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  • Review Article
  • Published:

Editor meets silencer: crosstalk between RNA editing and RNA interference

Nature Reviews Molecular Cell Biology volume 7, pages 919–931 (2006)Cite this article

Key Points

  • Adenosine to inosine (A→I) RNA editing is catalysed by ADAR (adenosine deaminases acting on RNA) proteins.

  • Three mammalian ADAR genes (ADAR1–3), the products of which have common functional domains, have been identified.

  • Protein-coding sequences of a limited number of genes, such as the glutamate receptor GluR2 and serotonin receptor 2C, are edited, which results in dramatic alterations of protein functions.

  • Deficiencies in the A→I RNA editing mechanism cause human diseases and pathophysiologies.

  • Recent bioinformatics studies identified numerous A→I RNA editing sites genome wide in Alu and long interspersed element (LINE) repetitive RNA sequences located in introns and untranslated regions, but identified only a few sites in protein-coding exons.

  • The biogenesis of certain microRNAs is regulated by the editing of their precursors.

  • A→I RNA editing and RNA-interference mechanisms seem to interact and compete for common substrate double-stranded RNAs.

Abstract

The most prevalent type of RNA editing is mediated by ADAR (adenosine deaminase acting on RNA) enzymes, which convert adenosines to inosines (a process known as A→I RNA editing) in double-stranded (ds)RNA substrates. A→I RNA editing was long thought to affect only selected transcripts by altering the proteins they encode. However, genome-wide screening has revealed numerous editing sites within inverted Alu repeats in introns and untranslated regions. Also, recent evidence indicates that A→I RNA editing crosstalks with RNA-interference pathways, which, like A→I RNA editing, involve dsRNAs. A→I RNA editing therefore seems to have additional functions, including the regulation of retrotransposons and gene silencing, which adds a new urgency to the challenges of fully understanding ADAR functions.

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Figure 1: Deamination of adenosine to inosine by ADAR.
Figure 2: Types of dsRBD-containing protein: ADAR-family proteins and proteins that are required for miRNA biogenesis.
Figure 3: Functional changes by A→I RNA editing of coding sequences.
Figure 4: Extensive A→I RNA editing of non-coding repeat sequences.
Figure 5: Possible regulatory functions for non-coding RNA editing.
Figure 6: Interaction between RNA editing and RNA-interference pathways.
Figure 7: Regulation of microRNA processing and expression by RNA editing.

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References

  1. Bentley, D. L. Rules of engagement: co-transcriptional recruitment of pre-mRNA processing factors. Curr. Opin. Cell Biol. 17, 251–256 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. Gott, J. M. & Emeson, R. B. Functions and mechanisms of RNA editing. Annu. Rev. Genet. 34, 499–531 (2000).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Keegan, L. P., Leroy, A., Sproul, D. & O'Connell, M. A. Adenosine deaminases acting on RNA (ADARs): RNA-editing enzymes. Genome Biol. 5, 209 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Valente, L. & Nishikura, K. ADAR gene family and A-to-I RNA editing: diverse roles in posttranscriptional gene regulation. Prog. Nucleic Acid Res. Mol. Biol. 79, 299–338 (2005). An up-to-date review on A→I editing and ADAR genes.

    Article  CAS  PubMed  Google Scholar 

  6. 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).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Levanon, E. Y. et al. Systematic identification of abundant A-to-I editing sites in the human transcriptome. Nature Biotechnol. 22, 1001–1005 (2004). References 6–9 report a genome-wide screening strategy, leading to the identification of numerous A→I editing sites in non-coding Alu repeat RNAs.

    Article  CAS  Google Scholar 

  10. Fire, A. et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806–811 (1998).

    Article  CAS  PubMed  Google Scholar 

  11. Filipowicz, W., Jaskiewicz, L., Kolb, F. A. & Pillai, R. S. Post-transcriptional gene silencing by siRNAs and miRNAs. Curr. Opin. Struct. Biol. 15, 331–341 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Du, T. & Zamore, P. D. microPrimer: the biogenesis and function of microRNA. Development 132, 4645–4652 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Hannon, G. J. RNA interference. Nature 418, 244–251 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Kim, V. N. MicroRNA biogenesis: coordinated cropping and dicing. Nature Rev. Mol. Cell Biol. 6, 376–385 (2005).

