Adenosine-to-inosine RNA editing in cancer: molecular mechanisms and downstream targets

Abstract

Adenosine-to-inosine (A-to-I), one of the most prevalent RNA modifications, has recently garnered significant attention. The A-to-I modification actively contributes to biological and pathological processes by affecting the structure and function of various RNA molecules, including double-stranded RNA, transfer RNA, microRNA, and viral RNA. Increasing evidence suggests that A-to-I plays a crucial role in the development of human disease, particularly in cancer, and aberrant A-to-I levels are closely associated with tumorigenesis and progression through regulation of the expression of multiple oncogenes and tumor suppressor genes. Currently, the underlying molecular mechanisms of A-to-I modification in cancer are not comprehensively understood. Here, we review the latest advances regarding the A-to-I editing pathways implicated in cancer, describing their biological functions and their connections to the disease.

Keywords

adenosine-to-inosine (A-to-I) / RNA modification / ADARs / ADATs / cancer

References

[1] Abrahamsson AE, Geron I, Gotlib J et al. Glycogen synthase kinase 3beta missplicing contributes to leukemia stem cell generation. Proc Natl Acad Sci USA 2009;106:3925–3929.

[2] Amin EM, Liu Y, Deng S et al. The RNA-editing enzyme ADAR promotes lung adenocarcinoma migration and invasion by stabilizing FAK. Sci Signaling 2017;10:eaah3941.

[3] Anadón C, Guil S, Simó-Riudalbas L et al. Gene amplification-associated overexpression of the RNA editing enzyme ADAR1 enhances human lung tumorigenesis. Oncogene 2016;35:4407–4413.

[4] Anantharaman A, Tripathi V, Khan A et al. ADAR2 regulates RNA stability by modifying access of decay-promoting RNA-binding proteins. Nucleic Acids Res 2017;45:4189–4201.

[5] Ashley CN, Broni E, Miller WA. ADAR family proteins: a structural review. Curr Issues Mol Biol 2024;46:3919–3945.

[6] Austin RJ, Xia T, Ren J et al. Designed arginine-rich RNA-binding peptides with picomolar affinity. J Am Chem Soc 2002;124:10966–10967.

[7] Azizian NG, Li Y. XPO1-dependent nuclear export as a target for cancer therapy. J Hematol Oncol 2020;13:61.

[8] Bahn JH, Lee J-H, Li G et al. Accurate identification of A-to-I RNA editing in human by transcriptome sequencing. Genome Res 2012;22:142–150.

[9] Baker AR, Slack FJ. ADAR1 and its implications in cancer development and treatment. Trends Genet: TIG 2022;38:821–830.

[10] Baker AR, Miliotis C, Ramírez-Moya J et al. Transcriptome profiling of ADAR1 targets in triple-negative breast cancer cells reveals mechanisms for regulating growth and invasion. Mol Cancer Res: MCR 2022;20:960–971.

[11] Barbieri I, Kouzarides T. Role of RNA modifications in cancer. Nat Rev Cancer 2020;20:303–322.

[12] Baron-Benhamou J, Gehring NH, Kulozik AE et al. Using the lambdaN peptide to tether proteins to RNAs. Methods Mol Biol (Clifton, NJ) 2004;257:135–154.

[13] Barraud P, Banerjee S, Mohamed WI et al. 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 2014;111:E1852–E1861.

[14] Bass BL. RNA editing by adenosine deaminases that act on RNA. Annu Rev Biochem 2002;71:817–846.

[15] Bass BL, Weintraub H. An unwinding activity that covalently modifies its double-stranded RNA substrate. Cell 1988;55:1089–1098.

[16] Bazak L, Haviv A, Barak M et al. A-to-I RNA editing occurs at over a hundred million genomic sites, located in a majority of human genes. Genome Res 2014;24:365–376.

[17] Becker HF, Corda Y, Mathews MB et al. Inosine and N1-methylinosine within a synthetic oligomer mimicking the anticodon loop of human tRNA(Ala) are major epitopes for anti-PL-12 myositis autoantibodies. RNA (New York, NY) 1999;5:865–875.

[18] Behm M, Wahlstedt H, Widmark A et al. Accumulation of nuclear ADAR2 regulates adenosine-to-inosine RNA editing during neuronal development. J Cell Sci 2017;130:745–753.

[19] Björk GR, Jacobsson K, Nilsson K et al. A primordial tRNA modification required for the evolution of life? EMBO J 2001;20:231–239.

[20] Boccaletto P, Machnicka MA, Purta E et al. MODOMICS: a database of RNA modification pathways. 2017 update. Nucleic Acids Res 2018;46:D303–D307.

[21] Borchert GM, Gilmore BL, Spengler RM et al. Adenosine deamination in human transcripts generates novel microRNA binding sites. Hum Mol Genet 2009;18:4801–4807.

[22] Bornelöv S, Selmi T, Flad S et al. Codon usage optimization in pluripotent embryonic stem cells. Genome Biol 2019;20:119.

[23] Boulay K, Ghram M, Viranaicken W et al. Cell cycle-dependent regulation of the RNA-binding protein Staufen1. Nucleic Acids Res 2014;42:7867–7883.

