A-to-I RNA editing — immune protector and transcriptome diversifier


Modifications of RNA affect its function and stability. RNA editing is unique among these modifications because it not only alters the cellular fate of RNA molecules but also alters their sequence relative to the genome. The most common type of RNA editing is A-to-I editing by double-stranded RNA-specific adenosine deaminase (ADAR) enzymes. Recent transcriptomic studies have identified a number of ‘recoding’ sites at which A-to-I editing results in non-synonymous substitutions in protein-coding sequences. Many of these recoding sites are conserved within (but not usually across) lineages, are under positive selection and have functional and evolutionary importance. However, systematic mapping of the editome across the animal kingdom has revealed that most A-to-I editing sites are located within mobile elements in non-coding parts of the genome. Editing of these non-coding sites is thought to have a critical role in protecting against activation of innate immunity by self-transcripts. Both recoding and non-coding events have implications for genome evolution and, when deregulated, may lead to disease. Finally, ADARs are now being adapted for RNA engineering purposes.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: A-to-I RNA editing is catalysed by ADAR enzymes and is the most common type of RNA editing in Metazoa.
Fig. 2: A-to-I RNA editing and how it is detected.
Fig. 3: Editing can modify protein function, generate new protein products, alter gene regulation and provide immune protection against endogenous dsRNAs.
Fig. 4: Extent and consequences of editing in repetitive elements.
Fig. 5: RNA editing generates transcriptomic diversity.
Fig. 6: Capacity and limitations of RNA editing as a means for adaptation.
Fig. 7: Utilizing ADARs for RNA probing and engineering.


  1. 1.

    Blencowe, B. J. Alternative splicing: new insights from global analyses. Cell 126, 37–47 (2006).

  2. 2.

    Di Giammartino, D. C., Nishida, K. & Manley, J. L. Mechanisms and consequences of alternative polyadenylation. Mol. Cell 43, 853–866 (2011).

  3. 3.

    Boccaletto, P. et al. MODOMICS: a database of RNA modification pathways. 2017 update. Nucleic Acids Res. 46, D303–D307 (2018).

  4. 4.

    Peer, E., Rechavi, G. & Dominissini, D. Epitranscriptomics: regulation of mRNA metabolism through modifications. Curr. Opin. Chem. Biol. 41, 93–98 (2017).

  5. 5.

    Safra, M. et al. The m1A landscape on cytosolic and mitochondrial mRNA at single-base resolution. Nature 551, 251–255 (2017).

  6. 6.

    Benne, R. et al. Major transcript of the frameshifted coxII gene from trypanosome mitochondria contains four nucleotides that are not encoded in the DNA. Cell 46, 819–826 (1986).

  7. 7.

    Takenaka, M. et al. RNA editing in plant mitochondria —connecting RNA target sequences and acting proteins. Mitochondrion 19, 191–197 (2014).

  8. 8.

    Wedekind, J. E., Dance, G. S. C., Sowden, M. P. & Smith, H. C. Messenger RNA editing in mammals: new members of the APOBEC family seeking roles in the family business. Trends Genet. 19, 207–216 (2003).

  9. 9.

    Bass, B. L. RNA editing by adenosine deaminases that act on RNA. Annu. Rev. Biochem. 71, 817–846 (2002).

  10. 10.

    Savva, Y.a, Rieder, L. E. & Reenan, R. A. The ADAR protein family. Genome Biol. 13, 252 (2012).

  11. 11.

    Nishikura, K. Functions and regulation of RNA editing by ADAR deaminases. Annu. Rev. Biochem. 79, 321–349 (2010).

  12. 12.

    Lonsdale, J. et al. The genotype-tissue expression (GTEx) project. Nat. Genet. 45, 580–585 (2013).

  13. 13.

    Thomas, J. M. & Beal, P. A. How do ADARs bind RNA? New protein-RNA structures illuminate substrate recognition by the RNA editing ADARs. BioEssays 39, 1600187 (2017).

  14. 14.

    Kleinberger, Y. & Eisenberg, E. Large-scale analysis of structural, sequence and thermodynamic characteristics of A-to-I RNA editing sites in human Alu repeats. BMC Genomics 11, 453 (2010).

  15. 15.

    Eggington, J. M., Greene, T. & Bass, B. L. Predicting sites of ADAR editing in double-stranded RNA. Nat. Commun. 2, 319 (2011).

  16. 16.

    Levanon, E. Y. et al. Systematic identification of abundant A-to-I editing sites in the human transcriptome. Nat. Biotechnol. 22, 1001–1005 (2004).

  17. 17.

    Athanasiadis, A., Rich, A. & Maas, S. Widespread A-to-I RNA editing of Alu-containing mRNAs in the human transcriptome. PLoS Biol. 2, e391 (2004).

  18. 18.

    Blow, M., Futreal, A. P., Wooster, R. & Stratton, M. R. A survey of RNA editing in human brain. Genome Res. 14, 2379–2387 (2004).

  19. 19.

    Kim, D. D. Y. et al. Widespread RNA editing of embedded Alu elements in the human transcriptome. Genome Res. 14, 1719–1725 (2004).

