of developmental expression of the RNA editing enzyme rADAR2. Neuroscience 95:869–879
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. doi:10.1016/j.celrep.2015.08.080
Peng Z, Cheng Y, Tan BC, Kang L, Tian Z, Zhu Y, Zhang W, Liang Y, Hu X, Tan X, Guo J, Dong Z, Liang Y, Bao L, Wang J (2012) Comprehensive analysis of RNA-Seq data reveals extensive RNA editing in a human transcriptome. Nat Biotechnol 30:253–260. doi:10.1038/nbt.2122
Penn AC, Balik A, Greger IH (2013) Reciprocal regulation of A-to-I RNA editing and the vertebrate nervous system. Front Neurosci 7:61. doi:10.3389/fnins.2013.00061
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. doi:10.1016/j.immuni.2015.11.001
Picardi E, Manzari C, Mastropasqua F, Aiello I, D’Erchia AM, Pesole G (2015) Profiling RNA editing in human tissues: towards the inosinome Atlas. Sci Rep 5:14941. doi:10.1038/srep14941
Polson AG, Bass BL (1994) Preferential selection of adenosines for modification by double-stranded RNA adenosine deaminase. EMBO J 13:5701–5711
Poulsen H, Nilsson J, Damgaard CK, Egebjerg J, Kjems J (2001) CRM1 mediates the export of ADAR1 through a nuclear export signal within the Z-DNA binding domain. Mol Cell Biol 21:7862–7871
Qin YR, Qiao JJ, Chan THM, Zhu YH, Li FF, Liu H, Fei J, Li Y, Guan XY, Chen L (2014) Adenosine-to-inosine RNA editing mediated by adars in esophageal squamous cell carcinoma. Can Res 74:840–851. doi:10.1158/0008-5472.CAN-13-2545
Qiu S, Li W, Xiong H, Liu D, Bai Y, Wu K, Zhang X, Yang H, Ma K, Hou Y, Li B (2016) Single-cell RNA sequencing reveals dynamic changes in A-to-I RNA editome during early human embryogenesis. BMC Genom 17:766. doi:10.1186/s12864-016-3115-2
Ramos A, Grunert S, Adams J, Micklem DR, Proctor MR, Freund S, Bycroft M, St Johnston D, Varani G (2000) RNA recognition by a Staufen double-stranded RNA-binding domain. EMBO J 19:997–1009
Ramos PS, Shedlock AM, Langefeld CD (2015) Genetics of autoimmune diseases: insights from population genetics. J Hum Genet 60:657
Rebagliati MR, Melton DA (1987) Antisense RNA injections in fertilized frog eggs reveal an RNA duplex unwinding activity. Cell 48:599–605
Rice GI, Kasher PR, Forte GM, Mannion NM, Greenwood SM, Szynkiewicz M, Dickerson JE, Bhaskar SS, Zampini M, Briggs TA, Jenkinson EM, Bacino CA, Battini R, Bertini E, Brogan PA, Brueton LA, Carpanelli M, De Laet C, de Lonlay P, del Toro M, Desguerre I, Fazzi E, Garcia-Cazorla A, Heiberg A, Kawaguchi M, Kumar R, Lin JP, Lourenco CM, Male AM, Marques W Jr, Mignot C, Olivieri I, Orcesi S, Prabhakar P, Rasmussen M, Robinson RA, Rozenberg F, Schmidt JL, Steindl K, Tan TY, van der Merwe WG, Vanderver A, Vassallo G, Wakeling EL, Wassmer E, Whittaker E, Livingston JH, Lebon P, Suzuki T, McLaughlin PJ, Keegan LP, O’Connell MA, Lovell SC, Crow YJ (2012) Mutations in ADAR1 cause Aicardi–Goutieres syndrome associated with a type I interferon signature. Nat Genet 44:1243–1248. doi:10.1038/ng.2414
Robinson J, Paluch J, Dickman D, Joiner W (2016) ADAR-mediated RNA editing suppresses sleep by acting as a brake on glutamatergic synaptic plasticity. Nat Commun 7:10512. doi:10.1038/ncomms10512
Rossetti C, Picardi E, Ye M, Camilli G, D’Erchia AM, Cucina L, Locatelli F, Fianchi L, Teofili L, Pesole G, Gallo A, Sorrentino R (2017) RNA editing signature during myeloid leukemia cell differentiation. Leukemia. doi:10.1038/leu.2017.134
