The Editor’s I on Disease Development
Authors: Mamta Jain, Michael F. Jantsch, Konstantin Licht
Journal: Trends in Genetics (2019)

Adenosine deaminase acting on RNA (ADAR)1 expression is largely correlated with tumor progression and has been identified as a new promising target for cancer immunotherapy.It has recently emerged that RNA editing plays a pivotal role in coronary heart disease.Double-stranded RNA sensors such as MDA5 provide innate immunity against several viral infections; however, dysregulation of RNA sensing can lead to autoimmune disorders.A-to-I RNA editing is tightly controlled and regulated at multiple levels.Site-directed RNA editing may develop into RNA therapeutics against human disease. Adenosine-to-inosine (A-to-I) editing of RNA leads to deamination of adenosine to inosine. Inosine is interpreted as guanosine by the cellular machinery, thus altering the coding, folding, splicing, or transport of transcripts. A-to-I editing is tightly regulated. Altered editing has severe consequences for human health and can cause interferonopathies, neurological disorders, and cardiovascular disease, as well as impacting on cancer progression. ADAR1-mediated RNA editing plays an important role in antiviral immunity and is essential for distinguishing between endogenous and viral RNA, thereby preventing autoimmune disorders. Interestingly, A-to-I editing can be used not only to correct genomic mutations at the RNA level but also to modulate tumor antigenicity with large therapeutic potential. We highlight recent developments in the field, focusing on cancer and other human diseases. Adenosine-to-inosine (A-to-I) editing of RNA leads to deamination of adenosine to inosine. Inosine is interpreted as guanosine by the cellular machinery, thus altering the coding, folding, splicing, or transport of transcripts. A-to-I editing is tightly regulated. Altered editing has severe consequences for human health and can cause interferonopathies, neurological disorders, and cardiovascular disease, as well as impacting on cancer progression. ADAR1-mediated RNA editing plays an important role in antiviral immunity and is essential for distinguishing between endogenous and viral RNA, thereby preventing autoimmune disorders. Interestingly, A-to-I editing can be used not only to correct genomic mutations at the RNA level but also to modulate tumor antigenicity with large therapeutic potential. We highlight recent developments in the field, focusing on cancer and other human diseases. High-throughput sequencing and mass spectrometry have identified massive and diverse RNA modifications which have bolstered the idea that gene expression can be regulated at the transcript level [1Licht K. Jantsch M.F. Rapid and dynamic transcriptome regulation by RNA editing and RNA modifications.J. Cell Biol. 2016; 213: 15-22Crossref PubMed Scopus (88) Google Scholar, 2Roignant J.Y. Soller M. m6A in mRNA: an ancient mechanism for fine-tuning gene expression.Trends Genet. 2017; 33: 380-390Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar]. A-to-I editing (see Glossary) is a prevalent type of RNA modification during which adenosines in double-stranded (ds) or structured RNAs are deaminated, leading to nucleotide differences between RNA and DNA. Inosine is primarily interpreted as guanosine by the cellular machinery but can also be decoded as adenosine or uridine [3Basilio C. et al.Synthetic polynucleotides and the amino acid code. V.Proc. Natl. Acad. Sci. U S A. 1962; 48: 613-616Crossref PubMed Scopus (138) Google Scholar, 4Licht K. et al.Inosine induces context-dependent recoding and translational stalling.Nucleic Acids Res. 2019; 