  20. 20.

    Ramaswami, G. & Li, J. B. Identification of human RNA editing sites: a historical perspective. Methods 107, 42–47 (2016). This paper reviews the development of computational approaches for detecting RNA editing sites.

  21. 21.

    Ramaswami, G. & Li, J. B. RADAR: a rigorously annotated database of A-to-I RNA editing. Nucleic Acids Res. 42, D109–D113 (2014).

  22. 22.

    Picardi, E., D’Erchia, A. M., Lo Giudice, C. & Pesole, G. REDIportal: a comprehensive database of A-to-I RNA editing events in humans. Nucleic Acids Res. 45, D750–D757 (2017).

  23. 23.

    Rosenthal, J. J. C. & Seeburg, P. H. A-To-I RNA editing: effects on proteins key to neural excitability. Neuron 74, 432–439 (2012).

  24. 24.

    Tomaselli, S., Locatelli, F. & Gallo, A. The RNA editing enzymes ADARs: mechanism of action and human disease. Cell Tissue Res. 356, 527–532 (2014).

  25. 25.

    Rosenthal, J. J. C. The emerging role of RNA editing in plasticity. J. Exp. Biol. 218, 1812–1821 (2015). This review discusses the contribution of recoding events to proteome diversity.

  26. 26.

    Nishikura, K. A-To-I editing of coding and non-coding RNAs by ADARs. Nat. Rev. Mol. Cell. Biol. 17, 83–96 (2016).

  27. 27.

    Gallo, A., Vukic, D., Michalík, D., O’Connell, M. A. & Keegan, L. P. ADAR RNA editing in human disease; more to it than meets the I. Hum. Genet. 136, 1265–1278 (2017). This article summarizes the link between altered RNA editing and human pathologies.

  28. 28.

    Basilio, C., Wahba, A. J., Lengyel, P., Speyer, J. F. & Ochoa, S. Synthetic polynucleotides and the amino acid code, V. Proc. Natl Acad. Sci. USA 48, 613–616 (1962).

  29. 29.

    Hoopengardner, B., Bhalla, T., Staber, C. & Reenan, R. Nervous system targets of RNA editing identified by comparative genomics. Science 301, 832–836 (2003).

  30. 30.

    Sommer, B., Kohler, M., Sprengel, R. & Seeburg, P. H. RNA editing in brain controls a determinant of ion flow in glutamate-gated channels. Cell 67, 11–19 (1991).

  31. 31.

    Burns, C. M. et al. Regulation of serotonin-2C receptor G-protein coupling by RNA editing. Nature 387, 303–308 (1997).

  32. 32.

    Zhang, R., Deng, P., Jacobson, D. & Li, J. B. Evolutionary analysis reveals regulatory and functional landscape of coding and non-coding RNA editing. PLoS Genet. 13, e1006563 (2017).

  33. 33.

    Duan, Y., Dou, S., Luo, S., Zhang, H. & Lu, J. Adaptation of A-to-I RNA editing in Drosophila. PLoS Genet. 13, e1006648 (2017).

  34. 34.

    Yu, Y. et al. The landscape of A-to-I RNA editome is shaped by both positive and purifying selection. PLoS Genet. 12, e1006191 (2016).

  35. 35.

    Graveley, B. R. et al. The developmental transcriptome of Drosophila melanogaster. Nature 471, 473–479 (2011).

  36. 36.

    St Laurent, G. et al. Genome-wide analysis of A-to-I RNA editing by single-molecule sequencing in Drosophila. Nat. Struct. Mol. Biol. 20, 1333–1339 (2013).

  37. 37.

    Liscovitch-Brauer, N. et al. Trade-off between transcriptome plasticity and genome evolution in cephalopods. Cell 169, 191–202.e11 (2017). This study demonstrates that recoding in cephalopods is extensive and is maintained by evolution.

  38. 38.

    Alon, S. et al. The majority of transcripts in the squid nervous system are extensively recoded by A-to-I RNA editing. eLife 4, e05198 (2015).

  39. 39.

    Ryan, M. Y., Maloney, R., Reenan, R. & Horn, R. Characterization of five RNA editing sites in shab potassium channels. Channels 2, 202–209.

  40. 40.

    Ingleby, L., Maloney, R., Jepson, J., Horn, R. & Reenan, R. Regulated RNA editing and functional epistasis in shaker potassium channels. J. Gen. Physiol. 133, 17–27 (2009).

  41. 41.

    Levanon, E. Y. et al. Evolutionarily conserved human targets of adenosine to inosine RNA editing. Nucleic Acids Res. 33, 1162–1168 (2005).

  42. 42.

    Li, J. B. et al. Genome-wide identification of human RNA editing sites by parallel DNA capturing and sequencing. Science 324, 1210–1213 (2009).

  43. 43.

    Stulić, M. & Jantsch, M. F. Spatio-temporal profiling olamin A RNA-editing reveals ADAR preferences and high editing levels outside neuronal tissues. RNA Biol. 10, 1611–1617 (2013).

  44. 44.

    Paz-Yaacov, N. et al. Elevated RNA editing activity is a major contributor to transcriptomic diversity in tumors. Cell Rep. 13, 267–276 (2015).