[24] Chan THM, Lin CH, Qi L et al. A disrupted RNA editing balance mediated by ADARs (adenosine deaminases that act on RNA) in human hepatocellular carcinoma. Gut 2014;63:832–843.

[25] Chan CTY, Deng W, Li F et al. Highly predictive reprogramming of tRNA modifications is linked to selective expression of codon-biased genes. Chem Res Toxicol 2015;28:978–988.

[26] Chan THM, Qamra A, Tan KT et al. ADAR-mediated RNA editing predicts progression and prognosis of gastric cancer. Gastroenterology 2016;151:637–650.e10.

[27] Chari A, Vogl DT, Gavriatopoulou M et al. Oral Selinexor-dexamethasone for triple-class refractory multiple myeloma. N Engl J Med 2019;381:727–738.

[28] Chen YG, Hur S. Cellular origins of dsRNA, their recognition and consequences. Nat Rev Mol Cell Biol 2022;23:286–301.

[29] Chen L-L, Yang L. Regulation of circRNA biogenesis. RNA Biology 2015;12:381–388.

[30] Chen CX, Cho DS, Wang Q et al. A third member of the RNA-specific adenosine deaminase gene family, ADAR3, contains both single-and double-stranded RNA binding domains. RNA (New York, NY) 2000;6:755–767.

[31] Chen L-L, DeCerbo JN, Carmichael GG. Alu element-mediated gene silencing. EMBO J 2008;27:1694–1705.

[32] Chen L, Li Y, Lin CH et al. Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma. Nat Med 2013;19:209–216.

[33] Chen W, He W, Cai H et al. A-to-I RNA editing of BLCAP lost the inhibition to STAT3 activation in cervical cancer. Oncotarget 2017a;8:39417–39429.

[34] Chen Y-B, Liao X-Y, Zhang J-B et al. ADAR2 functions as a tumor suppressor via editing IGFBP7 in esophageal squamous cell carcinoma. Int J Oncol 2017b;50:622–630.

[35] Chen R, Ishak CA, De Carvalho DD. Endogenous retroelements and the viral mimicry response in cancer therapy and cellular homeostasis. Cancer Discov 2021;11:2707–2725.

[36] Choudhry H. High-throughput screening to identify potential inhibitors of the Zα domain of the adenosine deaminase 1 (ADAR1). Saudi J Biol Sci 2021;28:6297–6304.

[37] Choudhury Y, Tay FC, Lam DH et al. Attenuated adenosine-to-inosine editing of microRNA-376a* promotes invasiveness of glioblastoma cells. J Clin Invest 2012;122:4059–4076.

[38] Chung H, Calis JJA, Wu X et al. Human ADAR1 prevents endogenous RNA from triggering translational shutdown. Cell 2018;172:811–824.

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

[40] Crawford Parks TE, Marcellus KA, Langill J et al. Novel roles for Staufen1 in embryonal and alveolar rhabdomyosarcoma via c-myc-dependent and -independent events. Sci Rep 2017;7:42342.

[41] Crews LA, Ma W, Ladel L et al. Reversal of malignant ADAR1 splice isoform switching with rebecsinib. Cell Stem Cell 2023;30:250–263.e6.

[42] Crick FH. Codon—anticodon pairing: the wobble hypothesis. J Mol Biol 1966;19:548–555.

[43] Dai S, Liu M, Liu M et al. Population-based genetic analysis in infertile men reveals novel mutations of ADAD family members in patients with impaired spermatogenesis. Hum Mol Genet 2023;32:1814–1825.

[44] Darwish C, Farina K, Tremblay D. The core concepts of core binding factor acute myeloid leukemia: current considerations for prognosis and treatment. Blood Rev 2023;62:101117.

[45] Datta R, Adamska JZ, Bhate A et al. A-to-I RNA editing by ADAR and its therapeutic applications: from viral infections to cancer immunotherapy. Wiley Interdiscip Rev RNA 2023;15:e1817.

[46] Deiuliis JA. MicroRNAs as regulators of metabolic disease: pathophysiologic significance and emerging role as biomarkers and therapeutics. Int J Obes (Lond) 2016;40:88–101.

[47] de Reuver R, Maelfait J. Novel insights into double-stranded RNA-mediated immunopathology. Nat Rev Immunol 2023;24:235–249.

[48] Desterro JMP, Keegan LP, Lafarga M et al. Dynamic association of RNA-editing enzymes with the nucleolus. J Cell Sci 2003;116:1805–1818.

[49] Dixit S, Henderson JC, Alfonzo JD. Multi-substrate specificity and the evolutionary basis for interdependence in tRNA editing and methylation enzymes. Front Genet 2019;10:104.

[50] Dou N, Yu S, Ye X et al. Aberrant overexpression of ADAR1 promotes gastric cancer progression by activating mTOR/p70S6K signaling. Oncotarget 2016;7:86161–86173.

[51] Droogmans L, Roovers M, Bujnicki JM et al. Cloning and characterization of tRNA (m1A58) methyltransferase (TrmI) from Thermus thermophilus HB27, a protein required for cell growth at extreme temperatures. Nucleic Acids Res 2003;31:2148–2156.

[52] Edmonds CG, Crain PF, Gupta R et al. Posttranscriptional modification of tRNA in thermophilic archaea (Archaebacteria). J Bacteriol 1991;173:3138–3148.