47: 3-14Crossref PubMed Scopus (63) Google Scholar]. Hence, adenosine deamination can affect coding potential and translation efficiency, change splice sites,or mask endogenous RNAs from the innate immune system [1Licht K. Jantsch M.F. Rapid and dynamic transcriptome regulation by RNA editing and RNA modifications.J. Cell Biol. 2016; 213: 15-22Crossref PubMed Scopus (88) Google Scholar, 4Licht K. et al.Inosine induces context-dependent recoding and translational stalling.Nucleic Acids Res. 2019; 47: 3-14Crossref PubMed Scopus (63) Google Scholar]. In humans, editing occurs at millions of sites, mostly in noncoding parts of the transcriptome such as introns and untranslated regions (UTRs) [5Picardi E. et al.Profiling RNA editing in human tissues: towards the inosinome Atlas.Sci. Rep. 2015; 5: 14941Crossref PubMed Scopus (154) Google Scholar, 6Ramaswami G. et al.Identifying RNA editing sites using RNA sequencing data alone.Nat. Methods. 2013; 10: 128-132Crossref PubMed Scopus (266) Google Scholar, 7Li J.B. et al.Genome-wide identification of human RNA editing sites by parallel DNA capturing and sequencing.Science. 2009; 324: 1210-1213Crossref PubMed Scopus (417) Google Scholar]. By contrast, editing in protein-coding regions of transcripts is relatively rare, and only about 40 such sites are conserved in mammals [8Pinto Y. et al.Mammalian conserved ADAR targets comprise only a small fragment of the human editosome.Genome Biol. 2014; 15: R5Crossref PubMed Scopus (126) Google Scholar]. A-to-I editing is catalyzed by the adenosine deaminase acting on RNA (ADAR) family of enzymes which require dsRNA for binding and editing. Two catalytically active ADARs (ADAR1 and ADAR2) are expressed in mammals. ADAR3 is a third member of the family but is catalytically inactive [9Chen C.X. et al.A third member of the RNA-specific adenosine deaminase gene family, ADAR3, contains both single- and double-stranded RNA binding domains.RNA. 2000; 6: 755-767Crossref PubMed Scopus (371) Google Scholar]. ADAR1 is expressed in two isoforms. A shorter isoform (ADAR1-p110) is expressed from a constitutively active promoter, whereas a longer isoform (ADAR1-p150) is interferon (IFN)-inducible [10Patterson J.B. Samuel C.E. Expression and regulation by interferon of a double-stranded-RNA-specific adenosine deaminase from human cells: evidence for two forms of the deaminase.Mol. Cell. Biol. 1995; 15: 5376-5388Crossref PubMed Scopus (431) Google Scholar]. Mice lacking ADAR1 die at embryonic (E) day 12.5 accompanied by an elevated IFN response [11Hartner J.C. et al.Liver disintegration in the mouse embryo caused by deficiency in the RNA-editing enzyme ADAR1.J. Biol. 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Lethality can be rescued when cytoplasmic sensors of (viral) dsRNAs are also deleted, suggesting that inosines help to discriminate 'self' from 'non-self' dsRNA [14Mannion N.M. et al.The RNA-editing enzyme ADAR1 controls innate immune responses to RNA.Cell Rep. 2014; 9: 1482-1494Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar, 15Pestal K. et al.Isoforms of RNA-editing enzyme ADAR1 independently control nucleic acid sensor MDA5-driven autoimmunity and multi-organ development.Immunity. 2015; 43: 933-944Abstract Full Text Full Text PDF PubMed Scopus (269) Google Scholar, 16Liddicoat B.J. et al.RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself.Science. 2015; 349: 1115-1120Crossref PubMed Scopus (467) Google Scholar]. Adar2 knockout mice die within 3 weeks after birth [17Brusa R. et al.Early-onset epilepsy and postnatal lethality associated with an editing-deficient GluR-B allele in mice.Science. 