  45. 45.

    Chen, L. et al. Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma. Nat. Med. 19, 209–216 (2013).

  46. 46.

    Yeo, J., Goodman, R.a, Schirle, N. T., David, S. S. & Beal, P. A. RNA editing changes the lesion specificity for the DNA repair enzyme NEIL1. Proc. Natl Acad. Sci. USA 107, 20715–20719 (2010).

  47. 47.

    Tan, M. H. et al. Dynamic landscape and regulation of RNA editing in mammals. Nature 550, 249–254 (2017). This article describes a comprehensive screen of RNA editing across a large number of human and mouse samples.

  48. 48.

    Higuchi, M. et al. Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2. Nature 406, 78–81 (2000).

  49. 49.

    Horsch, M. et al. Requirement of the RNA-editing enzyme ADAR2 for normal physiology in mice. J. Biol. Chem. 286, 18614–18622 (2011).

  50. 50.

    Bhalla, T., Rosenthal, J. J. C., Holmgren, M. & Reenan, R. Control of human potassium channel inactivation by editing of a small mRNA hairpin. Nat. Struct. Mol. Biol. 11, 950–956 (2004).

  51. 51.

    Daniel, C., Wahlstedt, H., Ohlson, J., Björk, P. & Ohman, M. Adenosine-to-inosine RNA editing affects trafficking of the gamma-aminobutyric acid type A (GABA(A)) receptor. J. Biol. Chem. 286, 2031–2040 (2011).

  52. 52.

    Lomeli, H. et al. Control of kinetic properties of AMPA receptor channels by nuclear RNA editing. Science 266, 1709–1713 (1994).

  53. 53.

    Egebjerg, J. & Heinemann, S. F. Ca2+ permeability of unedited and edited versions of the kainate selective glutamate receptor GluR6. Proc. Natl Acad. Sci. USA 90, 755–759 (1993).

  54. 54.

    Sailer, A. et al. Generation and analysis of GluR5(Q636R) kainate receptor mutant mice. J. Neurosci. 19, 8757–8764 (1999).

  55. 55.

    Pinto, Y., Cohen, H. Y. & Levanon, E. Y. Mammalian conserved ADAR targets comprise only a small fragment of the human editosome. Genome Biol. 15, R5 (2014).

  56. 56.

    Xu, G. & Zhang, J. Human coding RNA editing is generally nonadaptive. Proc. Natl Acad. Sci. USA 111, 3769–3774 (2014). This article discusses the general evolutionary role of recoding in humans.

  57. 57.

    Lev-Maor, G. et al. RNA-editing-mediated exon evolution. Genome Biol. 8, R29 (2007).

  58. 58.

    Pinto, Y., Buchumenski, I., Levanon, E. Y. & Eisenberg, E. Human cancer tissues exhibit reduced A-to-I editing of miRNAs coupled with elevated editing of their targets. Nucleic Acids Res. 46, 71–82.

  59. 59.

    Kawahara, Y. et al. Redirection of silencing targets by adenosine-to-inosine editing of miRNAs. Science 315, 1137–1140 (2007).

  60. 60.

    Wang, Y. et al. Systematic characterization of A-to-I RNA editing hotspots in microRNAs across human cancers. Genome Res. 27, 1112–1125 (2017).

  61. 61.

    Vesely, C., Tauber, S., Sedlazeck, F. J., von Haeseler, A. & Jantsch, M. F. Adenosine deaminases that act on RNA induce reproducible changes in abundance and sequence of embryonic miRNAs. Genome Res. 22, 1468–1476 (2012).

  62. 62.

    Ivanov, A. et al. Analysis of intron sequences reveals hallmarks of circular RNA biogenesis in animals. Cell Rep. 10, 170–177 (2014).

  63. 63.

    Liddicoat, B. J. et al. RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself. Science 349, 1115–1120 (2015).

  64. 64.

    Pestal, K. et al. Isoforms of RNA-editing enzyme ADAR1 independently control nucleic acid sensor MDA5-driven autoimmunity and multi-organ development. Immunity 43, 933–944 (2015).

  65. 65.

    Mannion, N. M. et al. The RNA-editing enzyme ADAR1 controls innate immune responses to RNA. Cell Rep. 9, 1482–1494 (2014). References 63, 64 and 65 provide compelling evidence that the main function of ADAR1 editing is to inhibit self-activation of innate immunity by endogenous dsRNA.

  66. 66.

    Weber, F., Wagner, V., Rasmussen, S. B., Hartmann, R. & Paludan, S. R. 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 (2006).

  67. 67.

    Feng, Q. et al. MDA5 detects the double-stranded RNA replicative form in picornavirus-infected cells. Cell Rep. 2, 1187–1196 (2012).

  68. 68.

    Chung, H. et al. Human ADAR1 prevents endogenous RNA from triggering translational shutdown. Cell 172, 811–824.e14 (2018).

  69. 69.

    Ahmad, S. et al. Breaching self-tolerance to alu duplex RNA underlies MDA5-mediated inflammation. Cell 172, 797–810.e13 (2018).

  70. 70.

