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Review Articles

To protect and modify double-stranded RNA – the critical roles of ADARs in development, immunity and oncogenesis

ORCID Icon, ORCID Icon, ORCID Icon, ORCID Icon & ORCID Icon
Pages 54-87 | Received 01 Sep 2020, Accepted 24 Nov 2020, Published online: 27 Dec 2020

References

  • Ahmad S, Mu X, Yang F, Greenwald E, Park JW, Jacob E, Zhang CZ, Hur S. 2018. Breaching self-tolerance to Alu duplex RNA underlies MDA5-mediated inflammation. Cell. 172(4):797–810 e13.
  • Akira S, Uematsu S, Takeuchi O. 2006. Pathogen recognition and innate immunity. Cell. 124:783–801.
  • Albertin CB, Simakov O, Mitros T, Wang ZY, Pungor JR, Edsinger-Gonzales E, Brenner S, Ragsdale CW, Rokhsar DS. 2015. The octopus genome and the evolution of cephalopod neural and morphological novelties. Nature. 524:220–224.
  • Alon S, Garrett SC, Levanon EY, Olson S, Graveley BR, Rosenthal JJ, Eisenberg E. 2015. The majority of transcripts in the squid nervous system are extensively recoded by A-to-I RNA editing. Elife. 4:e05198.
  • Aquino-Jarquin G. 2020. Novel engineered programmable systems for ADAR-mediated RNA editing. Mol Ther Nucleic Acids. 19:1065–1072.
  • 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.
  • 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.
  • Bajad P, Ebner F, Amman F, Szabo B, Kapoor U, Manjali G, Hildebrandt A, Janisiw MP, Jantsch MF. 2020. An internal deletion of ADAR rescued by MAVS deficiency leads to a minute phenotype. Nucleic Acids Res. 48:3286–3303.
  • Barak M, Porath HT, Finkelstein G, Knisbacher BA, Buchumenski I, Roth SH, Levanon EY, Eisenberg E. 2020. Purifying selection of long dsRNA is the first line of defense against false activation of innate immunity. Genome Biol. 21:26.
  • Barraud P, Banerjee S, Mohamed WI, Jantsch MF, Allain FH. 2014. 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:E1852–61.
  • 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.
  • Berger I, Winston W, Manoharan R, Schwartz T, Alfken J, Kim YG, Lowenhaupt K, Herbert A, Rich A. 1998. Spectroscopic characterization of a DNA-binding domain, Z alpha, from the editing enzyme, dsRNA adenosine deaminase: evidence for left-handed Z-DNA in the Z alpha-DNA complex. Biochemistry. 37:13313–13321.
  • Bhalla T, Rosenthal JJ, Holmgren M, Reenan R. 2004. Control of human potassium channel inactivation by editing of a small mRNA hairpin. Nat Struct Mol Biol. 11:950–956.
  • Blow MJ, Grocock RJ, van Dongen S, Enright AJ, Dicks E, Futreal PA, Wooster R, Stratton MR. 2006. RNA editing of human microRNAs. Genome Biol. 7:R27.
  • 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.
  • Capshew CR, Dusenbury KL, Hundley HA. 2012. Inverted Alu dsRNA structures do not affect localization but can alter translation efficiency of human mRNAs independent of RNA editing. Nucleic Acids Res. 40:8637–8645.
  • 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.
  • Cesarini V, Silvestris DA, Tassinari V, Tomaselli S, Alon S, Eisenberg E, Locatelli F, Gallo A. 2018. ADAR2/miR-589-3p axis controls glioblastoma cell migration/invasion. Nucleic Acids Res. 46(4):2045–2059.
  • Chalk AM, Taylor S, Heraud-Farlow JE, Walkley CR. 2019. The majority of A-to-I RNA editing is not required for mammalian homeostasis. Genome Biol. 20:268.
  • Chan TH, Lin CH, Qi L, Fei J, Li Y, Yong KJ, Liu M, Song Y, Chow RK, Ng VH, et al. 2014. A disrupted RNA editing balance mediated by ADARs (adenosine deaminases that act on RNA) in human hepatocellular carcinoma. Gut. 63:832–843.
  • Chan TH, Qamra A, Tan KT, Guo J, Yang H, Qi L, Lin JS, Ng VH, Song Y, Hong H, et al. 2016. ADAR-mediated RNA editing predicts progression and prognosis of gastric cancer. Gastroenterology. 151(4):637–650 e10.
  • 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, et al. 2013. Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma. Nat Med. 19:209–216.
  • Chen LL, Carmichael GG. 2009. 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.
  • Chen LL, Yang L. 2017. ALUternative regulation for gene expression. Trends Cell Biol. 27:480–490.
  • 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.
  • 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(11):4059–4076.
  • Chung H, Calis JJA, Wu X, Sun T, Yu Y, Sarbanes SL, Dao Thi VL, Shilvock AR, Hoffmann HH, Rosenberg BR, et al. 2018. Human ADAR1 prevents endogenous RNA from triggering translational shutdown. Cell. 172(4):811–824 e14.
  • Crow Y, Keshavan N, Barbet JP, Bercu G, Bondet V, Boussard C, Dedieu N, Duffy D, Hully M, Giardini A, et al. 2020. Cardiac valve involvement in ADAR-related type I interferonopathy. J Med Genet. 57(7):475–478.
  • Deffit SN, Hundley HA. 2016. To edit or not to edit: regulation of ADAR editing specificity and efficiency. Wiley Interdiscip Rev RNA. 7:113–127.
  • Deffit SN, Yee BA, Manning AC, Rajendren S, Vadlamani P, Wheeler EC, Domissy A, Washburn MC, Yeo GW, Hundley HA. 2017. The C. elegans neural editome reveals an ADAR target mRNA required for proper chemotaxis. Elife. 6:e28625.
  • Deng P, Khan A, Jacobson D, Sambrani N, McGurk L, Li X, Jayasree A, Hejatko J, Shohat-Ophir G, O'Connell MA, et al. 2020. Adar RNA editing-dependent and -independent effects are required for brain and innate immune functions in Drosophila. Nat Commun. 11:1580.
  • Dexheimer PJ, Cochella L. 2020. MicroRNAs: from mechanism to organism. Front Cell Dev Biol. 8:409.
  • Di Meglio P, Villanova F, Nestle FO. 2014. Psoriasis. Cold Spring Harb Perspect Med. 4(8):a015354.
  • Doyle M, Jantsch MF. 2002. New and old roles of the double-stranded RNA-binding domain. J Struct Biol. 140:147–153.