1995; 270: 1677-1680Crossref PubMed Scopus (485) Google Scholar]. This phenotype can be rescued when a pre-edited allele of the glutamate receptor Gria2 gene is coexpressed, demonstrating that ADAR2-mediated editing of Gria2 is essential [18Higuchi M. et al.Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2.Nature. 2000; 406: 78-81Crossref PubMed Scopus (736) Google Scholar]. We review the role of A-to-I editing in disease, including its impact on cancer progression and innate immunity. We also discuss recent advances in site-directed editing which can be used to repair genomic mutations at the RNA level, and how this technology may pave the way towards the establishment of new RNA-based drugs. A-to-I editing is tightly regulated, and deregulation of editing is associated with neurological disorders and some cancers [19Gurevich I. et al.Altered editing of serotonin 2C receptor pre-mRNA in the prefrontal cortex of depressed suicide victims.Neuron. 2002; 34: 349-356Abstract Full Text Full Text PDF PubMed Scopus (321) Google Scholar, 20Khermesh K. et al.Reduced levels of protein recoding by A-to-I RNA editing in Alzheimer's disease.RNA. 2016; 22: 290-302Crossref PubMed Scopus (83) Google Scholar, 21Tran S.S. et al.Widespread RNA editing dysregulation in brains from autistic individuals.Nat. Neurosci. 2019; 22: 25-36Crossref PubMed Scopus (86) Google Scholar, 22Quinones-Valdez G. et al.Regulation of RNA editing by RNA-binding proteins in human cells.Commun. Biol. 2019; 2: 19Crossref PubMed Scopus (64) Google Scholar]. Conceptually, A-to-I editing can be regulated by (i) altering the expression and activity of ADARs, (ii) changing the subcellular localization of ADARs, (iii) competition between RNA-binding proteins and noncoding RNAs that alter target accessibility, and (iv) by competing RNA modifications.(i)Analysis of genotype tissue expression (GTEX) RNA-seq data from hundreds of human tissue-derived datasets shows a moderate correlation (R = 0.55) of overall editing levels with the expression of ADAR1 and ADAR2 when the negative impact of ADAR3 on editing is subtracted [23Tan M.H. et al.Dynamic landscape and regulation of RNA editing in mammals.Nature. 2017; 550: 249-254Crossref PubMed Scopus (308) Google Scholar]. However, the moderate correlation suggests additional regulatory mechanisms. AIMP2 may be the strongest negative regulator affecting ADAR protein stability [23Tan M.H. et al.Dynamic landscape and regulation of RNA editing in mammals.Nature. 2017; 550: 249-254Crossref PubMed Scopus (308) Google Scholar]. Similarly, the E3 ubiquitin ligase WWP2 targets ADAR2 for degradation [24Marcucci R. et al.Pin1 and WWP2 regulate GluR2 Q/R site RNA editing by ADAR2 with opposing effects.EMBO J. 2011; 30: 4211-4222Crossref PubMed Scopus (95) Google Scholar]. Conversely TDP-43 enhances ADAR1 expression (Figure 1A) [22Quinones-Valdez G. et al.Regulation of RNA editing by RNA-binding proteins in human cells.Commun. Biol. 2019; 2: 19Crossref PubMed Scopus (64) Google Scholar].(ii)ADAR1-p110 and ADAR2 preferentially localize to the nucleus. However, ADAR1-p110 shuttles between the nucleus and the cytoplasm [25Eckmann C.R. et al.The human but not the Xenopus RNA-editing enzyme ADAR1 has an atypical nuclear localization signal and displays the characteristics of a shuttling protein.Mol. Biol. Cell. 2001; 12: 1911-1924Crossref PubMed Scopus (88) Google Scholar]. Different stimuli lead to increased cytoplasmic localization; these include binding to dsRNA and stress-induced phosphorylation of ADAR1 which may help cells to cope with stress (Figure 1B) [26Sakurai M. et al.ADAR1 controls apoptosis of stressed cells by inhibiting Staufen1-mediated