    Heraud-Farlow, J. E. et al. Protein recoding by ADAR1-mediated RNA editing is not essential for normal development and homeostasis. Genome Biol. 18, 166 (2017).

  71. 71.

    Rice, G. I. et al. Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature. Nat. Genet. 44, 1243–1248 (2012).

  72. 72.

    Bazak, L. et al. A-To-I RNA editing occurs at over a hundred million genomic sites, located in a majority of human genes. Genome Res. 24, 365–376 (2014). This study reveals the scope of editing in repetitive elements.

  73. 73.

    Porath, H. T., Knisbacher, B. A., Eisenberg, E. & Levanon, E. Y. Massive A-to-I RNA editing is common across the metazoa and correlates with dsRNA abundancee. Genome Biol. 18, 185 (2017).

  74. 74.

    Porath, H. T. et al. A-To-I RNA editing in the earliest-diverging eumetazoan phyla. Mol. Biol. Evol. 34, 1890–1901 (2017).

  75. 75.

    Neeman, Y., Levanon, E. Y., Jantsch, M. F. & Eisenberg, E. RNA editing level in the mouse is determined by the genomic repeat repertoire. RNA 12, 1802–1809 (2006).

  76. 76.

    Bazak, L., Levanon, E. Y. & Eisenberg, E. Genome-wide analysis of Alu editability. Nucleic Acids Res. 42, 6876–6884 (2014).

  77. 77.

    Feschotte, C. Transposable elements and the evolution of regulatory networks. Nat. Rev. Genet. 9, 397–405 (2008).

  78. 78.

    Deininger, P. L., Moran, J. V., Batzer, M. A. & Kazazian, H. H. Mobile elements and mammalian genome evolution. Curr. Opin. Genet. Dev. 13, 651–658 (2003).

  79. 79.

    Lowe, C. B., Bejerano, G. & Haussler, D. Thousands of human mobile element fragments undergo strong purifying selection near developmental genes. Proc. Natl Acad. Sci. USA 104, 8005–8010 (2007).

  80. 80.

    Ramaswami, G. et al. Genetic mapping uncovers cis-regulatory landscape of RNA editing. Nat. Commun. 6, 8194 (2015).

  81. 81.

    Daniel, C., Widmark, A., Rigardt, D. & Öhman, M. Editing inducer elements increases A-to-I editing efficiency in the mammalian transcriptome. Genome Biol. 18, 195 (2017).

  82. 82.

    Daniel, C., Venø, M. T., Ekdahl, Y., Kjems, J. & Öhman, M. A distant cis acting intronic element induces site-selective RNA editing. Nucleic Acids Res. 40, 9876–9886 (2012).

  83. 83.

    Daniel, C., Silberberg, G., Behm, M. & Ohman, M. Alu elements shape the primate transcriptome by cis-regulation of RNA editing. Genome Biol. 15, R28 (2014).

  84. 84.

    Möller-Krull, M., Zemann, A., Roos, C., Brosius, J. & Schmitz, J. Beyond DNA: RNA editing and steps toward alu exonization in primates. J. Mol. Biol. 382, 601–609 (2008).

  85. 85.

    Dagan, T., Sorek, R., Sharon, E., Ast, G. & Graur, D. AluGene: a database of Alu elements incorporated within protein-coding genes. Nucleic Acids Res. 32, D489–D492 (2004).

  86. 86.

    Paz-Yaacov, N. et al. Adenosine-to-inosine RNA editing shapes transcriptome diversity in primates. Proc. Natl Acad. Sci. USA 107, 12174–12179 (2010).

  87. 87.

    Rieder, L. E., Staber, C. J., Hoopengardner, B. & Reenan, R. A. Tertiary structural elements determine the extent and specificity of messenger RNA editing. Nat. Commun. 4, 2232 (2013).

  88. 88.

    Sapiro, A. L., Deng, P., Zhang, R. & Li, J. B. Cis regulatory effects on A-to-I RNA editing in related Drosophila species. Cell Rep. 11, 697–703 (2015).

  89. 89.

    Wahlstedt, H. et al. Large-scale mRNA sequencing determines global regulation of RNA editing during brain development. Genome Res. 19, 978–986 (2009).

  90. 90.

    Gommans, W. M., Mullen, S. P. & Maas, S. RNA editing: a driving force for adaptive evolution? BioEssays 31, 1137–1145 (2009).

  91. 91.

    Reenan, R. A. Molecular determinants and guided evolution of species-specific RNA editing. Nature 434, 409–413 (2005).

  92. 92.

    Greenberger, S. et al. Consistent levels of A-to-I RNA editing across individuals in coding sequences and non-conserved Alu repeats. BMC Genomics 11, 608 (2010).

  93. 93.

    Picardi, E. et al. Profiling RNA editing in human tissues: towards the inosinome atlas. Sci. Rep. 5, 14941 (2015).

  94. 94.

    Oakes, E., Anderson, A., Cohen-Gadol, A. & Hundley, H. A. 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 (2017).

  95. 95.

    Marcucci, R. et al. Pin1 and WWP2 regulate GluR2 Q/R site RNA editing by ADAR2 with opposing effects. EMBO J. 30, 4211–4222 (2011).