[53] Eisenberg E, Levanon EY. A-to-I RNA editing —immune protector and transcriptome diversifier. Nat Rev Genet 2018;19:473–490.

[54] Elias Y, Huang RH. Biochemical and structural studies of A-to-I editing by tRNA:A34 deaminases at the wobble position of transfer RNA. Biochemistry 2005;44:12057–12065.

[55] Fan XC, Steitz JA. Overexpression of HuR, a nuclear-cytoplasmic shuttling protein, increases the in vivo stability of ARE-containing mRNAs. EMBO J 1998;17:3448–3460.

[56] Fink EC, Ebert BL. The novel mechanism of lenalidomide activity. Blood 2015;126:2366–2369.

[57] Flippot R, Beinse G, Boilève A et al. Long non-coding RNAs in genitourinary malignancies: a whole new world. Nat Rev Urol 2019;16:484–504.

[58] Fritz J, Strehblow A, Taschner A et al. RNA-regulated interaction of transportin-1 and exportin-5 with the double-stranded RNA-binding domain regulates nucleocytoplasmic shuttling of ADAR1. Mol Cell Biol 2009;29:1487–1497.

[59] Fu L, Qin Y-R, Ming X-Y et al. RNA editing of SLC22A3 drives early tumor invasion and metastasis in familial esophageal cancer. Proc Natl Acad Sci USA 2017;114:E4631–E4640.

[60] Galeano F, Rossetti C, Tomaselli S et al. ADAR2-editing activity inhibits glioblastoma growth through the modulation of the CDC14B/Skp2/p21/p27 axis. Oncogene 2013;32:998–1009.

[61] Gommans WM, Mullen SP, Maas S. RNA editing: a driving force for adaptive evolution? BioEssays 2009;31:1137–1145.

[62] Gong C, Maquat LE. lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3′ UTRs via Alu elements. Nature 2011;470:284–288.

[63] Gravina GL, Senapedis W, McCauley D et al. Nucleo-cytoplasmic transport as a therapeutic target of cancer. J Hematol Oncol 2014;7:85.

[64] Grosjean H, Constantinesco F, Foiret D et al. A novel enzymatic pathway leading to 1-methylinosine modification in Haloferax volcanii tRNA. Nucleic Acids Res 1995;23:4312–4319.

[65] Grosjean H, Auxilien S, Constantinesco F et al. Enzymatic conversion of adenosine to inosine and to N1-methylinosine in transfer RNAs: a review. Biochimie 1996;78:488–501.

[66] Gumireddy K, Li A, Kossenkov AV et al. The mRNA-edited form of GABRA3 suppresses GABRA3-mediated Akt activation and breast cancer metastasis. Nat Commun 2016;7:10715.

[67] Guo M, Chan HMT, Zhou Q-L et al. Core binding factor fusion downregulation of ADAR2 RNA editing contributes to AML leukemogenesis. Blood 2023;141:3078–3090.

[68] Han F, Hu M, Zhang L et al. A-to-I RNA editing of BLCAP promotes cell proliferation by losing the inhibitory of Rb1 in colorectal cancer. Exp Cell Res 2022;417:113209.

[69] Hariharan A, Qi W, Rehrauer H et al. Heterogeneous RNA editing and influence of ADAR2 on mesothelioma chemoresistance and the tumor microenvironment. Mol Oncol 2022;16:3949–3974.

[70] Herbert A, Alfken J, Kim YG et al. A Z-DNA binding domain present in the human editing enzyme, double-stranded RNA adenosine deaminase. Proc Natl Acad Sci USA 1997;94:8421–8426.

[71] Hogg M, Paro S, Keegan LP et al. RNA editing by mammalian ADARs. Adv Genet 2011;73:87–120.

[72] Hong X, Wei Z, He L et al. High-throughput virtual screening to identify potential small molecule inhibitors of the Zα domain of the adenosine deaminases acting on RNA 1(ADAR1). Eur J Pharm Sci 2024;193:106672.

[73] Ishizuka JJ, Manguso RT, Cheruiyot CK et al. Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade. Nature 2019;565:43–48.

[74] Islam KN, Ajao A, Venkataramani K et al. The RNA-binding protein Adad1 is necessary for germ cell maintenance and meiosis in zebrafish. PLoS Genet 2023;19:e1010589.

[75] Ivanov A, Memczak S, Wyler E et al. Analysis of intron sequences reveals hallmarks of circular RNA biogenesis in animals. Cell Reports 2015;10:170–177.

[76] Jarmoskaite I, Li JB. Multifaceted roles of RNA editing enzyme ADAR1 in innate immunity. RNA 2024;30:500–511.

[77] Jiang Q, Crews LA, Barrett CL et al. ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia. Proc Natl Acad Sci USA 2013;110:1041–1046.

[78] Jiang Q, Isquith J, Zipeto MA et al. Hyper-editing of cell-cycle regulatory and tumor suppressor RNA promotes malignant progenitor propagation. Cancer Cell 2019;35:81–94. e7.

[79] Jiang L, Park MJ, Cho CJ et al. ADAR1 suppresses interferon signaling in gastric cancer cells by microRNA-302a-mediated IRF9/STAT1 regulation. Int J Mol Sci 2020;21:6195.