mRNA decay.Nat. Struct. Mol. Biol. 2017; 24: 534-543Crossref PubMed Scopus (86) Google Scholar, 27Fritz J. et al.RNA-regulated interaction of transportin-1 and exportin-5 with the double-stranded RNA-binding domain regulates nucleocytoplasmic shuttling of ADAR1.Mol. Cell. Biol. 2009; 29: 1487-1497Crossref PubMed Scopus (87) Google Scholar]. Within the nucleus, ADAR activity is regulated by nucleolar sequestration [28Desterro J.M. et al.Dynamic association of RNA-editing enzymes with the nucleolus.J. Cell Sci. 2003; 116: 1805-1818Crossref PubMed Scopus (198) Google Scholar, 29Sansam C.L. et al.Modulation of RNA editing by functional nucleolar sequestration of ADAR2.Proc. Natl. Acad. Sci. U S A. 2003; 100: 14018-14023Crossref PubMed Scopus (144) Google Scholar]. The importance of correct localization is exemplified by a group of patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia where ADAR2 partially localizes to the cytoplasm, causing alterations in editing patterns [30Moore S. et al.ADAR2 mislocalization and widespread RNA editing aberrations in C9orf72-mediated ALS/FTD.Acta Neuropathol. 2019; 138: 49-65Crossref PubMed Scopus (33) Google Scholar].(iii)Numerous RNA-binding proteins alter editing in a site-specific manner, likely by altering the accessibility of ADAR to its target or by changing the secondary structure of the target (e.g., helicases) [22Quinones-Valdez G. et al.Regulation of RNA editing by RNA-binding proteins in human cells.Commun. Biol. 2019; 2: 19Crossref PubMed Scopus (64) Google Scholar, 31Garncarz W. et al.A high-throughput screen to identify enhancers of ADAR-mediated RNA-editing.RNA Biol. 2013; 10: 192-204Crossref PubMed Scopus (56) Google Scholar, 32Tariq A. et al.RNA-interacting proteins act as site-specific repressors of ADAR2-mediated RNA editing and fluctuate upon neuronal stimulation.Nucleic Acids Res. 2013; 41: 2581-2593Crossref PubMed Scopus (57) Google Scholar]. The fragile X proteins FMRP and FXR1P are interesting examples. FMRP promotes site-specific editing whereas FXR1P inhibits editing, which may in part explain the global hypoediting observed in individuals with autism spectrum disorder (ASD) (Figure 1C) [21Tran S.S. et al.Widespread RNA editing dysregulation in brains from autistic individuals.Nat. Neurosci. 2019; 22: 25-36Crossref PubMed Scopus (86) Google Scholar, 22Quinones-Valdez G. et al.Regulation of RNA editing by RNA-binding proteins in human cells.Commun. Biol. 2019; 2: 19Crossref PubMed Scopus (64) Google Scholar, 33Bhogal B. et al.Modulation of dADAR-dependent RNA editing by the Drosophila fragile X mental retardation protein.Nat. Neurosci. 2011; 14: 1517-1524Crossref PubMed Scopus (65) Google Scholar]. Similarly, small noncoding RNAs can alter A-to-I editing. The small nucleolar (sno)RNA HBII-52 seemingly interferes with editing of the serotonin receptor HTR2C transcript in the nucleolus [34Vitali P. et al.ADAR2-mediated editing of RNA substrates in the nucleolus is inhibited by C/D small nucleolar RNAs.J. Cell Biol. 2005; 169: 745-753Crossref PubMed Scopus (191) Google Scholar]. Conversely, expression of HBII-52 is decreased in patients with Prader–Willi syndrome, while editing levels of the HTR2C transcript are increased [35Kishore S. Stamm S. The snoRNA HBII-52 regulates alternative splicing of the serotonin receptor 2C.Science. 