  • Doyle M, Jantsch MF. 2003. Distinct in vivo roles for double-stranded RNA-binding domains of the Xenopus RNA-editing enzyme ADAR1 in chromosomal targeting. J Cell Biol. 161:309–319.
  • Ekdahl Y, Farahani HS, Behm M, Lagergren J, Öhman M. 2012. A-to-I editing of microRNAs in the mammalian brain increases during development. Genome Res. 22:1477–1487.
  • Elbarbary RA, Li W, Tian B, Maquat LE. 2013. STAU1 binding 3' UTR IRAlus complements nuclear retention to protect cells from PKR-mediated translational shutdown. Genes Dev. 27:1495–1510.
  • Fischer SEJ, Ruvkun G. 2020. Caenorhabditis elegans ADAR editing and the ERI-6/7/MOV10 RNAi pathway silence endogenous viral elements and LTR retrotransposons. Proc Natl Acad Sci USA. 117:5987–5996.
  • Fitzpatrick T, Huang S. 2012. 3'-UTR-located inverted Alu repeats facilitate mRNA translational repression and stress granule accumulation. Nucleus. 3:359–369.
  • Fritz J, Strehblow A, Taschner A, Schopoff S, Pasierbek P, Jantsch MF. 2009. 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.
  • Fritzell K, Xu LD, Lagergren J, Ohman M. 2018. ADARs and editing: the role of A-to-I RNA modification in cancer progression. Semin Cell Dev Biol. 79:123–130.
  • Fu L, Qin YR, Ming XY, Zuo XB, Diao YW, Zhang LY, Ai J, Liu BL, Huang TX, Cao TT, Tan BB, et al. 2017. RNA editing of SLC22A3 drives early tumor invasion and metastasis in familial esophageal cancer. Proc Natl Acad Sci USA. 114(23):E4631–E40.
  • Gabriely G, Wurdinger T, Kesari S, Esau CC, Burchard J, Linsley PS, Krichevsky AM. 2008. MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators. Mol Cell Biol. 28:5369–5380.
  • Gacem N, Kavo A, Zerad L, Richard L, Mathis S, Kapur RP, Parisot M, Amiel J, Dufour S, de la Grange P, et al. 2020. ADAR1 mediated regulation of neural crest derived melanocytes and Schwann cell development. Nat Commun. 11:198.
  • Galardi S, Mercatelli N, Giorda E, Massalini S, Frajese GV, Ciafre SA, Farace MG. 2007. miR-221 and miR-222 expression affects the proliferation potential of human prostate carcinoma cell lines by targeting p27Kip1. J Biol Chem. 282:23716–23724.
  • Galeano F, Rossetti C, Tomaselli S, Cifaldi L, Lezzerini M, Pezzullo M, Boldrini R, Massimi L, Di Rocco CM, Locatelli F, et al. 2013. ADAR2-editing activity inhibits glioblastoma growth through the modulation of the CDC14B/Skp2/p21/p27 axis. Oncogene. 32:998–1009.
  • Galipon J, Ishii R, Suzuki Y, Tomita M, Ui-Tei K. 2017. Differential binding of three major human ADAR isoforms to coding and long non-coding transcripts. Genes. 8(2):68.
  • Gallo A, Keegan LP, Ring GM, O'Connell MA. 2003. An ADAR that edits transcripts encoding ion channel subunits functions as a dimer. Embo J. 22:3421–3430.
  • Gammon DB, Mello CC. 2015. RNA interference-mediated antiviral defense in insects. Curr Opin Insect Sci. 8:111–120.
  • Ganem NS, Ben-Asher N, Lamm AT. 2017. In cancer, A-to-I RNA editing can be the driver, the passenger, or the mechanic. Drug Resist Updat. 32:16–22.
  • Ganem NS, Ben-Asher N, Manning AC, Deffit SN, Washburn MC, Wheeler EC, Yeo GW, Zgayer OB, Mantsur E, Hundley HA, et al. 2019. Disruption in A-to-I editing levels affects C. elegans development more than a complete lack of editing. Cell Rep. 27(4):1244–1253 e4.
  • Gannon HS, Zou T, Kiessling MK, Gao GF, Cai D, Choi PS, Ivan AP, Buchumenski I, Berger AC, Goldstein JT, et al. 2018. Identification of ADAR1 adenosine deaminase dependency in a subset of cancer cells. Nat Commun. 9:5450.
  • Gantier MP, Williams BR. 2007. The response of mammalian cells to double-stranded RNA. Cytokine Growth Factor Rev. 18:363–371.
  • George CX, Samuel CE. 1999. 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.
  • Gerber A, O'Connell MA, Keller W. 1997. Two forms of human double-stranded RNA-specific editase 1 (hRED1) generated by the insertion of an Alu cassette. RNA. 3:453–463.
  • Gleghorn ML, Maquat LE. 2014. Black sheep' that don't leave the double-stranded RNA-binding domain fold. Trends Biochem Sci. 39:328–340.
  • Goodman RA, Macbeth MR, Beal PA. 2012. ADAR proteins: structure and catalytic mechanism. Curr Top Microbiol Immunol. 353:1–33.
  • 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.
  • Greenberger S, Levanon EY, Paz-Yaacov N, Barzilai A, Safran M, Osenberg S, Amariglio N, Rechavi G, Eisenberg E. 2010. Consistent levels of A-to-I RNA editing across individuals in coding sequences and non-conserved Alu repeats. BMC Genomics. 11:608.
  • Grice LF, Degnan BM. 2015. The origin of the ADAR gene family and animal RNA editing. BMC Evol Biol. 15:4.
  • Gumireddy K, Li A, Kossenkov AV, Sakurai M, Yan J, Li Y, Xu H, Wang J, Zhang PJ, Zhang L, et al. 2016. The mRNA-edited form of GABRA3 suppresses GABRA3-mediated Akt activation and breast cancer metastasis. Nat Commun. 7:10715.
  • Han J, An O, Hong H, Chan THM, Song Y, Shen H, Tang SJ, Lin JS, Ng VHE, Tay DJT, et al. 2020. Suppression of adenosine-to-inosine (A-to-I) RNA editome by death associated protein 3 (DAP3) promotes cancer progression. Sci Adv. 6:eaba5136.
  • Han L, Diao L, Yu S, Xu X, Li J, Zhang R, Yang Y, Werner HMJ, 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.
  • Han SW, Kim HP, Shin JY, Jeong EG, Lee WC, Kim KY, Park SY, Lee DW, Won JK, Jeong SY, et al. 2014. RNA editing in RHOQ promotes invasion potential in colorectal cancer. J Exp Med. 211(4):613–621.