[80] Jiao H, Wachsmuth L, Wolf S et al. ADAR1 averts fatal type I interferon induction by ZBP1. Nature 2022;607:776–783.

[81] Jühling F, Mörl M, Hartmann RK et al. tRNAdb 2009: compilation of tRNA sequences and tRNA genes. Nucleic Acids Res 2009;37:D159–D162.

[82] Karki R, Sundaram B, Sharma BR et al. ADAR1 restricts ZBP1-mediated immune response and PANoptosis to promote tumorigenesis. Cell Reports 2021;37:109858.

[83] Katrekar D, Xiang Y, Palmer N et al. Comprehensive interrogation of the ADAR2 deaminase domain for engineering enhanced RNA editing activity and specificity. ELife 2022;11:e75555.

[84] Keegan LP, Hajji K, O’Connell MA. Adenosine deaminase acting on RNA (ADAR) enzymes: a journey from weird to wondrous. Acc Chem Res 2023;56:3165–3174.

[85] Keryer-Bibens C, Barreau C, Osborne HB. Tethering of proteins to RNAs by bacteriophage proteins. Biol Cell 2008;100:125–138.

[86] Kim SH, Quigley GJ, Suddath FL et al. Three-dimensional structure of yeast phenylalanine transfer RNA: folding of the polynucleotide chain. Science (New York, NY) 1973;179:285–288.

[87] Kim HS, Na MJ, Son KH et al. ADAR1-dependent miR-3144-3p editing simultaneously induces MSI2 expression and suppresses SLC38A4 expression in liver cancer. Exp Mol Med 2023;55:95–107.

[88] Klinge S, Woolford JL. Ribosome assembly coming into focus. Nat Rev Mol Cell Biol 2019;20:116–131.

[89] Kotla V, Goel S, Nischal S et al. Mechanism of action of lenalidomide in hematological malignancies. J Hematol Oncol 2009;2:36.

[90] Kubo M, Imanaka T. mRNA secondary structure in an open reading frame reduces translation efficiency in Bacillus subtilis. J Bacteriol 1989;171:4080–4082.

[91] Kuriakose T, Man SM, Malireddi RKS et al. ZBP1/DAI is an innate sensor of influenza virus triggering the NLRP3 inflammasome and programmed cell death pathways. Sci Immunol 2016;1:aag2045.

[92] Lazzari E, Mondala PK, Santos ND et al. Alu-dependent RNA editing of GLI1 promotes malignant regeneration in multiple myeloma. Nat Commun 2017;8:1922.

[93] Levanon EY, Eisenberg E, Yelin R et al. Systematic identification of abundant A-to-I editing sites in the human transcriptome. Nat Biotechnol 2004;22:1001–1005.

[94] Levanon EY, Cohen-Fultheim R, Eisenberg E. In search of critical dsRNA targets of ADAR1. Trends Genet: TIG 2024;40:250–259.

[95] Lev-Maor G, Sorek R, Levanon EY et al. RNA-editing-mediated exon evolution. Genome Biol 2007;8:R29.

[96] Li S, Mason CE. The pivotal regulatory landscape of RNA modifications. Annu Rev Genomics Hum Genet 2014;15:127–150.

[97] Li M, Yan C, Jiao Y et al. Site-directed RNA editing by harnessing ADARs: advances and challenges. Funct Integr Genomics 2022a;22:1089–1103.

[98] Li Q, Gloudemans MJ, Geisinger JM et al. RNA editing underlies genetic risk of common inflammatory diseases. Nature 2022b;608:569–577.

[99] Li Y, Wang N-X, Yin C et al. RNA editing enzyme ADAR1 regulates METTL3 in an editing dependent manner to promote breast cancer progression via METTL3/ARHGAP5/YTHDF1 axis. Int J Mol Sci 2022c;23:9656.

[100] Liang H, Landweber LF. Hypothesis: RNA editing of microRNA target sites in humans? RNA 2007;13:463–467.

[101] Licht K, Hartl M, Amman F et al. Inosine induces context-dependent recoding and translational stalling. Nucleic Acids Res 2019;47:3–14.

[102] Liu H, Golji J, Brodeur LK et al. Tumor-derived IFN triggers chronic pathway agonism and sensitivity to ADAR loss. Nat Med 2019;25:95–102.

[103] Liu J, Wang F, Zhang Y et al. ADAR1-mediated RNA editing and its role in cancer. Front Cell Dev Biol 2022;10:956649.

[104] López de Silanes I, Fan J, Yang X et al. Role of the RNA-binding protein HuR in colon carcinogenesis. Oncogene 2003;22:7146–7154.

[105] Lu Y, Nagamori I, Kobayashi H et al. ADAD2 functions in spermiogenesis and piRNA biogenesis in mice. Andrology 2023;11:698–709.

[106] Lyons SM, Fay MM, Ivanov P. The role of RNA modifications in the regulation of tRNA cleavage. FEBS Lett 2018;592:2828–2844.

[107] Lyu X, Yang Q, Li L et al. Adaptation of codon usage to tRNA I34 modification controls translation kinetics and proteome landscape. PLoS Genet 2020;16:e1008836.