2006; 311: 230-232Crossref PubMed Scopus (517) Google Scholar]. Interestingly, mice solely expressing the fully edited HTR2C protein isoform exhibit characteristics of Prader–Willi syndrome [36Morabito M.V. et al.Mice with altered serotonin 2C receptor RNA editing display characteristics of Prader-Willi syndrome.Neurobiol. Dis. 2010; 39: 169-180Crossref PubMed Scopus (107) Google Scholar]. However, the mechanism underlying how snoRNA HBII-52 affects A-to-I editing is unclear. It is possible that HBII-52-guided methylation may affect RNA structure and thereby editing. Alternatively, the snoRNA could affect editing by changing the alternative splicing of HTR2C (see below and [35Kishore S. Stamm S. The snoRNA HBII-52 regulates alternative splicing of the serotonin receptor 2C.Science. 2006; 311: 230-232Crossref PubMed Scopus (517) Google Scholar]).(iv)The regulation of editing via modifications in the target RNA is less well explored. In vitro data demonstrate that both adenine methylation at the 6 position (m6A) and 2′O-methylation prevent editing by ADARs [37Veliz E.A. et al.Substrate analogues for an RNA-editing adenosine deaminase: mechanistic investigation and inhibitor design.J. Am. Chem. Soc. 2003; 125: 10867-10876Crossref PubMed Scopus (52) Google Scholar, 38Yi-Brunozzi H.Y. et al.Synthetic substrate analogs for the RNA-editing adenosine deaminase ADAR-2.Nucleic Acids Res. 1999; 27: 2912-2917Crossref PubMed Scopus (49) Google Scholar]. Moreover, depletion of m6A leads to increased A-to-I editing, suggesting a negative correlation between the two types of modification [39Xiang J.F. et al.N6-methyladenosines modulate A-to-I RNA editing.Mol Cell. 2018; 69: 126-135.e126Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar]. However, there is currently no indication that methylation in vivo directly prevents editing. Likely, structural changes introduced by the m6A modification affect the binding of ADAR [39Xiang J.F. et al.N6-methyladenosines modulate A-to-I RNA editing.Mol Cell. 2018; 69: 126-135.e126Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar]. Nevertheless, it might be interesting to test how other abundant RNA modifications affect the editing landscape. The majority of editing takes place cotranscriptionally, presumably on nascent RNA [40Rodriguez J. et al.Nascent-seq indicates widespread cotranscriptional RNA editing in Drosophila.Mol. Cell. 2012; 47: 27-37Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 41Hsiao Y.E. et al.RNA editing in nascent RNA affects pre-mRNA splicing.Genome Res. 2018; 28: 812-823Crossref PubMed Scopus (68) Google Scholar]. Consistently, A-to-I editing is particularly prevalent in intron regions of transcripts [5Picardi E. et al.Profiling RNA editing in human tissues: towards the inosinome Atlas.Sci. Rep. 2015; 5: 14941Crossref PubMed Scopus (154) Google Scholar]. In addition, exonic editing sites frequently require intronic elements to form editing-competent RNA duplexes [42Herb A. et al.Q/R site editing in kainate receptor GluR5 and GluR6 pre-mRNAs requires distant intronic sequences.Proc. Natl. Acad. Sci. U S A. 1996; 93: 1875-1880Crossref PubMed Scopus (136) Google Scholar, 43Higuchi M. et al.RNA editing of AMPA receptor subunit Glur-B – a base-paired intron–exon structure determines position and efficiency.Cell. 1993; 75: 1361-1370Abstract Full Text PDF PubMed Scopus (517) Google Scholar, 44Burns C.M. et al.Regulation of serotonin-2C receptor G-protein coupling by RNA editing.Nature. 1997; 387: 303-308Crossref PubMed Scopus (758) Google Scholar] (Figure 1D). In these cases A-to-I editing needs to take place before mRNA splicing [45Tajaddod M. et al.The dynamic epitranscriptome: A to I editing modulates genetic information.Chromosoma. 2015; 125: 51-63Crossref PubMed Scopus (27) Google Scholar]. In line with this, A-to-I editing modulates alternative splicing for a large set of transcripts [41Hsiao Y.E. et al.RNA editing in nascent RNA affects pre-mRNA splicing.Genome Res. 2018; 28: 812-823Crossref PubMed Scopus (68) Google Scholar, 46Rueter S.M. et al.Regulation of alternative splicing by RNA editing.Nature. 