  • 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.
  • 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.
  • Hayashi M, Suzuki T. 2013. Dyschromatosis symmetrica hereditaria. J Dermatol. 40:336–343.
  • Helwak A, Tollervey D. 2014. Mapping the miRNA interactome by cross-linking ligation and sequencing of hybrids (CLASH). Nat Protoc. 9:711–728.
  • Heraud-Farlow JE, Chalk AM, Linder SE, Li Q, Taylor S, White JM, Pang L, Liddicoat BJ, Gupte A, Li JB, et al. 2017. Protein recoding by ADAR1-mediated RNA editing is not essential for normal development and homeostasis. Genome Biol. 18:166.
  • Herbert A, Alfken J, Kim YG, Mian IS, Nishikura K, Rich A. 1997. A Z-DNA binding domain present in the human editing enzyme, double-stranded RNA adenosine deaminase. Proc Natl Acad Sci USA. 94:8421–8426.
  • Higuchi M, Maas S, Single FN, Hartner J, Rozov A, Burnashev N, Feldmeyer D, Sprengel R, Seeburg PH. 2000. Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2. Nature. 406:78–81.
  • Hoopengardner B, Bhalla T, Staber C, Reenan R. 2003. Nervous system targets of RNA editing identified by comparative genomics. Science. 301(5634):832–836.
  • Hough RF, Lingam AT, Bass BL. 1999. Caenorhabditis elegans mRNAs that encode a protein similar to ADARs derive from an operon containing six genes. Nucleic Acids Res. 27(17):3424–3432.
  • Hsiao YE, Bahn JH, Yang Y, Lin X, Tran S, Yang EW, Quinones-Valdez G, Xiao X. 2018. RNA editing in nascent RNA affects pre-mRNA splicing. Genome Res. 28(6):812–823.
  • Hu X, Chen J, Shi X, Feng F, Lau KW, Chen Y, Chen Y, Jiang L, Cui F, Zhang Y, et al. 2017. RNA editing of AZIN1 induces the malignant progression of non-small-cell lung cancers. Tumour Biol. 39(8):1010428317700001
  • Hu X, Wan S, Ou Y, Zhou B, Zhu J, Yi X, Guan Y, Jia W, Liu X, Wang Q, et al. 2015. RNA over-editing of BLCAP contributes to hepatocarcinogenesis identified by whole-genome and transcriptome sequencing. Cancer Lett. 357(2):510–519.
  • Hundley HA, Krauchuk AA, Bass BL. 2008. C. elegans and H. sapiens mRNAs with edited 3' UTRs are present on polysomes. RNA. 14:2050–2060.
  • Hung T, Pratt GA, Sundararaman B, Townsend MJ, Chaivorapol C, Bhangale T, Graham RR, Ortmann W, Criswell LA, Yeo GW, et al. 2015. The Ro60 autoantigen binds endogenous retroelements and regulates inflammatory gene expression. Science. 350:455–459.
  • Hur S. 2019. Double-stranded RNA sensors and modulators in innate immunity. Annu Rev Immunol. 37:349–375.
  • Ingleby L, Maloney R, Jepson J, Horn R, Reenan R. 2009. Regulated RNA editing and functional epistasis in Shaker potassium channels. J Gen Physiol. 133:17–27.
  • Ishizuka JJ, Manguso RT, Cheruiyot CK, Bi K, Panda A, Iracheta-Vellve A, Miller BC, Du PP, Yates KB, Dubrot J, Buchumenski I, Comstock DE, et al. 2019. Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade. Nature. 565:43–48.
  • Jacobs BL, Langland JO. 1996. When two strands are better than one: the mediators and modulators of the cellular responses to double-stranded RNA. Virology. 219:339–349.
  • Jain M, Jantsch MF, Licht K. 2019. The Editor's I on Disease Development. Trends Genet. 35:903–913.
  • Jiang T, Shi T, Zhang H, Hu J, Song Y, Wei J, Ren S, Zhou C. 2019. Tumor neoantigens: from basic research to clinical applications. J Hematol Oncol. 12:93.
  • Kapoor U, Licht K, Amman F, Jakobi T, Martin D, Dieterich C, Jantsch MF. 2020. ADAR-deficiency perturbs the global splicing landscape in mouse tissues. Genome Res. 30:1107–1118.
  • Katrekar D, Chen G, Meluzzi D, Ganesh A, Worlikar A, Shih YR, Varghese S, Mali P. 2019. In vivo RNA editing of point mutations via RNA-guided adenosine deaminases. Nat Methods. 16:239–242.
  • Kawahara Y, Zinshteyn B, Chendrimada TP, Shiekhattar R, Nishikura K. 2007. RNA editing of the microRNA-151 precursor blocks cleavage by the Dicer-TRBP complex. EMBO Rep. 8:763–769.
  • Kawahara Y, Zinshteyn B, Sethupathy P, Iizasa H, Hatzigeorgiou AG, Nishikura K. 2007. Redirection of silencing targets by adenosine-to-inosine editing of miRNAs. Science. 315:1137–1140.
  • 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.
  • Keppler A, Gendreizig S, Gronemeyer T, Pick H, Vogel H, Johnsson K. 2003. A general method for the covalent labeling of fusion proteins with small molecules in vivo. Nat Biotechnol. 21:86–89.
  • Khan A, Paro S, McGurk L, Sambrani N, Hogg MC, Brindle J, Pennetta G, Keegan LP, O'Connell MA. 2020. Membrane and synaptic defects leading to neurodegeneration in ADAR mutant drosophila are rescued by increased autophagy. BMC Biol. 18:15.
  • Kim DD, Kim TT, Walsh T, Kobayashi Y, Matise TC, Buyske S, Gabriel A. 2004. Widespread RNA editing of embedded alu elements in the human transcriptome. Genome Res. 14:1719–1725.
  • Knight SW, Bass BL. 2002. The role of RNA editing by ADARs in RNAi. Mol Cell. 10:809–817.
  • Knuutila S, Bjorkqvist AM, Autio K, Tarkkanen M, Wolf M, Monni O, Szymanska J, Larramendy ML, Tapper J, Pere H, et al. 1998. DNA copy number amplifications in human neoplasms: review of comparative genomic hybridization studies. Am J Pathol. 152:1107–1123.
  • Kondo T, Suzuki T, Mitsuhashi Y, Ito S, Kono M, Komine M, Akita H, Tomita Y. 2008. Six novel mutations of the ADAR1 gene in patients with dyschromatosis symmetrica hereditaria: histological observation and comparison of genotypes and clinical phenotypes. J Dermatol. 35:395–406.