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
Sansam CL, Wells KS, Emeson RB (2003) Modulation of RNA editing by functional nucleolar sequestration of ADAR2. Proc Natl Acad Sci USA 100(24):14018–14023. doi:10.1073/pnas.2336131100
Schade M, Turner CJ, Kuhne R, Schmieder P, Lowenhaupt K, Herbert A, Rich A, Oschkinat H (1999) The solution structure of the Zalpha domain of the human RNA editing enzyme ADAR1 reveals a prepositioned binding surface for Z-DNA. Proc Natl Acad Sci USA 96:12465–12470
Schoft VK, Schopoff S, Jantsch MF (2007) Regulation of glutamate receptor B pre-mRNA splicing by RNA editing. Nucleic Acids Res 35:3723–3732
Schoggins JW, Wilson SJ, Panis M, Murphy MY, Jones CT, Bieniasz P, Rice CM (2011) A diverse array of gene products are effectors of the type I interferon antiviral response. Nature 472:481
Schwartz T, Rould MA, Lowenhaupt K, Herbert A, Rich A (1999) Crystal structure of the Zalpha domain of the human editing enzyme ADAR1 bound to left-handed Z-DNA. Science 284:1841–1845
Shah SP, Morin RD, Khattra J, Prentice L, Pugh T, Burleigh A, Delaney A, Gelmon K, Guliany R, Senz J, Steidl C, Holt RA, Jones S, Sun M, Leung G, Moore R, Severson T, Taylor GA, Teschendorff AE, Tse K, Turashvili G, Varhol R, Warren RL, Watson P, Zhao Y, Caldas C, Huntsman D, Hirst M, Marra MA, Aparicio S (2009) Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature 461:809–813. doi:10.1038/nature08489
Shoshan E, Mobley AK, Braeuer RR, Kamiya T, Huang L, Vasquez ME, Salameh A, Lee HJ, Kim SJ, Ivan C, Velazquez-Torres G, Nip KM, Zhu K, Brooks D, Jones SJ, Birol I, Mosqueda M, Wen YY, Eterovic AK, Sood AK, Hwu P, Gershenwald JE, Robertson AG, Calin GA, Markel G, Fidler IJ, Bar-Eli M (2015) Reduced adenosine-to-inosine miR-455-5p editing promotes melanoma growth and metastasis. Nat Cell Biol 17:311–321. doi:10.1038/ncb3110
Singh M, Kesterson RA, Jacobs MM, Joers JM, Gore JC, Emeson RB (2007) Hyperphagia-mediated obesity in transgenic mice misexpressing the RNA-editing enzyme ADAR2. J Biol Chem 282:22448–22459
Slavov D, Crnogorac-Jurcevic T, Clark M, Gardiner K (2000) Comparative analysis of the DRADA A-to-I RNA editing gene from mammals, pufferfish and zebrafish. Gene 250:53–60
Solomon O, Eyal E, Amariglio N, Unger R, Rechavi G (2016) e23D: database and visualization of A-to-I RNA editing sites mapped to 3D protein structures. Bioinformatics 32:2213–2215
Sommer B, Köhler M, Sprengel R, Seeburg PH (1991) RNA editing in brain controls a determinant of ion flow in glutamate-gated channels. Cell 67:11–19
St Johnston D, Brown NH, Gall JG, Jantsch M (1992) A conserved double-stranded RNA-binding domain. Proc Natl Acad Sci USA 89:10979–10983
Stefl R, Oberstrass FC, Hood JL, Jourdan M, Zimmermann M, Skrisovska L, Maris C, Peng L, Hofr C, Emeson RB, Allain FH (2010) The solution structure of the ADAR2 dsRBM-RNA complex reveals a sequence-specific readout of the minor groove. Cell 143:225–237
Steinman RA, Yang Q, Gasparetto M, Robinson LJ, Liu X, Lenzner DE, Hou J, Smith C, Wang Q (2013) Deletion of the RNA-editing enzyme ADAR1 causes regression of established chronic myelogenous leukemia in mice. Int J Cancer 132:1741–1750. doi:10.1002/ijc.27851