1999; 399: 75-80Crossref PubMed Scopus (502) Google Scholar, 47Schoft V.K. et al.Regulation of glutamate receptor B pre-mRNA splicing by RNA editing.Nucleic Acids Res. 2007; 35: 3723-3732Crossref PubMed Scopus (71) Google Scholar, 48Penn A.C. et al.Steric antisense inhibition of AMPA receptor Q/R editing reveals tight coupling to intronic editing sites and splicing.Nucleic Acids Res. 2013; 41: 1113-1123Crossref PubMed Scopus (25) Google Scholar]. A particularly interesting example is the autoregulation of ADAR2 [46Rueter S.M. et al.Regulation of alternative splicing by RNA editing.Nature. 1999; 399: 75-80Crossref PubMed Scopus (502) Google Scholar]: ADAR2 edits an AA dinucleotide to an AI dinucleotide within its own pre-mRNA. This leads to the creation of a novel 3′ spice site (AI = AG) leading to inclusion of an additional 47 nt in the open reading frame, and ultimately to the creation of a truncated and probably unstable ADAR2 protein [46Rueter S.M. et al.Regulation of alternative splicing by RNA editing.Nature. 1999; 399: 75-80Crossref PubMed Scopus (502) Google Scholar] (Figure 1D). Similarly, an A-to-I editing event in the tyrosine phosphatase PTPN6 pre-mRNA converts a branch-point adenosine into inosine and prevents splicing. This leads to intron retention and ultimately to the generation of a nonfunctional protein, which may play a role in acute myeloid leukemia [49Beghini A. et al.RNA hyperediting and alternative splicing of hematopoietic cell phosphatase (PTPN6) gene in acute myeloid leukemia.Hum. Mol. Genet. 2000; 9: 2297-2304Crossref PubMed Scopus (121) Google Scholar]. Similarly, only edited Gria2 pre-mRNA is spliced efficiently, and unedited pre-mRNA is retained in the nucleus [18Higuchi M. et al.Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2.Nature. 2000; 406: 78-81Crossref PubMed Scopus (736) Google Scholar, 47Schoft V.K. et al.Regulation of glutamate receptor B pre-mRNA splicing by RNA editing.Nucleic Acids Res. 2007; 35: 3723-3732Crossref PubMed Scopus (71) Google Scholar, 48Penn A.C. et al.Steric antisense inhibition of AMPA receptor Q/R editing reveals tight coupling to intronic editing sites and splicing.Nucleic Acids Res. 2013; 41: 1113-1123Crossref PubMed Scopus (25) Google Scholar] (Figure 1D). Moreover, ADAR proteins can interfere with pre-mRNA processing independently of A-to-I editing [50Licht K. Jantsch M.F. The other face of an editor: ADAR1 functions in editing-independent ways.BioEssays. 2017; 39: 1700129Crossref Scopus (12) Google Scholar]. For instance, ADAR1 can compete with 3′-UTR processing factors and thereby influence transcript length [51Bahn J.H. et al.Genomic analysis of ADAR1 binding and its involvement in multiple RNA processing pathways.Nat. Commun. 2015; 6: 6355Crossref PubMed Scopus (98) Google Scholar]. ADAR proteins can also reduce circular RNA expression [52Rybak-Wolf A. et al.Circular RNAs in the mammalian brain are highly abundant, conserved, and dynamically expressed.Mol. Cell. 2015; 58: 870-885Abstract Full Text Full Text PDF PubMed Scopus (1509) Google Scholar, 53Ivanov A. et al.Analysis of intron sequences reveals hallmarks of circular RNA biogenesis in animals.Cell Rep. 2015; 10: 170-177Abstract Full Text Full Text PDF PubMed Scopus (680) Google Scholar]. It is assumed that ADARs increase the rate of 'backsplicing' required for circular (circ)RNA biogenesis by binding to these reverse complementary sequences, editing these sequences, and thereby decreasing their stability, which in turn reduces circRNA