[108] Ma C, Wang X, Yang F et al. Circular RNA hsa_circ_0004872 inhibits gastric cancer progression via the miR-224/Smad4/ADAR1 successive regulatory circuit. Mol Cancer 2020;19:157.

[109] Maas S, Gommans WM. Identification of a selective nuclear import signal in adenosine deaminases acting on RNA. Nucleic Acids Res 2009;37:5822–5829.

[110] Maas S, Gerber AP, Rich A. Identification and characterization of a human tRNA-specific adenosine deaminase related to the ADAR family of pre-mRNA editing enzymes. Proc Natl Acad Sci USA 1999;96:8895–8900.

[111] Machnicka MA, Milanowska K, Osman Oglou O et al. MODOMICS: a database of RNA modification pathways—2013 update. Nucleic Acids Res 2013;41:D262–D267.

[112] Mallela A, Nishikura K. A-to-I editing of protein coding and noncoding RNAs. Crit Rev Biochem Mol Biol 2012;47:493–501.

[113] Marcucci R, Brindle J, Paro S et al. Pin1 and WWP2 regulate GluR2 Q/R site RNA editing by ADAR2 with opposing effects. EMBO J 2011;30:4211–4222.

[114] McKenney KM, Rubio MAT, Alfonzo JD. The evolution of substrate specificity by tRNA modification enzymes. The Enzymes 2017;41:51–88.

[115] Meisner N-C, Hackermüller J, Uhl V et al. mRNA openers and closers: modulating AU-rich element-controlled mRNA stability by a molecular switch in mRNA secondary structure. Chembiochem 2004;5:1432–1447.

[116] Mendoza HG, Matos VJ, Park S et al. Selective inhibition of ADAR1 using 8-azanebularine-modified RNA duplexes. Biochemistry 2023;62:1376–1387.

[117] Montiel-Gonzalez MF, Vallecillo-Viejo I, Yudowski GA et al. Correction of mutations within the cystic fibrosis transmembrane conductance regulator by site-directed RNA editing. Proc Natl Acad Sci USA 2013;110:18285–18290.

[118] Montiel-González MF, Vallecillo-Viejo IC, Rosenthal JJC. An efficient system for selectively altering genetic information within mRNAs. Nucleic Acids Res 2016;44:e157.

[119] Nakamura K, Shigeyasu K, Okamoto K et al. ADAR1 and AZIN1 RNA editing function as an oncogene and contributes to immortalization in endometrial cancer. Gynecol Oncol 2022;166:326–333.

[120] Nakano M, Fukami T, Gotoh S et al. A-to-I RNA editing up-regulates human dihydrofolate reductase in breast cancer. J Biol Chem 2017;292:4873–4884.

[121] Nemlich Y, Greenberg E, Ortenberg R et al. MicroRNA-mediated loss of ADAR1 in metastatic melanoma promotes tumor growth. J Clin Invest 2013;123:2703–2718.

[122] Nemlich Y, Baruch EN, Besser MJ et al. ADAR1-mediated regulation of melanoma invasion. Nat Commun 2018;9:2154.

[123] Nemlich Y, Besser MJ, Schachter J et al. ADAR1 regulates melanoma cell invasiveness by controlling beta3-integrin via microRNA-30 family members. Am J Cancer Res 2020;10:2677–2686.

[124] Nishikura K. Functions and regulation of RNA editing by ADAR deaminases. Annu Rev Biochem 2010;79:321–349.

[125] Nishikura K. A-to-I editing of coding and non-coding RNAs by ADARs. Nat Rev Mol Cell Biol 2016;17:83–96.

[126] Novoa EM, Ribas de Pouplana L. Speeding with control: codon usage, tRNAs, and ribosomes. Trends Genet: TIG 2012;28:574–581.

[127] Oakes E, Anderson A, Cohen-Gadol A et al. Adenosine deaminase that acts on RNA 3 (ADAR3) binding to glutamate receptor subunit B pre-mRNA inhibits RNA editing in glioblastoma. J Biol Chem 2017;292:4326–4335.

[128] Ota H, Sakurai M, Gupta R et al. ADAR1 forms a complex with dicer to promote microRNA processing and RNA-induced gene silencing. Cell 2013;153:575–589.

[129] Parmley JL, Huynen MA. Clustering of codons with rare cognate tRNAs in human genes suggests an extra level of expression regulation. PLoS Genet 2009;5:e1000548.

[130] Patterson JB, Samuel CE. 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 1995;15:5376–5388.

[131] Peng Z, Cheng Y, Tan BC-M et al. Comprehensive analysis of RNA-seq data reveals extensive RNA editing in a human transcriptome. Nat Biotechnol 2012;30:253–260.

[132] Phizicky EM, Hopper AK. tRNA biology charges to the front. Genes Develop 2010;24:1832–1860.

[133] Picardi E, Manzari C, Mastropasqua F et al. Profiling RNA editing in human tissues: towards the inosinome Atlas. Sci Rep 2015;5:14941.

[134] Polson AG, Bass BL, Casey JL. RNA editing of hepatitis delta virus antigenome by dsRNA-adenosine deaminase. Nature 1996;380:454–456.

[135] Porath HT, Carmi S, Levanon EY. A genome-wide map of hyper-edited RNA reveals numerous new sites. Nat Commun 2014;5:4726.