  • Kong XY, Vik ES, Nawaz MS, Berges N, Dahl TB, Vågbø C, Suganthan R, Segers F, Holm S, Quiles-Jiménez A, et al. 2020. Deletion of Endonuclease V suppresses chemically induced hepatocellular carcinoma. Nucleic Acids Res. 48:4463–4479.
  • Kono M, Suganuma M, Akiyama M, Ito Y, Ujiie H, Morimoto K. 2014. Novel ADAR1 mutations including a single amino acid deletion in the deaminase domain underlie dyschromatosis symmetrica hereditaria in Japanese families. Int J Dermatol. 53:e194-6.
  • Krovat BC, Jantsch MF. 1996. Comparative mutational analysis of the double-stranded RNA binding domains of Xenopus laevis RNA-binding protein A. J Biol Chem. 271:28112–28119.
  • Kung CP, Cottrell KA, Ryu S, Bramel ER, Kladney RD, Bao EA, Freeman EC, Sabloak T, Maggi L, Jr., Weber JD. 2020. Evaluating the therapeutic potential of ADAR1 inhibition for triple-negative breast cancer. Oncogene.
  • Kuttan A, Bass BL. 2012. Mechanistic insights into editing-site specificity of ADARs. Proc Natl Acad Sci USA. 109:E3295–E3304.
  • Lai F, Drakas R, Nishikura K. 1995. Mutagenic analysis of double-stranded RNA adenosine deaminase, a candidate enzyme for RNA editing of glutamate-gated ion channel transcripts. J Biol Chem. 270:17098–17105.
  • Lai ML, Yang LJ, Zhu XH, Li M. 2012. A novel mutation of the DSRAD gene in a Chinese family with dyschromatosis symmetrica hereditaria. Genet Mol Res. 11:1731–1737.
  • Lamers MM, van den Hoogen BG, Haagmans BL. 2019. ADAR1: "editor-in-chief" of cytoplasmic innate immunity. Front Immunol. 10:1763.
  • Lazzari E, Mondala PK, Santos ND, Miller AC, Pineda G, Jiang Q, Leu H, Ali SA, Ganesan AP, Wu CN, et al. 2017. Alu-dependent RNA editing of GLI1 promotes malignant regeneration in multiple myeloma. Nat Commun. 8(1):1922
  • Lehmann KA, Bass BL. 1999. The importance of internal loops within RNA substrates of ADAR1. J Mol Biol. 291(1):1–13.
  • Lev-Maor G, Sorek R, Levanon EY, Paz N, Eisenberg E, Ast G. 2007. RNA-editing-mediated exon evolution. Genome Biol. 8:R29.
  • Levanon EY, Eisenberg E, Yelin R, Nemzer S, Hallegger M, Shemesh R, Fligelman ZY, Shoshan A, Pollock SR, Sztybel D, Olshansky M, et al. 2004. Systematic identification of abundant A-to-I editing sites in the human transcriptome. Nat Biotechnol. 22(8):1001–1005.
  • Li B, Han Q, Zhu Y, Yu Y, Wang J, Jiang X. 2012. Down-regulation of miR-214 contributes to intrahepatic cholangiocarcinoma metastasis by targeting Twist. Febs J. 279(13):2393–2398.
  • Liu WH, Chen CH, Yeh KH, Li CL, Wu YJ, Chen DS, Chen PJ, Yeh SH. 2013. ADAR2-mediated editing of miR-214 and miR-122 precursor and antisense RNA transcripts in liver cancers. PLoS One. 8(12):e81922
  • Liang H, Landweber LF. 2007. Hypothesis: RNA editing of microRNA target sites in humans? RNA. 13:463–467.
  • Licht K, Hartl M, Amman F, Anrather D, Janisiw MP, Jantsch MF. 2019. Inosine induces context-dependent recoding and translational stalling. Nucleic Acids Res. 47:3–14.
  • Licht K, Kapoor U, Amman F, Picardi E, Martin D, Bajad P, Jantsch MF. 2019. A high resolution A-to-I editing map in the mouse identifies editing events controlled by pre-mRNA splicing. Genome Res. 29(9):1453–1463.
  • Liddicoat BJ, Chalk AM, Walkley CR. 2016. ADAR1, inosine and the immune sensing system: distinguishing self from non-self. Wiley Interdiscip Rev RNA. 7:157–172.
  • 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. 349:1115–1120.
  • Liscovitch N, Bazak L, Levanon EY, Chechik G. 2014. Positive correlation between ADAR expression and its targets suggests a complex regulation mediated by RNA editing in the human brain. RNA Biol. 11:1447–1456.
  • Liu H, Golji J, Brodeur LK, Chung FS, Chen JT, deBeaumont RS, Bullock CP, Jones MD, Kerr G, Li L, et al. 2019. Tumor-derived IFN triggers chronic pathway agonism and sensitivity to ADAR loss. Nat Med. 25:95–102.
  • Liu Q, Jiang L, Liu WL, Kang XJ, Ao Y, Sun M, Luo Y, Song Y, Lo WH, Zhang X. 2006. Two novel mutations and evidence for haploinsufficiency of the ADAR gene in dyschromatosis symmetrica hereditaria. Br J Dermatol. 154:636–642.
  • Liu Q, Wang Z, Wu Y, Cao L, Tang Q, Xing X, Ma H, Zhang S, Luo Y. 2014. Five novel mutations in the ADAR1 gene associated with dyschromatosis symmetrica hereditaria. BMC Med Genet. 15:69.
  • Liu Y, Emeson RB, Samuel CE. 1999. Serotonin-2C receptor pre-mRNA editing in rat brain and in vitro by splice site variants of the interferon-inducible double-stranded RNA-specific adenosine deaminase ADAR1. J Biol Chem. 274:18351–18358.
  • 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 USA. 97:12541–12546.
  • 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.
  • Liu Y, Samuel CE. 1999. Editing of glutamate receptor subunit B pre-mRNA by splice-site variants of interferon-inducible double-stranded RNA-specific adenosine deaminase ADAR1. J Biol Chem. 274:5070–5077.
  • Livingston JH, Crow YJ. 2016. Neurologic phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, and IFIH1: Aicardi-Goutieres syndrome and beyond. Neuropediatrics. 47:355–360.
  • Livingston JH, Lin JP, Dale RC, Gill D, Brogan P, Munnich A, Kurian MA, Gonzalez-Martinez V, De Goede CG, Falconer A, Forte G, et al. 2014. A type I interferon signature identifies bilateral striatal necrosis due to mutations in ADAR1. J Med Genet. 51:76–82.