    Article  CAS  Google Scholar 

  16. Meister, G. & Tuschl, T. Mechanisms of gene silencing by double-stranded RNA. Nature 431, 343–349 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Bass, B. L. Double-stranded RNA as a template for gene silencing. Cell 101, 235–238 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Luciano, D. J., Mirsky, H., Vendetti, N. J. & Maas, S. RNA editing of a miRNA precursor. RNA 10, 1174–1177 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yang, W. et al. Modulation of microRNA processing and expression through RNA editing by ADAR deaminases. Nature Struct. Mol. Biol. 13, 13–21 (2006). Shows that A→I editing of a miRNA-142 precursor suppresses its processing by Drosha–DGCR8 and also that the highly edited precursor RNAs are degraded by Tudor-SN.

    Article  CAS  Google Scholar 

  20. Pfeffer, S. et al. Identification of microRNAs of the herpesvirus family. Nature Methods 2, 269–276 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Blow, M. J. et al. RNA editing of human microRNAs. Genome Biol. 7, R27 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Yang, W. et al. ADAR1 RNA deaminase limits short interfering RNA efficacy in mammalian cells. J. Biol. Chem. 280, 3946–3953 (2005). Shows that ADAR1L functions as an RNAi suppressor by sequestering siRNAs.

    Article  CAS  PubMed  Google Scholar 

  23. Tonkin, L. A. & Bass, B. L. Mutations in RNAi rescue aberrant chemotaxis of ADAR mutants. Science 302, 1725 (2003). Shows the RNAi dependence of ADAR-null worm phenotypes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Tonkin, L. A. et al. RNA editing by ADARs is important for normal behavior in Caenorhabditis elegans. EMBO J. 21, 6025–6035 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Knight, S. W. & Bass, B. L. The role of RNA editing by ADARs in RNAi. Mol. Cell 10, 809–817 (2002). Shows, for the first time, that A→I editing prevents RNAi-mediated transgene silencing, which implies an interaction between RNAi and RNA-editing pathways.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  27. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bass, B. L. & Weintraub, H. A developmentally regulated activity that unwinds RNA duplexes. Cell 48, 607–613 (1987).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  30. Kim, U., Wang, Y., Sanford, T., Zeng, Y. & Nishikura, K. Molecular cloning of cDNA for double-stranded RNA adenosine deaminase, a candidate enzyme for nuclear RNA editing. Proc. Natl Acad. Sci. USA 91, 11457–11461 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Melcher, T. et al. A mammalian RNA editing enzyme. Nature 379, 460–464 (1996).

    Article  CAS  PubMed  Google Scholar 

  32. Lai, F., Chen, C. X., Carter, K. C. & Nishikura, K. Editing of glutamate receptor B subunit ion channel RNAs by four alternatively spliced DRADA2 double-stranded RNA adenosine deaminases. Mol. Cell. Biol. 17, 2413–2424 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gerber, A., O'Connell, M. A. & Keller, W. Two forms of human double-stranded RNA-specific editase 1 (hRED1) generated by the insertion of an Alu cassette. RNA 3, 453–463 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Melcher, T. et al. RED2, a brain-specific member of the RNA-specific adenosine deaminase family. J. Biol. Chem. 271, 31795–31798 (1996).

    Article  CAS  PubMed  Google Scholar 

  35. Chen, 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 6, 755–767 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Palladino, M. J., Keegan, L. P., O'Connell, M. A. & Reenan, R. A. A-to-I pre-mRNA editing in Drosophila is primarily involved in adult nervous system function and integrity. Cell 102, 437–449 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. Ryter, J. M. & Schultz, S. C. Molecular basis of double-stranded RNA-protein interactions: structure of a dsRNA-binding domain complexed with dsRNA. EMBO J. 17, 7505–7513 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lai, F., Drakas, R. & Nishikura, K. Mutagenic analysis of double-stranded RNA adenosine deaminase, a candidate enzyme for RNA editing of glutamate-gated ion channel transcripts. J. Biol. Chem. 270, 17098–17105 (1995).

    Article  CAS  PubMed  Google Scholar 

  39. Macbeth, M. R. et al. Inositol hexakisphosphate is bound in the ADAR2 core and required for RNA editing. Science 309, 1534–1539 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kawakubo, K. & Samuel, C. E. Human RNA-specific adenosine deaminase (ADAR1) gene specifies transcripts that initiate from a constitutively active alternative promoter. Gene 258, 165–172 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Yang, J. H. et al. Widespread inosine-containing mRNA in lymphocytes regulated by ADAR1 in response to inflammation. Immunology 109, 15–23 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Peng, P. L. et al. ADAR2-dependent RNA editing of AMPA receptor subunit GluR2 determines vulnerability of neurons in forebrain ischemia. Neuron 49, 719–733 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Desterro, J. M. et al. Dynamic association of RNA-editing enzymes with the nucleolus. J. Cell Sci. 116, 1805–1818 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Poulsen, H., Nilsson, J., Damgaard, C. K., Egebjerg, J. & Kjems, J. CRM1 mediates the export of ADAR1 through a nuclear export signal within the Z-DNA binding domain. Mol. Cell. Biol. 21, 7862–7871 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Sansam, C. L., Wells, K. S. & Emeson, R. B. Modulation of RNA editing by functional nucleolar sequestration of ADAR2. Proc. Natl Acad. Sci. USA 100, 14018–14023 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Nishikura, K. et al. Substrate specificity of the dsRNA unwinding/modifying activity. EMBO J. 10, 3523–3532 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lehmann, K. A. & Bass, B. L. The importance of internal loops within RNA substrates of ADAR1. J. Mol. Biol. 291, 1–13 (1999).