[136] Poulsen H, Nilsson J, Damgaard CK et al. CRM1 mediates the export of ADAR1 through a nuclear export signal within the Z-DNA binding domain. Mol Cell Biol 2001;21:7862–7871.

[137] Qian CJ, He YS, Guo T et al. ADAR-mediated RNA editing regulates PVR immune checkpoint in colorectal cancer. Biochem Biophys Res Commun 2024;695:149373.

[138] Qin Y-R, Qiao J-J, Chan THM et al. Adenosine-to-inosine RNA editing mediated by ADARs in esophageal squamous cell carcinoma. Cancer Res 2014;74:840–851.

[139] Qu L, Yi Z, Zhu S et al. Programmable RNA editing by recruiting endogenous ADAR using engineered RNAs. Nat Biotechnol 2019;37:1059–1069.

[140] Rafels-Ybern A, Torres AG, Camacho N et al. The expansion of inosine at the wobble position of tRNAs, and its role in the evolution of proteomes. Mol Biol Evol 2019;36:650–662.

[141] Raghava Kurup R, Oakes EK, Vadlamani P et al. ADAR3 activates NF-κB signaling and promotes glioblastoma cell resistance to temozolomide. Sci Rep 2022;12:13362.

[142] Ramaswami G, Li JB. RADAR: a rigorously annotated database of A-to-I RNA editing. Nucleic Acids Res 2014;42:D109–D113.

[143] Ramaswami G, Lin W, Piskol R et al. Accurate identification of human Alu and non-Alu RNA editing sites. Nat Methods 2012;9:579–581.

[144] Ramírez-Moya J, Baker AR, Slack FJ et al. ADAR1-mediated RNA editing is a novel oncogenic process in thyroid cancer and regulates miR-200 activity. Oncogene 2020;39:3738–3753.

[145] Ramírez-Moya J, Miliotis C, Baker AR et al. An ADAR1-dependent RNA editing event in the cyclin-dependent kinase CDK13 promotes thyroid cancer hallmarks. Mol Cancer 2021;20:115.

[146] Reautschnig P, Wahn N, Wettengel J et al. CLUSTER guide RNAs enable precise and efficient RNA editing with endogenous ADAR enzymes in vivo. Nat Biotechnol 2022;40:759–768.

[147] Rebagliati MR, Melton DA. Antisense RNA injections in fertilized frog eggs reveal an RNA duplex unwinding activity. Cell 1987;48:599–605.

[148] Roberts JT, Patterson DG, King VM et al. ADAR mediated RNA editing modulates MicroRNA targeting in human breast cancer. Processes (Basel, Switzerland) 2018;6:42.

[149] Roundtree IA, He C. RNA epigenetics—chemical messages for posttranscriptional gene regulation. Curr Opin Chem Biol 2016;30:46–51.

[150] Roundtree IA, Evans ME, Pan T et al. Dynamic RNA modifications in gene expression regulation. Cell 2017;169:1187–1200.

[151] Sakata K-I, Maeda K, Sakurai N et al. ADAR2 regulates malignant behaviour of mesothelioma cells independent of RNA-editing activity. Anticancer Res 2020;40:1307–1314.

[152] Sakurai M, Yano T, Kawabata H et al. Inosine cyanoethylation identifies A-to-I RNA editing sites in the human transcriptome. Nat Chem Biol 2010;6:733–740.

[153] Sakurai M, Shiromoto Y, Ota H et al. ADAR1 controls apoptosis of stressed cells by inhibiting Staufen1-mediated mRNA decay. Nat Struct Mol Biol 2017;24:534–543.

[154] Saletore Y, Meyer K, Korlach J et al. The birth of the epitranscriptome: deciphering the function of RNA modifications. Genome Biol 2012;13:175.

[155] Serafimova IM, Pufall MA, Krishnan S et al. Reversible targeting of noncatalytic cysteines with chemically tuned electrophiles. Nat Chem Biol 2012;8:471–476.

[156] Shelton PM, Duran A, Nakanishi Y et al. The secretion of miR-200s by a PKCζ/ADAR2 signaling axis promotes liver metastasis in colorectal cancer. Cell Rep 2018;23:1178–1191.

[157] Shen P, Yang T, Chen Q et al. CircNEIL3 regulatory loop promotes pancreatic ductal adenocarcinoma progression via miRNA sponging and A-to-I RNA-editing. Mol Cancer 2021;20:51.

[158] Shen H, An O, Ren X et al. ADARs act as potent regulators of circular transcriptome in cancer. Nat Commun 2022;13:1508.

[159] Shevchenko G, Morris KV. All I’s on the RADAR: role of ADAR in gene regulation. FEBS Lett 2018;592:2860–2873.

[160] Shi L, Yan P, Liang Y et al. Circular RNA expression is suppressed by androgen receptor (AR)-regulated adenosine deaminase that acts on RNA (ADAR1) in human hepatocellular carcinoma. Cell Death Dis 2017;8:e3171.

[161] Shibata C, Otsuka M, Shimizu T et al. Extracellular vesicle-mediated RNA editing may underlie the heterogeneity and spread of hepatocellular carcinoma in human tissue and in vitro. Oncol Rep 2023;50:194.