  • Loo YM, Gale M, Jr. 2011. Immune signaling by RIG-I-like receptors. Immunity. 34:680–692.
  • Maas S, Gommans WM. 2009a. Identification of a selective nuclear import signal in adenosine deaminases acting on RNA. Nucleic Acids Res. 37:5822–5829.
  • Maas S, Gommans WM. 2009b. Novel exon of mammalian ADAR2 extends open reading frame. PLOS One. 4:e4225.
  • Maas S, Melcher T, Herb A, Seeburg PH, Keller W, Krause S, Higuchi M, O'Connell MA. 1996. Structural requirements for RNA editing in glutamate receptor pre-mRNAs by recombinant double-stranded RNA adenosine deaminase. J Biol Chem. 271:12221–12226.
  • Maas S, Patt S, Schrey M, Rich A. 2001. Underediting of glutamate receptor GluR-B mRNA in malignant gliomas. Proc Natl Acad Sci U S A. 98(25):14687–14692.
  • Mannion NM, Greenwood SM, Young R, Cox S, Brindle J, Read D, Nellaker C, Vesely C, Ponting CP, McLaughlin PJ, Jantsch MF, et al. 2014. The RNA-editing enzyme ADAR1 controls innate immune responses to RNA. Cell Rep. 9:1482–1494.
  • 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.
  • 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.
  • Merkle T, Merz S, Reautschnig P, Blaha A, Li Q, Vogel P, Wettengel J, Li JB, Stafforst T. 2019. Precise RNA editing by recruiting endogenous ADARs with antisense oligonucleotides. Nat Biotechnol. 37:133–138.
  • Mizrahi RA, Schirle NT, Beal PA. 2013. Potent and selective inhibition of A-to-I RNA editing with 2'-O-methyl/locked nucleic acid-containing antisense oligoribonucleotides. ACS Chem Biol. 8:832–839.
  • Mladenova D, Barry G, Konen LM, Pineda SS, Guennewig B, Avesson L, Zinn R, Schonrock N, Bitar M, Jonkhout N, et al. 2018. Adar3 is involved in learning and memory in mice. Front Neurosci. 12:243.
  • Mohibi S, Chen X, Zhang J. 2019. Cancer the'RBP'eutics-RNA-binding proteins as therapeutic targets for cancer. Pharmacol Ther. 203:107390.
  • Montiel-Gonzalez MF, Diaz Quiroz JF, Rosenthal JJC. 2019. Current strategies for site-directed RNA editing using ADARs. Methods. 156:16–24.
  • Montiel-Gonzalez MF, Vallecillo-Viejo I, Yudowski GA, Rosenthal JJ. 2013. Correction of mutations within the cystic fibrosis transmembrane conductance regulator by site-directed RNA editing. Proc Natl Acad Sci USA. 110:18285–18290.
  • Montiel-Gonzalez MF, Vallecillo-Viejo IC, Rosenthal JJ. 2016. An efficient system for selectively altering genetic information within mRNAs. Nucleic Acids Res. 44:e157.
  • Moulton VR, Suarez-Fueyo A, Meidan E, Li H, Mizui M, Tsokos GC. 2017. Pathogenesis of human systemic lupus erythematosus: a cellular perspective. Trends Mol Med. 23:615–635.
  • Nakano M, Fukami T, Gotoh S, Nakajima M. 2017. A-to-I RNA Editing Up-regulates Human Dihydrofolate Reductase in Breast Cancer. J Biol Chem. 292(12):4873–4884.
  • Nanduri S, Carpick BW, Yang Y, Williams BR, Qin J. 1998. Structure of the double-stranded RNA-binding domain of the protein kinase PKR reveals the molecular basis of its dsRNA-mediated activation. Embo J. 17:5458–5465.
  • Nishikura K. 2010. Functions and regulation of RNA editing by ADAR deaminases. Annu Rev Biochem. 79:321–349.
  • Nishikura K, Yoo C, Kim U, Murray JM, Estes PA, Cash FE, Liebhaber SA. 1991. Substrate specificity of the dsRNA unwinding/modifying activity. Embo J. 10:3523–3532.
  • 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.
  • Oh DB, Kim YG, Rich A. 2002. Z-DNA-binding proteins can act as potent effectors of gene expression in vivo. Proc Natl Acad Sci USA. 99:16666–16671.
  • Ohlson J, Enstero M, Sjoberg BM, Ohman M. 2005. A method to find tissue-specific novel sites of selective adenosine deamination. Nucleic Acids Res. 33:e167.
  • 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.
  • 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.
  • Palavicini JP, Correa-Rojas RA, Rosenthal JJ. 2012. Extra double-stranded RNA binding domain (dsRBD) in a squid RNA editing enzyme confers resistance to high salt environment. J Biol Chem. 287:17754–17764.
  • Palavicini JP, O'Connell MA, Rosenthal JJ. 2009. An extra double-stranded RNA binding domain confers high activity to a squid RNA editing enzyme. RNA. 15:1208–1218.
  • 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(7):1004–1018.
  • 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.
  • Parrish S, Fire A. 2001. Distinct roles for RDE-1 and RDE-4 during RNA interference in Caenorhabditis elegans. RNA. 7:1397–1402.
  • 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.
  • Paz N, Levanon EY, Amariglio N, Heimberger AB, Ram Z, Constantini S, Barbash ZS, Adamsky K, Safran M, Hirschberg A, et al. 2007. Altered adenosine-to-inosine RNA editing in human cancer. Genome Res. 17:1586–1595.
  • 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.
  • Peng X, Xu X, Wang Y, Hawke DH, Yu S, Han L, Zhou Z, Mojumdar K, Jeong KJ, Labrie M, Tsang YH, et al. 2018. A-to-I RNA editing contributes to proteomic diversity in cancer. Cancer Cell. 33(5):817–828 e7.
  • Penn AC, Balik A, Greger IH. 2013. Steric antisense inhibition of AMPA receptor Q/R editing reveals tight coupling to intronic editing sites and splicing. Nucleic Acids Res. 41:1113–1123.
  • 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.
  • 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.
  • Pinto Y, Buchumenski I, Levanon EY, Eisenberg E. 2018. Human cancer tissues exhibit reduced A-to-I editing of miRNAs coupled with elevated editing of their targets. Nucleic Acids Res. 46:71–82.