  96. 96.

    Behm, M., Wahlstedt, H., Widmark, A., Eriksson, M. & Öhman, M. Accumulation of nuclear ADAR2 regulates adenosine-to-inosine RNA editing during neuronal development. J. Cell Sci. 130, 745–753 (2017).

  97. 97.

    Garncarz, W., Tariq, A., Handl, C., Pusch, O. & Jantsch, M. F. A high-throughput screen to identify enhancers of ADAR-mediated RNA-editing. RNA Biol. 10, 192–204 (2013).

  98. 98.

    Garrett, S. & Rosenthal, J. J. C. RNA editing underlies temperature adaptation in K+ channels from polar octopuses. Science 335, 848–851 (2012).

  99. 99.

    Rieder, L. E. et al. Dynamic response of RNA editing to temperature in Drosophila. BMC Biol. 13, 1 (2015).

  100. 100.

    Buchumenski, I. et al. Dynamic hyper-editing underlies temperature adaptation in Drosophila. PLoS Genet. 13, e1006931 (2017).

  101. 101.

    Garrett, S. C. & Rosenthal, J. J. C. A role for A-to-I RNA editing in temperature adaptation. Physiology 27, 362–369 (2012).

  102. 102.

    Robinson, J. E., Paluch, J., Dickman, D. K. & Joiner, W. J. ADAR-mediated RNA editing suppresses sleep by acting as a brake on glutamatergic synaptic plasticity. Nat. Commun. 7, 10512 (2016).

  103. 103.

    Terajima, H. et al. ADARB1 catalyzes circadian A-to-I editing and regulates RNA rhythm. Nat. Genet. 49, 146–151 (2016).

  104. 104.

    Yablonovitch, A. L., Deng, P., Jacobson, D. & Li, J. B. The evolution and adaptation of A-to-I RNA editing. PLoS Genet. 13, e1007064 (2017).

  105. 105.

    Yablonovitch, A. L. et al. Regulation of gene expression and RNA editing in Drosophila adapting to divergent microclimates. Nat. Commun. 8, 1570 (2017).

  106. 106.

    Galeano, F., Tomaselli, S., Locatelli, F. & Gallo, A. A-To-I RNA editing: the ‘ADAR’ side of human cancer. Semin. Cell Dev. Biol. 23, 244–250 (2012).

  107. 107.

    Burns, M. B. et al. APOBEC3B is an enzymatic source of mutation in breast cancer. Nature 494, 366–370 (2013).

  108. 108.

    Nik-Zainal, S. et al. Mutational processes molding the genomes of 21 breast cancers. Cell 149, 979–993 (2012).

  109. 109.

    Fumagalli, D. et al. Principles governing A-to-I RNA editing in the breast cancer transcriptome article principles governing A-to-I RNA editing in the breast cancer transcriptome. Cell Rep. 13, 277–289 (2015).

  110. 110.

    Han, L. et al. The genomic landscape and clinical relevance of A-to-I RNA editing in human cancers. Cancer Cell 28, 515–528 (2015). References 44, 109 and 110 show that editing is elevated in cancer and introduce the concept that so-called RNA mutation putatively helps promote malignancy.

  111. 111.

    Shoshan, E. et al. Reduced adenosine-to-inosine miR-455-5p editing promotes melanoma growth and metastasis. Nat. Cell Biol. 17, 311–321 (2015).

  112. 112.

    Shimokawa, T. et al. RNA editing of the GLI1 transcription factor modulates the output of hedgehog signaling. RNA Biol. 10, 321–333 (2013).

  113. 113.

    Cesarini, V. et al. ADAR2/miR-589-3p axis controls glioblastoma cell migration/invasion. Nucleic Acids Res. 46, 2045–2059 (2018).

  114. 114.

    George, C. X., Ramaswami, G., Li, J. B. & Samuel, C. E. Editing of cellular self-RNAs by adenosine deaminase ADAR1 suppresses innate immune stress responses. J. Biol. Chem. 291, 6158–6168 (2016).

  115. 115.

    Danan-Gotthold, M., Guyon, C., Giraud, M., Levanon, E. Y. & Abramson, J. Extensive RNA editing and splicing increase immune self-representation diversity in medullary thymic epithelial cells. Genome Biol. 17, 219 (2016).

  116. 116.

    Kawahara, Y. et al. Glutamate receptors: RNA editing and death of motor neurons. Nature 427, 801 (2004).

  117. 117.

    Srivastava, P. K. et al. Genome-wide analysis of differential RNA editing in epilepsy. Genome Res. 27, 440–450 (2017).

  118. 118.

    Gurevich, I. et al. Altered editing of serotonin 2C receptor pre-mRNA in the prefrontal cortex of depressed suicide victims. Neuron 34, 349–356 (2002).

  119. 119.

    Silberberg, G., Lundin, D., Navon, R. & Öhman, M. Deregulation of the A-to-I RNA editing mechanism in psychiatric disorders. Hum. Mol. Genet. 21, 311–321 (2012).

  120. 120.