[162] Shigeyasu K, Okugawa Y, Toden S et al. AZIN1 RNA editing confers cancer stemness and enhances oncogenic potential in colorectal cancer. JCI Insight 2018;3:e99976.

[163] Shoshan E, Mobley AK, Braeuer RR et al. Reduced adenosine-to-inosine miR-455-5p editing promotes melanoma growth and metastasis. Nat Cell Biol 2015;17:311–321.

[164] Silvestris DA, Scopa C, Hanchi S et al. De Novo A-to-I RNA editing discovery in lncRNA. Cancers 2020;12:2959.

[165] Slezak-Prochazka I, Durmus S, Kroesen B-J et al. MicroRNAs, macrocontrol: regulation of miRNA processing. RNA (New York, NY) 2010;16:1087–1095.

[166] Snyder E, Chukrallah L, Seltzer K et al. ADAD1 and ADAD2, testis-specific adenosine deaminase domain-containing proteins, are required for male fertility. Sci Rep 2020;10:11536.

[167] Song C, Sakurai M, Shiromoto Y et al. Functions of the RNA editing enzyme ADAR1 and their relevance to human diseases. Genes 2016;7:129.

[168] Soundararajan R, Stearns TM, Griswold AL et al. Detection of canonical A-to-G editing events at 3’ UTRs and microRNA target sites in human lungs using next-generation sequencing. Oncotarget 2015;6:35726–35736.

[169] Stafforst T, Schneider MF. An RNA-deaminase conjugate selectively repairs point mutations. Angew Chem Int Ed Engl 2012;51:11166–11169.

[170] Stefl R, Xu M, Skrisovska L et al. Structure and specific RNA binding of ADAR2 double-stranded RNA binding motifs. Structure (London, England : 1993) 2006;14:345–355.

[171] Strehblow A, Hallegger M, Jantsch MF. 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 2002;13:3822–3835.

[172] Sun Y, Fan J, Wang B et al. The aberrant expression of ADAR1 promotes resistance to BET inhibitors in pancreatic cancer by stabilizing c-Myc. Am J Cancer Res 2020;10:148–163.

[173] Takeda S, Shigeyasu K, Okugawa Y et al. Activation of AZIN1 RNA editing is a novel mechanism that promotes invasive potential of cancer-associated fibroblasts in colorectal cancer. Cancer Lett 2019;444:127–135.

[174] Tan MH. Identification of bona fide RNA editing sites: history, challenges, and opportunities. Acc Chem Res 2023;56:3033–3044.

[175] Tan MH, Li Q, Shanmugam R et al; GTEx Consortium. Dynamic landscape and regulation of RNA editing in mammals. Nature 2017;550:249–254.

[176] Tassinari V, Cesarini V, Tomaselli S et al. ADAR1 is a new target of METTL3 and plays a pro-oncogenic role in glioblastoma by an editing-independent mechanism. Genome Biol 2021;22:51.

[177] Teoh PJ, An O, Chung T-H et al. Aberrant hyperediting of the myeloma transcriptome by ADAR1 confers oncogenicity and is a marker of poor prognosis. Blood 2018;132:1304–1317.

[178] Thapa RJ, Ingram JP, Ragan KB et al. DAI senses influenza A virus genomic RNA and activates RIPK3-dependent cell death. Cell Host Microbe 2016;20:674–681.

[179] Theodoropoulos N, Lancman G, Chari A. Targeting nuclear export proteins in multiple myeloma therapy. Target Oncol 2020;15:697–708.

[180] Thomas H. Gastric cancer: dysregulation of RNA editing in gastric cancer. Nat Rev Gastroenterol Hepatol 2016;13:500.

[181] Tomaselli S, Bonamassa B, Alisi A et al. ADAR enzyme and miRNA story: a nucleotide that can make the difference. Int J Mol Sci 2013;14:22796–22816.

[182] Tomaselli S, Galeano F, Alon S et al. Modulation of microRNA editing, expression and processing by ADAR2 deaminase in glioblastoma. Genome Biol 2015;16:5.

[183] Tong H, Huang J, Xiao Q et al. High-fidelity Cas13 variants for targeted RNA degradation with minimal collateral effects. Nat Biotechnol 2023;41:108–119.

[184] Upton JW, Kaiser WJ, Mocarski ES. DAI/ZBP1/DLM-1 complexes with RIP3 to mediate virus-induced programmed necrosis that is targeted by murine cytomegalovirus vIRA. Cell Host Microbe 2012;11:290–297.

[185] Velazquez-Torres G, Shoshan E, Ivan C et al. A-to-I miR-378a-3p editing can prevent melanoma progression via regulation of PARVA expression. Nat Commun 2018;9:461.

[186] Vercruysse T, De Bie J, Neggers JE et al. The second-generation exportin-1 inhibitor KPT-8602 demonstrates potent activity against acute lymphoblastic leukemia. Clin Cancer Res 2017;23:2528–2541.

[187] Vesely C, Jantsch MF. An I for an A: dynamic regulation of adenosine deamination-mediated RNA editing. Genes 2021;12:1026.

[188] Vik ES, Nawaz MS, Strøm Andersen P et al. Endonuclease V cleaves at inosines in RNA. Nat Commun 2013;4:2271.