  • Polson AG, Bass BL. 1994. Preferential selection of adenosines for modification by double-stranded RNA adenosine deaminase. Embo J. 13:5701–5711.
  • Porath HT, Schaffer AA, Kaniewska P, Alon S, Eisenberg E, Rosenthal J, Levanon EY, Levy O. 2017. A-to-I RNA editing in the earliest-diverging eumetazoan phyla. Mol Biol Evol. 34:1890–1901.
  • Poulsen H, Jorgensen R, Heding A, Nielsen FC, Bonven B, Egebjerg J. 2006. Dimerization of ADAR2 is mediated by the double-stranded RNA binding domain. RNA. 12:1350–1360.
  • 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.
  • Prasanth KV, Prasanth SG, Xuan Z, Hearn S, Freier SM, Bennett CF, Zhang MQ, Spector DL. 2005. Regulating gene expression through RNA nuclear retention. Cell. 123:249–263.
  • Qin YR, Qiao JJ, Chan TH, 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. Cancer Res. 74:840–851.
  • Quinones-Valdez G, Tran SS, Jun HI, Bahn JH, Yang EW, Zhan L, Brummer A, Wei X, Van Nostrand EL, Pratt GA, et al. 2019. Regulation of RNA editing by RNA-binding proteins in human cells. Commun Biol. 2:19.
  • Rajendren S, Manning AC, Al-Awadi H, Yamada K, Takagi Y, Hundley HA. 2018. A protein-protein interaction underlies the molecular basis for substrate recognition by an adenosine-to-inosine RNA-editing enzyme. Nucleic Acids Res. 46:9647–9659.
  • Ramirez-Moya J, Baker AR, Slack FJ, Santisteban P. 2020. ADAR1-mediated RNA editing is a novel oncogenic process in thyroid cancer and regulates miR-200 activity. Oncogene. 39(18):3738–3753.
  • 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.
  • Reich DP, Tyc KM, Bass BL. 2018. C. elegans ADARs antagonize silencing of cellular dsRNAs by the antiviral RNAi pathway. Genes Dev. 32:271–282.
  • Rice GI, Del Toro Duany Y, Jenkinson EM, Forte GM, Anderson BH, Ariaudo G, Bader-Meunier B, Baildam EM, Battini R, Beresford MW, et al. 2014. Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling. Nat Genet. 46(5):503–509.
  • 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.
  • Robert X, Gouet P. 2014. Deciphering key features in protein structures with the new ENDscript server. Nucleic Acids Res. 42:W320–4.
  • Rosenthal JJ. 2015. The emerging role of RNA editing in plasticity. J Exp Biol. 218:1812–1821.
  • Roth SH, Danan-Gotthold M, Ben-Izhak M, Rechavi G, Cohen CJ, Louzoun Y, Levanon EY. 2018. Increased RNA editing may provide a source for autoantigens in systemic lupus erythematosus. Cell Rep. 23:50–57.
  • Rueter SM, Dawson TR, Emeson RB. 1999. Regulation of alternative splicing by RNA editing. Nature. 399:75–80.
  • 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.
  • Saunders LR, Barber GN. 2003. The dsRNA binding protein family: critical roles, diverse cellular functions. FASEB J. 17:961–983.
  • Savva YA, Rieder LE, Reenan RA. 2012. The ADAR protein family. Genome Biol. 13:252.
  • 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.
  • Scadden AD. 2007. Inosine-containing dsRNA binds a stress-granule-like complex and downregulates gene expression in trans. Mol Cell. 28:491–500.
  • Scadden AD, O'Connell MA. 2005. Cleavage of dsRNAs hyper-edited by ADARs occurs at preferred editing sites. Nucleic Acids Res. 33:5954–5964.
  • Scadden AD, Smith CW. 2001. Specific cleavage of hyper-edited dsRNAs. Embo J. 20:4243–4252.
  • Schneider MF, Wettengel J, Hoffmann PC, Stafforst T. 2014. Optimal guideRNAs for re-directing deaminase activity of hADAR1 and hADAR2 in trans. Nucleic Acids Res. 42:e87.
  • Schoft VK, Schopoff S, Jantsch MF. 2007. Regulation of glutamate receptor B pre-mRNA splicing by RNA editing. Nucleic Acids Res. 35:3723–3732.
  • Sebastiani P, Montano M, Puca A, Solovieff N, Kojima T, Wang MC, Melista E, Meltzer M, Fischer SE, Andersen S, Hartley SH, et al. 2009. RNA editing genes associated with extreme old age in humans and with lifespan in C. elegans. PLOS One. 4:e8210.
  • Seth RB, Sun L, Ea CK, Chen ZJ. 2005. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell. 122:669–682.
  • Shallev L, Kopel E, Feiglin A, Leichner GS, Avni D, Sidi Y, Eisenberg E, Barzilai A, Levanon EY, Greenberger S. 2018. Decreased A-to-I RNA editing as a source of keratinocytes' dsRNA in psoriasis. RNA. 24:828–840.
  • Shevchenko G, Morris KV. 2018. All I's on the RADAR: role of ADAR in gene regulation. FEBS Lett. 592:2860–2873.
  • Shigeyasu K, Okugawa Y, Toden S, Miyoshi J, Toiyama Y, Nagasaka T, Takahashi N, Kusunoki M, Takayama T, Yamada Y, et al. 2018. AZIN1 RNA editing confers cancer stemness and enhances oncogenic potential in colorectal cancer. JCI Insight. 3(12):e99976.
  • Shimokawa T, Rahman MF, Tostar U, Sonkoly E, Stahle M, Pivarcsi A, Palaniswamy R, Zaphiropoulos PG. 2013. RNA editing of the GLI1 transcription factor modulates the output of Hedgehog signaling. RNA Biol. 10(2):321–333.
  • Shoshan E, Mobley AK, Braeuer RR, Kamiya T, Huang L, Vasquez ME, Salameh A, Lee HJ, Kim SJ, Ivan C, et al. 2015. Reduced adenosine-to-inosine miR-455-5p editing promotes melanoma growth and metastasis. Nat Cell Biol. 17(3):311–321.
  • Sinnamon JR, Kim SY, Corson GM, Song Z, Nakai H, Adelman JP, Mandel G. 2017. Site-directed RNA repair of endogenous Mecp2 RNA in neurons. Proc Natl Acad Sci USA. 114:E9395–E402.
  • Sinnamon JR, Kim SY, Fisk JR, Song Z, Nakai H, Jeng S, McWeeney SK, Mandel G. 2020. In Vivo repair of a protein underlying a neurological disorder by programmable RNA editing. Cell Rep. 32:107878.