Strehblow A, Hallegger M, Jantsch MF (2002) 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
Terajima H, Yoshitane H, Ozaki H, Suzuki Y, Shimba S, Kuroda S, Iwasaki W, Fukada Y (2017) ADARB1 catalyzes circadian A-to-I editing and regulates RNA rhythm. Nat Genet 49:146–151
Tomaselli S, Galeano F, Alon S, Raho S, Galardi S, Polito VA, Presutti C, Vincenti S, Eisenberg E, Locatelli F, Gallo A (2015) Modulation of microRNA editing, expression and processing by ADAR2 deaminase in glioblastoma. Genome Biol 16:5. doi:10.1186/s13059-014-0575-z
Veno MT, Bramsen JB, Bendixen C, Panitz F, Holm IE, Ohman M, Kjems J (2012) Spatio-temporal regulation of ADAR editing during development in porcine neural tissues. RNA Biol 9:1054–1065. doi:10.4161/rna.21082
Wahlstedt H, Daniel C, Ensterö M, Öhman M (2009) Large-scale mRNA sequencing determines global regulation of RNA editing during brain development. Genome Res 19:978–986
Walkley CR, Liddicoat B, Hartner JC (2012) Role of ADARs in mouse development. Curr Top Microbiol Immunol 353:197–220. doi:10.1007/82_2011_150
Wang Q, Miyakoda M, Yang W, Khillan J, Stachura DL, Weiss MJ, Nishikura K (2004) Stress-induced apoptosis associated with null mutation of ADAR1 RNA editing deaminase gene. J Biol Chem 279:4952–4961. doi:10.1074/jbc.M310162200
Wang IX, So E, Devlin JL, Zhao Y, Wu M, Cheung VG (2013) ADAR regulates RNA editing, transcript stability, and gene expression. Cell Rep 5:849–860. doi:10.1016/j.celrep.2013.10.002
Yang JH, Luo X, Nie Y, Su Y, Zhao Q, Kabir K, Zhang D, Rabinovici R (2003a) Widespread inosine-containing mRNA in lymphocytes regulated by ADAR1 in response to inflammation. Immunology 109:15–23
Yang JH, Nie Y, Zhao Q, Su Y, Pypaert M, Su H, Rabinovici R (2003b) Intracellular localization of differentially regulated RNA-specific adenosine deaminase isoforms in inflammation. J Biol Chem 278:45833–45842
Zhang Z, Kim T, Bao M, Facchinetti V, Jung SY, Ghaffari AA, Qin J, Cheng G, Liu YJ (2011) DDX1, DDX21, and DHX36 helicases form a complex with the adaptor molecule TRIF to sense dsRNA in dendritic cells. Immunity 34:866–878. doi:10.1016/j.immuni.2011.03.027
Zheng Y, Lorenzo C, Beal PA (2017) DNA editing in DNA/RNA hybrids by adenosine deaminases that act on RNA. Nucleic Acids Res 45:3369–3377. doi:10.1093/nar/gkx050
Zipeto MA, Court AC, Sadarangani A, Delos Santos NP, Balaian L, Chun HJ, Pineda G, Morris SR, Mason CN, Geron I, Barrett C, Goff DJ, Wall R, Pellecchia M, Minden M, Frazer KA, Marra MA, Crews LA, Jiang Q, Jamieson CH (2016) ADAR1 activation drives leukemia stem cell self-renewal by impairing Let-7 biogenesis. Cell Stem Cell 19:177–191. doi:10.1016/j.stem.2016.05.004
Acknowledgements
M.A. O’C has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under Grant agreement no 621368. A.G has received funding from the AIRC IG Grant no. 17615. We would like to thank two reviewers for detailed comments and additional references.
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Gallo, A., Vukic, D., Michalík, D. et al. ADAR RNA editing in human disease; more to it than meets the I. Hum Genet 136, 1265–1278 (2017). https://doi.org/10.1007/s00439-017-1837-0
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DOI: https://doi.org/10.1007/s00439-017-1837-0