biogenesis [53Ivanov A. et al.Analysis of intron sequences reveals hallmarks of circular RNA biogenesis in animals.Cell Rep. 2015; 10: 170-177Abstract Full Text Full Text PDF PubMed Scopus (680) Google Scholar]. Most interestingly, the efficiency of splicing can determine the extent of editing. Transcripts that are less efficiently spliced exhibit higher editing levels [54Licht K. et al.Adenosine to Inosine editing frequency controlled by splicing efficiency.Nucleic Acids Res. 2016; 44: 6398-6408Crossref PubMed Scopus (36) Google Scholar, 55Licht K. et al.A high resolution A-to-I editing map in the mouse identifies editing events controlled by pre-mRNA splicing.Genome Res. 2019; 29: 1453-1463Crossref PubMed Scopus (46) Google Scholar]. Consistently, poorly spliced transcripts and alternatively spliced pre-mRNAs are edited more frequently [40Rodriguez J. et al.Nascent-seq indicates widespread cotranscriptional RNA editing in Drosophila.Mol. Cell. 2012; 47: 27-37Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar]. Excitingly, splicing efficiency can contribute to the regulation of tissue-specific editing, as revealed by analysis of GTEx data [55Licht K. et al.A high resolution A-to-I editing map in the mouse identifies editing events controlled by pre-mRNA splicing.Genome Res. 2019; 29: 1453-1463Crossref PubMed Scopus (46) Google Scholar]. Collectively, editing levels are controlled cotranscriptionally. Consequently, proteins binding to pre-mRNA or influencing splicing are potent regulators of editing [22Quinones-Valdez G. et al.Regulation of RNA editing by RNA-binding proteins in human cells.Commun. Biol. 2019; 2: 19Crossref PubMed Scopus (64) Google Scholar, 31Garncarz W. et al.A high-throughput screen to identify enhancers of ADAR-mediated RNA-editing.RNA Biol. 2013; 10: 192-204Crossref PubMed Scopus (56) Google Scholar, 32Tariq A. et al.RNA-interacting proteins act as site-specific repressors of ADAR2-mediated RNA editing and fluctuate upon neuronal stimulation.Nucleic Acids Res. 2013; 41: 2581-2593Crossref PubMed Scopus (57) Google Scholar]. A-to-I editing affects the progression and metastasis of some cancers. Systematic analysis of RNA-seq data from The Cancer Genome Atlas (TCGA) showed that A-to-I RNA editing is dysregulated in 17 different cancer types relative to normal tissues [56Han L. et al.The genomic landscape and clinical relevance of A-to-I RNA editing in human cancers.Cancer Cell. 2015; 28: 515-528Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar]. Interestingly, the majority of these tumor samples showed tumor-specific hyperediting, and only a small fraction of tumors showed hypoediting [56Han L. et al.The genomic landscape and clinical relevance of A-to-I RNA editing in human cancers.Cancer Cell. 2015; 28: 515-528Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar] (Figure 2 and Table 1, Key Table). Overall, editing levels correlated with the expression levels of ADAR1 but not of ADAR2. Moreover, ADAR1 overexpression was found to be a common phenomenon in many tumors [56Han L. et al.The genomic landscape and clinical relevance of A-to-I RNA editing in human cancers.Cancer Cell. 2015; 28: 515-528Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar, 57Paz-Yaacov N. et al.Elevated RNA editing activity is a major contributor to transcriptomic diversity in tumors.Cell Rep. 2015; 13: 267-276Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar, 58Anadon C. et al.Gene amplification-associated overexpression of the RNA editing enzyme ADAR1 enhances human lung tumorigenesis.Oncogene. 