    Filippini, A. et al. Absence of the fragile X mental retardation protein results in defects of RNA editing of neuronal mRNAs in mouse. RNA Biol. 14, 1580–1591 (2017).

  121. 121.

    Shamay-Ramot, A. et al. Fmrp interacts with adar and regulates RNA editing, synaptic density and locomotor activity in zebrafish. PLoS Genet. 11, e1005702 (2015).

  122. 122.

    Bhogal, B. et al. Modulation of dADAR-dependent RNA editing by the Drosophila fragile X mental retardation protein. Nat. Neurosci. 14, 1517–1524 (2011).

  123. 123.

    Zhang, R. et al. Quantifying RNA allelic ratios by microfluidic multiplex PCR and sequencing. Nat. Methods 11, 51–54 (2014).

  124. 124.

    Gal-Mark, N. et al. Abnormalities in A-to-I RNA editing patterns in CNS injuries correlate with dynamic changes in cell type composition. Sci. Rep. 7, 43421 (2017).

  125. 125.

    Hwang, T. et al. Dynamic regulation of RNA editing in human brain development and disease. Nat. Neurosci. 19, 1093–1099 (2016).

  126. 126.

    Khermesh, K. et al. Reduced levels of protein recoding by A-to-I RNA editing in Alzheimer’ s disease. RNA 22, 1–13 (2016).

  127. 127.

    Eran, A. et al. Comparative RNA editing in autistic and neurotypical cerebella. Mol. Psychiatry 18, 1041–1048 (2013).

  128. 128.

    Mele, M. et al. The human transcriptome across tissues and individuals. Science 348, 660–665 (2015).

  129. 129.

    Stellos, K. et al. Adenosine-to-inosine RNA editing controls cathepsin S expression in atherosclerosis by enabling HuR-mediated post-transcriptional regulation. Nat. Med 22, 1140–1150 (2016).

  130. 130.

    Garalde, D. R. et al. Highly parallel direct RNA sequencing on an array of nanopores. Nat. Methods 15, 201–206 (2018).

  131. 131.

    Novoa, E. M., Mason, C. E. & Mattick, J. S. Charting the unknown epitranscriptome. Nat. Rev. Mol. Cell. Biol. 18, 339–340 (2017).

  132. 132.

    Picardi, E., Horner, D. S. & Pesole, G. Single-cell transcriptomics reveals specific RNA editing signatures in the human brain. RNA 23, 860–865 (2017).

  133. 133.

    Harjanto, D. et al. RNA editing generates cellular subsets with diverse sequence within populations. Nat. Commun. 7, 12145 (2016).

  134. 134.

    Liu, H. et al. Genome-wide A-to-I RNA editing in fungi independent of ADAR enzymes. Genome Res. 26, 499–509 (2016).

  135. 135.

    Liu, H. et al. A-To-I RNA editing is developmentally regulated and generally adaptive for sexual reproduction in Neurospora crassa. Proc. Natl Acad. Sci. USA 114, E7756–E7765 (2017).

  136. 136.

    Bar-Yaacov, D. et al. RNA editing in bacteria recodes multiple proteins and regulates an evolutionarily conserved toxin-antitoxin system. Genome Res. 27, 1696–1703 (2017).

  137. 137.

    McMahon, A. C. et al. TRIBE: hijacking an RNA-editing enzyme to identify cell-specific targets of RNA-binding proteins. Cell 165, 742–753 (2016).

  138. 138.

    Wettengel, J., Reautschnig, P., Geisler, S., Kahle, P. J. & Stafforst, T. Harnessing human ADAR2 for RNA repair - recoding a PINK1 mutation rescues mitophagy. Nucleic Acids Res. 45, 2797–2808 (2017).

  139. 139.

    Montiel-Gonzalez, M. F., Vallecillo-Viejo, I., Yudowski, G. A. & Rosenthal, J. J. C. Correction of mutations within the cystic fibrosis transmembrane conductance regulator by site-directed RNA editing. Proc. Natl Acad. Sci. USA 110, 18285–18290 (2013).

  140. 140.

    Vogel, P., Hanswillemenke, A. & Stafforst, T. Switching protein localization by site-directed RNA editing under control of light. ACS Synth. Biol. 6, 1642–1649 (2017).

  141. 141.

    Vallecillo-Viejo, I. C., Liscovitch-Brauer, N., Montiel-Gonzalez, M. F., Eisenberg, E. & Rosenthal, J. J. C. Abundant off-target edits from site-directed RNA editing can be reduced by nuclear localization of the editing enzyme. RNA Biol. 15, 104–114 (2018).

  142. 142.

    Bass, B. L. & Weintraub, H. An unwinding activity that covalently modifies its double-stranded RNA substrate. Cell 55, 1089–1098 (1988).

  143. 143.

    Rebagliati, M. R. & Melton, D. A. Antisense RNA injections in fertilized frog eggs reveal an RNA duplex unwinding activity. Cell 48, 599–605 (1987).

  144. 144.

    Wagner, R. W., Smith, J. E., Cooperman, B. S. & Nishikura, K. 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 86, 2647–2651 (1989).

  145. 145.