  • Slotkin W, Nishikura K. 2013. Adenosine-to-inosine RNA editing and human disease. Genome Med. 5:105.
  • Solomon O, Oren S, Safran M, Deshet-Unger N, Akiva P, Jacob-Hirsch J, Cesarkas K, Kabesa R, Amariglio N, Unger R, et al. 2013. Global regulation of alternative splicing by adenosine deaminase acting on RNA (ADAR). RNA. 19:591–604.
  • Song IH, Kim YA, Heo SH, Park IA, Lee M, Bang WS, Park HS, Gong G, Lee HJ. 2017. ADAR1 expression is associated with tumour-infiltrating lymphocytes in triple-negative breast cancer. Tumour Biol. 39:1010428317734816.
  • Song Y, Yang W, Fu Q, Wu L, Zhao X, Zhang Y, Zhang R. 2020. irCLASH reveals RNA substrates recognized by human ADARs. Nat Struct Mol Biol. 27(4):351–362.
  • St Johnston D, Brown NH, Gall JG, Jantsch M. 1992. A conserved double-stranded RNA-binding domain. Proc Natl Acad Sci U S A. 89:10979–10983.
  • St Laurent G, Tackett MR, Nechkin S, Shtokalo D, Antonets D, Savva YA, Maloney R, Kapranov P, Lawrence CE, Reenan RA. 2013. Genome-wide analysis of A-to-I RNA editing by single-molecule sequencing in Drosophila. Nat Struct Mol Biol. 20:1333–1339.
  • Stafforst T, Schneider MF. 2012. An RNA-deaminase conjugate selectively repairs point mutations. Angew Chem Int Ed Engl. 51:11166–11169.
  • 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.
  • Stefl R, Xu M, Skrisovska L, Emeson RB, Allain FH. 2006. Structure and specific RNA binding of ADAR2 double-stranded RNA binding motifs. Structure. 14:345–355.
  • Stephens OM, Haudenschild BL, Beal PA. 2004. The binding selectivity of ADAR2's dsRBMs contributes to RNA-editing selectivity. Chem Biol. 11:1239–1250.
  • Stephens OM, Yi-Brunozzi HY, Beal PA. 2000. Analysis of the RNA-editing reaction of ADAR2 with structural and fluorescent analogues of the GluR-B R/G editing site. Biochemistry. 39:12243–12251.
  • 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.
  • Sugimoto Y, Vigilante A, Darbo E, Zirra A, Militti C, D'Ambrogio A, Luscombe NM, Ule J. 2015. hiCLIP reveals the in vivo atlas of mRNA secondary structures recognized by Staufen 1. Nature. 519:491–494.
  • Tabara H, Yigit E, Siomi H, Mello CC. 2002. The dsRNA binding protein RDE-4 interacts with RDE-1, DCR-1, and a DExH-box helicase to direct RNAi in C. elegans. Cell. 109(7):861–871.
  • Tajaddod M, Jantsch MF, Licht K. 2016. The dynamic epitranscriptome: A to I editing modulates genetic information. Chromosoma. 125:51–63.
  • Tang SJ, Shen H, An O, Hong H, Li J, Song Y, Han J, Tay DJT, Ng VHE, Bellido Molias F, et al. 2020. Cis- and trans-regulations of pre-mRNA splicing by RNA editing enzymes influence cancer development. Nat Commun. 11:799.
  • Tang ZL, Wang S, Tu C, Wang T, Ma CW, Liu Y, Xiao SX, Wang XP. 2018. Eight novel mutations of the ADAR1 gene in Chinese patients with Dyschromatosis Symmetrica Hereditaria. Genet Test Mol Biomarkers. 22(2):104–108.
  • Teoh PJ, An O, Chung TH, Chooi JY, Toh SHM, Fan S, Wang W, Koh BTH, Fullwood MJ, Ooi MG, et al. 2018. Aberrant hyperediting of the myeloma transcriptome by ADAR1 confers oncogenicity and is a marker of poor prognosis. Blood. 132(12):1304–1317.
  • Thomas JM, Beal PA. 2017. How do ADARs bind RNA? New protein-RNA structures illuminate substrate recognition by the RNA editing ADARs. Bioessays. 39(4):1600187.
  • Thuy-Boun AS, Thomas JM, Grajo HL, Palumbo CM, Park S, Nguyen LT, Fisher AJ, Beal PA. 2020. Asymmetric dimerization of adenosine deaminase acting on RNA facilitates substrate recognition. Nucleic Acids Res.
  • Tomaselli S, Galeano F, Alon S, Raho S, Galardi S, Polito VA, Presutti C, Vincenti S, Eisenberg E, Locatelli F, et al. 2015. Modulation of microRNA editing, expression and processing by ADAR2 deaminase in glioblastoma. Genome Biol. 16:5.
  • Tonkin LA, Saccomanno L, Morse DP, Brodigan T, Krause M, Bass BL. 2002. RNA editing by ADARs is important for normal behavior in Caenorhabditis elegans. Embo J. 21:6025–6035.
  • Valente L, Nishikura K. 2007. 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.
  • Vallecillo-Viejo IC, Liscovitch-Brauer N, Montiel-Gonzalez MF, Eisenberg E, Rosenthal JJC. 2018. Abundant off-target edits from site-directed RNA editing can be reduced by nuclear localization of the editing enzyme. RNA Biol. 15:104–114.
  • Velazquez-Torres G, Shoshan E, Ivan C, Huang L, Fuentes-Mattei E, Paret H, Kim SJ, Rodriguez-Aguayo C, Xie V, Brooks D, et al. 2018. A-to-I miR-378a-3p editing can prevent melanoma progression via regulation of PARVA expression. Nat Commun. 9(1):461.
  • Vik ES, Nawaz MS, Strøm Andersen P, Fladeby C, Bjørås M, Dalhus B, Alseth I. 2013. Endonuclease V cleaves at inosines in RNA. Nat Commun. 4:2271.
  • Vitali P, Scadden AD. 2010. Double-stranded RNAs containing multiple IU pairs are sufficient to suppress interferon induction and apoptosis. Nat Struct Mol Biol. 17:1043–1050.
  • Wahlstedt H, Ohman M. 2011. Site-selective versus promiscuous A-to-I editing. Wiley Interdiscip Rev RNA. 2:761–771.
  • Walkley CR, Li JB. 2017. Rewriting the transcriptome: adenosine-to-inosine RNA editing by ADARs. Genome Biol. 18:205.