[189] Vogel P, Schneider MF, Wettengel J et al. Improving site-directed RNA editing in vitro and in cell culture by chemical modification of the guideRNA. Angew Chem Int Ed Engl 2014;53:6267–6271.

[190] Wagner RW, Smith JE, Cooperman BS et al. A double-stranded RNA unwinding activity introduces structural alterations by means of adenosine to inosine conversions in mammalian cells and Xenopus eggs. Proc Natl Acad Sci USA 1989;86:2647–2651.

[191] Walkley CR, Li JB. Rewriting the transcriptome: adenosine-to-inosine RNA editing by ADARs. Genome Biol 2017;18:205.

[192] Wang IX, So E, Devlin JL et al. ADAR regulates RNA editing, transcript stability, and gene expression. Cell Rep 2013a;5:849–860.

[193] Wang Q, Hui H, Guo Z et al. ADAR1 regulates ARHGAP26 gene expression through RNA editing by disrupting miR-30b-3p and miR-573 binding. RNA (New York, NY) 2013b;19:1525–1536.

[194] Wang H, Chen S, Wei J et al. A-to-I RNA editing in cancer: from evaluating the editing level to exploring the editing effects. Front Oncol 2020;10:632187.

[195] Wang H, Yang L, Liu R et al. ADAR1 affects gastric cancer cell metastasis and reverses cisplatin resistance through AZIN1. Anticancer Drugs 2023a;34:1132–1145.

[196] Wang Y, Zhao J, Wu J et al. Genome-wide perturbations of A-to-I RNA editing dysregulated circular RNAs promoting the development of cervical cancer. Comput Biol Med 2023b;166:107546.

[197] Wolf J, Gerber AP, Keller W. tadA, an essential tRNA-specific adenosine deaminase from Escherichia coli. EMBO J 2002;21:3841–3851.

[198] Wong T-L, Loh J-J, Lu S et al. ADAR1-mediated RNA editing of SCD1 drives drug resistance and self-renewal in gastric cancer. Nat Commun 2023;14:2861.

[199] Wu M, Jin M, Cao X et al. RNA editing enzyme adenosine deaminases acting on RNA 1 deficiency increases the sensitivity of non-small cell lung cancer cells to anlotinib by regulating CX3CR1-fractalkine expression. Drug Dev Res 2022;83:328–338.

[200] Xu L-D, Öhman M. ADAR1 editing and its role in cancer. Genes 2018;10:12.

[201] Xu TP, Liu XX, Xia R et al. SP1-induced upregulation of the long noncoding RNA TINCR regulates cell proliferation and apoptosis by affecting KLF2 mRNA stability in gastric cancer. Oncogene 2015;34:5648–5661.

[202] Xu C, Zhou Y, Xiao Q et al. Programmable RNA editing with compact CRISPR-Cas13 systems from uncultivated microbes. Nat Methods 2021;18:499–506.

[203] Yang C-C, Chen Y-T, Chang Y-F et al. ADAR1-mediated 3’ UTR editing and expression control of antiapoptosis genes fine-tunes cellular apoptosis response. Cell Death Dis 2017;8:e2833.

[204] Yang Q, Xu P, Liu Q et al. Depleting DDX1 sensitizes non-small cell lung cancer cells to chemotherapy by attenuating cancer stem cell traits. Life Sci 2023;323:121592.

[205] Yi Z, Qu L, Tang H et al. Engineered circular ADAR-recruiting RNAs increase the efficiency and fidelity of RNA editing in vitro and in vivo. Nat Biotechnol 2022;40:946–955.

[206] Yuan J, Xu L, Bao H-J et al. Biological roles of A-to-I editing: implications in innate immunity, cell death, and cancer immunotherapy. J Experiment Clin Cancer Res: CR 2023;42:149.

[207] Yujie Ding MM, Shi X, Ji J et al. ADAR1p150 regulates the biosynthesis and function of miRNA-149* in human melanoma. Biochem Biophys Res Commun 2020;523:900–907.

[208] Zhang L, Yang C-S, Varelas X et al. Altered RNA editing in 3’ UTR perturbs microRNA-mediated regulation of oncogenes and tumor-suppressors. Sci Rep 2016;6:23226.

[209] Zhang Y, Wang K, Zhao Z et al. ADAR3 expression is an independent prognostic factor in lower-grade diffuse gliomas and positively correlated with the editing level of GRIA2Q607R. Cancer Cell Int 2018;18:196.

[210] Zhang Q, Xiu B, Zhang L et al. Immunosuppressive lncRNA LINC00624 promotes tumor progression and therapy resistance through ADAR1 stabilization. J ImmunoTher Cancer 2022a;10:e004666.

[211] Zhang T, Yin C, Fedorov A et al. ADAR1 masks the cancer immunotherapeutic promise of ZBP1-driven necroptosis. Nature 2022b;606:594–602.

[212] Zhang Y, Feng D, Mu G et al. Light-triggered site-directed RNA editing by endogenous ADAR1 with photolabile guide RNA. Cell Chem Biol 2023;30:672–682.e5.

[213] Zinshteyn B, Nishikura K. Adenosine-to-inosine RNA editing. Wiley Interdiscip Rev Syst Biol Med 2009;1:202–209.

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