2016; 35: 4407-4413Crossref PubMed Scopus (63) Google Scholar, 59Qin Y.R. et al.Adenosine-to-inosine RNA editing mediated by ADARs in esophageal squamous cell carcinoma.Cancer Res. 2014; 74: 840-851Crossref PubMed Scopus (121) Google Scholar]. By comparing tumor subtype, stage, and survival rate, a series of clinically relevant editing sites could be identified that were mostly located in nonrepetitive noncoding RNAs, or within conserved mRNAs, leading to nonsynonymous codon changes. Most interestingly, several of these editing events can promote cell growth and survival [56Han L. et al.The genomic landscape and clinical relevance of A-to-I RNA editing in human cancers.Cancer Cell. 2015; 28: 515-528Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar].Table 1Key Table. List of Coding Editing Targets Implicated in Cancer DevelopmentGeneEditing siteFull nameEnzymeType of regulatorType of cancerRefsAzin1S367GAntizyme inhibitor 1ADAR1PositiveHepatocellular carcinomaEsophageal squamous cell carcinomaColorectal cancer45Tajaddod M. et al.The dynamic epitranscriptome: A to I editing modulates genetic information.Chromosoma. 2015; 125: 51-63Crossref PubMed Scopus (27) Google Scholar, 64Chen L. et al.Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma.Nat. Med. 2013; 19: 209-216Crossref PubMed Scopus (337) Google ScholarGabra3I342MGABA receptor α3ADAR1NegativeBreast cancer66Gumireddy K. et al.The mRNA-edited form of GABRA3 suppresses GABRA3-mediated Akt activation and breast cancer metastasis.Nat. Commun. 2016; 7: 10715Crossref PubMed Scopus (98) Google ScholarGria2Q607RGlutamate ionotropic receptor AMPA-type subunit 2ADAR2NegativeGlioblastoma82Maas S. et al.A-to-I RNA editing and human disease.RNA Biol. 2006; 3: 1-9Crossref PubMed Scopus (210) Google ScholarPODXLH241RPodocalyxin-likeADAR2NegativeGastric cancer61Chan T.H. et al.ADAR-mediated RNA editing predicts progression and prognosis of gastric cancer.Gastroenterology. 2016; 151: 637-650Abstract Full Text Full Text PDF PubMed Scopus (102) Google ScholarCDC14BCell division cycle 14BADAR2NegativeAstrocytomaGliobastoma multiforme60Galeano F. et al.ADAR2-editing activity inhibits glioblastoma growth through the modulation of the CDC14B/Skp2/p21/p27 axis.Oncogene. 2013; 32: 998-1009Crossref PubMed Scopus (103) Google ScholarRhoQN136SRas homolog family member QPositiveColorectal cancer63Han S.W. et al.RNA editing in RHOQ promotes invasion potential in colorectal cancer.J. Exp. Med. 2014; 211: 613-621Crossref PubMed Scopus (75) Google Scholar Open table in a new tab RNA editing levels can show a positive or negative correlation with cancer progression, but the functional consequences of these editing events for tumor progression are poorly understood (Table 1). Nevertheless, for some substrates such as transcripts encoding antizyme inhibitor 1 (Azin1), RhoQ, the actin-crosslinking protein podcalyxin-like (PODXL), the cell-cycle regulator CDC14B, and the DNA glycosylase NEIL1, their direct involvement in cellular migration, cell division, or DNA repair is consistent with a uniform alteration in editing patterns across different tumors [56Han L. et al.The genomic landscape and clinical relevance of A-to-I RNA editing in human cancers.Cancer Cell. 2015; 28: 515-528Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar, 60Galeano F. et al.ADAR2-editing activity inhibits glioblastoma growth through the modulation of the CDC14B/Skp2/p21/p27 axis.Oncogene. 2013; 32: 998-1009Crossref PubMed Scopus (103) Google Scholar, 61Chan T.H. et al.ADAR-mediated RNA editing predicts progression and prognosis of gastric cancer.Gastroenterology. 2016; 151: 637-650Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar, 62Yeo J. et al.RNA editing changes the lesion specificity