    Schrider, D. R., Gout, J.-F. & Hahn, M. W. Very few RNA and DNA sequence differences in the human transcriptome. PLoS One 6, e25842 (2011).

  146. 146.

    Kleinman, C. L. & Majewski, J. Comment on "widespread RNA and DNA sequence differences in the human transcriptome". Science 335, author reply 1302 (2012).

  147. 147.

    Eisenberg, E., Li, J. B. & Levanon, E. Y. Sequence based identification of RNA editing sites. RNA Biol. 7, 248–252 (2010).

  148. 148.

    Pickrell, J. K., Gilad, Y. & Pritchard, J. K. Comment on “widespread RNA and DNA sequence differences in the human transcriptome”. Science 335, author reply 1302 (2012).

  149. 149.

    Lin, W., Piskol, R., Tan, M. H. & Li, J. B. Comment on “Widespread RNA and DNA Sequence Differences in the Human Transcriptome”. Science 335, author reply 1302 (2012).

  150. 150.

    Piskol, R., Peng, Z., Wang, J. & Li, J. B. Lack of evidence for existence of noncanonical RNA editing. Nat. Biotechnol. 31, 19–20 (2013).

  151. 151.

    Ramaswami, G. et al. Accurate identification of human Alu and non-Alu RNA editing sites. Nat. Methods 9, 579–581 (2012).

  152. 152.

    Picardi, E. & Pesole, G. REDItools: high-throughput RNA editing detection made easy. Bioinformatics 29, 1813–1814 (2013).

  153. 153.

    Diroma, M. A., Ciaccia, L., Pesole, G. & Picardi, E. Elucidating the editome: bioinformatics approaches for RNA editing detection. Brief. Bioinform. https://doi.org/10.1093/bib/bbx129 (2017).

  154. 154.

    Bahn, J. H. et al. Accurate identification of A-to-I RNA editing in human by transcriptome sequencing. Genome Res. 22, 142–150 (2012).

  155. 155.

    Park, E., Williams, B., Wold, B. J. & Mortazavi, A. RNA editing in the human encode RNA-seq data. Genome Res. 22, 1626–1633 (2012).

  156. 156.

    Ramaswami, G. et al. Identifying RNA editing sites using RNA sequencing data alone. Nat. Methods 10, 128–132 (2013).

  157. 157.

    Zhang, Q. & Xiao, X. Genome sequence–independent identification of RNA editing sites. Nat. Methods 12, 347–350 (2015).

  158. 158.

    John, D., Weirick, T., Dimmeler, S. & Uchida, S. RNAEditor: easy detection of RNA editing events and the introduction of editing islands. Brief. Bioinform. 18, 993–1001 (2016).

  159. 159.

    Porath, H. T., Carmi, S. & Levanon, E. Y. A genome-wide map of hyper-edited RNA reveals numerous new sites. Nat. Commun. 5, 4726 (2014).

  160. 160.

    Carmi, S., Borukhov, I. & Levanon, E. Y. Identification of widespread ultra-edited human RNAs. PLoS Genet. 7, e1002317 (2011).

  161. 161.

    Sakurai, M. et al. A biochemical landscape of A-to-I RNA editing in the human brain transcriptome. Genome Res. 24, 522–534 (2014).

  162. 162.

    Bahn, J. H. et al. Genomic analysis of ADAR1 binding and its involvement in multiple RNA processing pathways. Nat. Commun. 6, 6355 (2015).

  163. 163.

    Cattenoz, P. B., Taft, R. J., Westhof, E. & Mattick, J. S. Transcriptome-wide identification of A > I RNA editing sites by inosine specific cleavage. RNA 19, 257–270 (2013).

  164. 164.

    Morse, D. P. & Bass, B. L. Detection of inosine in messenger RNA by inosine-specific cleavage. Biochemistry 36, 8429–8434 (1997).

  165. 165.

    Kiran, A. & Baranov, P. V. DARNED: a database of RNA editing in humans. Bioinformatics 26, 1772–1776 (2010).

  166. 166.

    Piechotta, M., Wyler, E., Ohler, U., Landthaler, M. & Dieterich, C. JACUSA: site-specific identification of RNA editing events from replicate sequencing data. BMC Bioinformatics 18, 7 (2017).

  167. 167.

    Wang, Z. et al. RES-scanner: a software package for genome-wide identification of RNA-editing sites. Gigascience 5, 37 (2016).

  168. 168.

    Zhang, F., Lu, Y., Yan, S., Xing, Q. & Tian, W. SPRINT: an SNP-free toolkit for identifying RNA editing sites. Bioinformatics 33, 3538–3548 (2017).

  169. 169.

    Patterson, 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. 15, 5376–5388 (1995).

  170. 170.

    Cho, D. S. C. et al. Requirement of dimerization for RNA editing activity of adenosine deaminases acting on RNA. J. Biol. Chem. 278, 17093–17102 (2003).

  171. 171.

    Keegan, L. P. et al. Functional conservation in human and Drosophila of metazoan ADAR2 involved in RNA editing: loss of ADAR1 in insects. Nucleic Acids Res. 39, 7249–7262 (2011).

  172. 172.