  • Wang P, Yu S, Liu J, Zhang D, Kang X. 2019. Seven novel mutations of ADAR in multi-ethnic pedigrees with Dyschromatosis symmetrica hereditaria in China. Mol Genet Genomic Med. 7:e00905.
  • Wang Q, Hui H, Guo Z, Zhang W, Hu Y, He T, Tai Y, Peng P, Wang L. 2013. ADAR1 regulates ARHGAP26 gene expression through RNA editing by disrupting miR-30b-3p and miR-573 binding. RNA. 19:1525–1536.
  • 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.
  • Wang Q, Zhang Z, Blackwell K, Carmichael GG. 2005. Vigilins bind to promiscuously A-to-I-edited RNAs and are involved in the formation of heterochromatin. Curr Biol. 15:384–391.
  • Wang R, Zhang S, Chen X, Li N, Li J, Jia R, Pan Y, Liang H. 2018. CircNT5E acts as a sponge of miR-422a to promote glioblastoma tumorigenesis. Cancer Res. 78:4812–4825.
  • Wang Y, Chung DH, Monteleone LR, Li J, Chiang Y, Toney MD, Beal PA. 2019. RNA binding candidates for human ADAR3 from substrates of a gain of function mutant expressed in neuronal cells. Nucleic Acids Res. 47:10801–10814.
  • Wang Y, Park S, Beal PA. 2018. Selective recognition of RNA substrates by ADAR deaminase domains. Biochemistry. 57:1640–1651.
  • Wang Y, Xu X, Yu S, Jeong KJ, Zhou Z, Han L, Tsang YH, Li J, Chen H, Mangala LS, et al. 2017. Systematic characterization of A-to-I RNA editing hotspots in microRNAs across human cancers. Genome Res. 27:1112–1125.
  • Wang Y, Zheng Y, Beal PA. 2017. Adenosine deaminases that act on RNA (ADARs). Enzymes. 41:215–268.
  • Ward SV, George CX, Welch MJ, Liou LY, Hahm B, Lewicki H, de la Torre JC, Samuel CE, Oldstone MB. 2011. RNA editing enzyme adenosine deaminase is a restriction factor for controlling measles virus replication that also is required for embryogenesis. Proc Natl Acad Sci USA. 108:331–336.
  • Warf MB, Shepherd BA, Johnson WE, Bass BL. 2012. Effects of ADARs on small RNA processing pathways in C. elegans. Genome Res. 22:1488–1498.
  • Washburn MC, Hundley HA. 2016. Trans and cis factors affecting A-to-I RNA editing efficiency of a noncoding editing target in C. elegans. RNA. 22:722–728.
  • Washburn MC, Kakaradov B, Sundararaman B, Wheeler E, Hoon S, Yeo GW, Hundley HA. 2014. The dsRBP and inactive editor ADR-1 utilizes dsRNA binding to regulate A-to-I RNA editing across the C. elegans transcriptome. Cell Rep. 6:599–607.
  • Weber F, Wagner V, Rasmussen SB, Hartmann R, Paludan SR. 2006. Double-stranded RNA is produced by positive-strand RNA viruses and DNA viruses but not in detectable amounts by negative-strand RNA viruses. J Virol. 80:5059–5064.
  • Wettengel J, Reautschnig P, Geisler S, Kahle PJ, Stafforst T. 2017. Harnessing human ADAR2 for RNA repair - Recoding a PINK1 mutation rescues mitophagy. Nucleic Acids Res. 45:2797–2808.
  • Wheeler EC, Washburn MC, Major F, Rusch DB, Hundley HA. 2015. Noncoding regions of C. elegans mRNA undergo selective adenosine to inosine deamination and contain a small number of editing sites per transcript. RNA Biol. 12:162–174.
  • Wolozin B, Ivanov P. 2019. Stress granules and neurodegeneration. Nat Rev Neurosci. 20:649–666.
  • Woolf TM, Chase JM, Stinchcomb DT. 1995. Toward the therapeutic editing of mutated RNA sequences. Proc Natl Acad Sci U S A. 92:8298–8302.
  • Xing Q, Wang M, Chen X, Qian X, Qin W, Gao J, Wu S, Gao R, Feng G, He L. 2005. Identification of a novel ADAR mutation in a Chinese family with dyschromatosis symmetrica hereditaria (DSH). Arch Dermatol Res. 297:139–142.
  • Xu X, Wang Y, Mojumdar K, Zhou Z, Jeong KJ, Mangala LS, Yu S, Tsang YH, Rodriguez-Aguayo C, Lu Y, et al. 2019. A-to-I-edited miRNA-379-5p inhibits cancer cell proliferation through CD97-induced apoptosis. J Clin Invest. 129:5343–5356.
  • Yang CC, Chen YT, Chang YF, Liu H, Kuo YP, Shih CT, Liao WC, Chen HW, Tsai WS, Tan BC. 2017. ADAR1-mediated 3' UTR editing and expression control of antiapoptosis genes fine-tunes cellular apoptosis response. Cell Death Dis. 8:e2833.
  • Yang S, Deng P, Zhu Z, Zhu J, Wang G, Zhang L, Chen AF, Wang T, Sarkar SN, Billiar TR, et al. 2014. 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.
  • Yang W, Chendrimada TP, Wang Q, Higuchi M, Seeburg PH, Shiekhattar R, Nishikura K. 2006. Modulation of microRNA processing and expression through RNA editing by ADAR deaminases. Nat Struct Mol Biol. 13:13–21.
  • Zhang M, Fritsche J, Roszik J, Williams LJ, Peng X, Chiu Y, Tsou CC, Hoffgaard F, Goldfinger V, Schoor O, et al. 2018. RNA editing derived epitopes function as cancer antigens to elicit immune responses. Nat Commun. 9:3919.
  • Zhang XJ, He PP, Li M, He CD, Yan KL, Cui Y, Yang S, Zhang KY, Gao M, Chen JJ, et al. 2004. Seven novel mutations of the ADAR gene in Chinese families and sporadic patients with dyschromatosis symmetrica hereditaria (DSH). Hum Mutat. 23:629–630.
  • Zhang Y, Wang K, Zhao Z, Sun S, Zhang K, Huang R, Zeng F, Hu H. 2018. ADAR3 expression is an independent prognostic factor in lower-grade diffuse gliomas and positively correlated with the editing level of GRIA2(Q607R). Cancer Cell Int. 18:196.
  • Zhang Z, Carmichael GG. 2001. The fate of dsRNA in the nucleus: a p54(nrb)-containing complex mediates the nuclear retention of promiscuously A-to-I edited RNAs. Cell. 106:465–475.

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