    Palavicini, J. P., O’Connell, M. A. & Rosenthal, J. J. C. An extra double-stranded RNA binding domain confers high activity to a squid RNA editing enzyme. RNA 15, 1208–1218 (2009).

  173. 173.

    Palavicini, J. P., Correa-Rojas, R. A. & Rosenthal, J. J. C. 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 (2012).

  174. 174.

    Li, Q. et al. Caste-specific RNA editomes in the leaf-cutting ant Acromyrmex echinatior. Nat. Commun. 5, 4943 (2014).

  175. 175.

    Zaranek, A. W., Levanon, E. Y., Zecharia, T., Clegg, T. & Church, G. M. A survey of genomic traces reveals a common sequencing error, RNA editing, and DNA editing. PLoS Genet. 6, 8 (2010).

  176. 176.

    Chen, J.-Y. et al. RNA Editome in rhesus macaque shaped by purifying selection. PLoS Genet. 10, e1004274 (2014).

  177. 177.

    Li, Z. et al. Evolutionary and ontogenetic changes in RNA editing in human, chimpanzee, and macaque brains. RNA 19, 1693–1702 (2013).

  178. 178.

    Chen, L. Characterization and comparison of human nuclear and cytosolic editomes. Proc. Natl Acad. Sci. USA 110, E2741–E2747 (2013).

  179. 179.

    Goldstein, B. et al. A-To-I RNA editing promotes developmental stage-specific gene and lncRNA expression. Genome Res. 27, 462–470 (2017).

  180. 180.

    Stafforst, T. & Schneider, M. F. An RNA-deaminase conjugate selectively repairs point mutations. Angew. Chem. Int. Ed. Engl. 51, 11166–11169 (2012).

  181. 181.

    Fukuda, M. et al. Construction of a guide-RNA for site-directed RNA mutagenesis utilising intracellular A-to-I RNA editing. Sci. Rep. 7, 41478 (2017).

  182. 182.

    Cox, D. B. T. et al. RNA editing with CRISPR-Cas13. Science 358, 1019–1027 (2017).

Download references


The authors thank O. Gabay for the graphical work and B. Knisbacher and the Levanon laboratory members for fruitful discussions. The authors also thank J. Rosenthal and J-B. Li for critical reading of the manuscript. This work was supported by the European Research Council (grant 311257), the Israel Science Foundation (1380/14) and the Minerva Stiftung ARCHES award from the Federal German Ministry for Education and Research (BMBF) to E.Y.L. E.E. was supported by the Israel Science Foundation (2673/17) and the United States-Israel Binational Science Foundation (094/2013).

Reviewer information

Nature Reviews Genetics thanks L. Keegan, M. Öhman and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

Both authors contributed to all aspects of this manuscript.

Correspondence to Eli Eisenberg or Erez Y. Levanon.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


Non-coding RNAs

RNA transcripts that are not translated into proteins but may have a regulatory function.


Short non-coding RNAs that regulate gene expression post-transcriptionally, mainly by binding to the 3′ untranslated region of mRNA.

Circular RNAs

RNA molecules that form a covalently closed continuous loop. They were found only recently, and the function of most of them is not known.

RNA modifications

Changes to the chemical composition of RNA molecules that have the potential to alter their function or stability.


The entire set of RNA editing events in a genome.

Non-synonymous substitutions

Replacement of one base by another within a coding region of a gene, which results in an amino acid change in the protein sequence.


Arises when the number of reads that include a given nucleotide is insufficient to provide reliable variant calling at that position in the reconstructed sequence.

Ultra-deep sequencing

The application of massively parallel sequencing methods to a small set of targets, yielding much higher read coverage than that obtained from standard whole-transcriptome RNA sequencing data.

Purifying selection

Selective removal of deleterious alleles from the general population.


Mobile elements that move around the genome through transcription into RNA followed by reverse transcription.

Mobile elements

DNA fragments that can move around within the genome. Most of the mammalian genome is composed of sequences derived from mobile genetic elements.


Recruitment of a new exon from non-protein-coding intronic DNA, mostly from mobile elements.

Synonymous substitutions

Replacement of one base by another within a coding region of a gene, which does not result in an amino acid change in the protein sequence.


A trait, a gene or a cellular process that has changed function during evolution.


The evolutionary process by which the genetic information carried by a population of organisms is adjusted to improve their fitness to the environment.


The process by which an individual organism adjusts to a short-term change in its environment (as opposed to genomic changes on evolutionary timescales, called adaptation).

Somatic mutation

An alteration in DNA that occurs after conception. Somatic mutations are not shared by all cells of the body.

Passenger mutations

Mutations that are caused by genomic instability, which is common in cancer cells, but do not promote malignancy.

Driver mutations

Mutations that provide cancer cells with a selective advantage and promote malignancy.

Nanopore sequencing platforms

Emerging sequencing methods by which a single molecule of DNA or RNA can be sequenced without the need for PCR amplification.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Eisenberg, E., Levanon, E.Y. A-to-I RNA editing — immune protector and transcriptome diversifier. Nat Rev Genet 19, 473–490 (2018) doi:10.1038/s41576-018-0006-1

Download citation

Further reading