    Article  CAS  PubMed  Google Scholar 

  49. Higuchi, M. et al. RNA editing of AMPA receptor subunit GluR-B: a base-paired intron–exon structure determines position and efficiency. Cell 75, 1361–1370 (1993).

    Article  CAS  PubMed  Google Scholar 

  50. Wang, Q. et al. Altered G protein-coupling functions of RNA editing isoform and splicing variant serotonin2C receptors. J. Neurochem. 74, 1290–1300 (2000).

    Article  CAS  PubMed  Google Scholar 

  51. Seeburg, P. H. & Hartner, J. Regulation of ion channel/neurotransmitter receptor function by RNA editing. Curr. Opin. Neurobiol. 13, 279–283 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Reenan, R. A. The RNA world meets behavior: A→I pre-mRNA editing in animals. Trends Genet. 17, 53–56 (2001).

    Article  CAS  PubMed  Google Scholar 

  53. Stefl, R., Xu, M., Skrisovska, L., Emeson, R. B. & Allain, F. H. Structure and specific RNA binding of ADAR2 double-stranded RNA binding motifs. Structure 14, 345–355 (2006).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  57. Reenan, R. A., Hanrahan, C. J. & Ganetzky, B. The mle(napts) RNA helicase mutation in Drosophila results in a splicing catastrophe of the para Na+ channel transcript in a region of RNA editing. Neuron 25, 139–149 (2000).

    Article  CAS  PubMed  Google Scholar 

  58. Polson, A. G., Bass, B. L. & Casey, J. L. RNA editing of hepatitis delta virus antigenome by dsRNA-adenosine deaminase. Nature 380, 454–456 (1996).

    Article  CAS  PubMed  Google Scholar 

  59. 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).

    Article  CAS  PubMed  Google Scholar 

  60. Wang, Q., Khillan, J., Gadue, P. & Nishikura, K. Requirement of the RNA editing deaminase ADAR1 gene for embryonic erythropoiesis. Science 290, 1765–1768 (2000).

    Article  CAS  PubMed  Google Scholar 

  61. Wang, Q. et al. Stress-induced apoptosis associated with null mutation of ADAR1 RNA editing deaminase gene. J. Biol. Chem. 279, 4952–4961 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. Hartner, J. C. et al. Liver disintegration in the mouse embryo caused by deficiency in the RNA-editing enzyme ADAR1. J. Biol. Chem. 279, 4894–4902 (2004).

    Article  CAS  PubMed  Google Scholar 

  63. Maas, S., Kawahara, Y., Tamburro, K. M. & Nishikura, K. A-to-I RNA editing and human disease. RNA Biol. 3, 1–9 (2006). An up-to-date review on human diseases caused by defective A→I editing.

    Article  CAS  PubMed  Google Scholar 

  64. Schmauss, C. Regulation of serotonin 2C receptor pre-mRNA editing by serotonin. Int. Rev. Neurobiol. 63, 83–100 (2005).

    Article  CAS  PubMed  Google Scholar 

  65. Miyamura, Y. et al. Mutations of the RNA-specific adenosine deaminase gene (DSRAD) are involved in dyschromatosis symmetrica hereditaria. Am. J. Hum. Genet. 73, 693–699 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  67. 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).

    Article  CAS  PubMed  Google Scholar 

  68. Niswender, C. M. et al. RNA editing of the human serotonin 5-HT2C receptor. Alterations in suicide and implications for serotonergic pharmacotherapy. Neuropsychopharmacology 24, 478–491 (2001).

    Article  CAS  PubMed  Google Scholar 

  69. Paul, M. S. & Bass, B. L. Inosine exists in mRNA at tissue-specific levels and is most abundant in brain mRNA. EMBO J. 17, 1120–1127 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Clutterbuck, D. R., Leroy, A., O'Connell, M. A. & Semple, C. A. A bioinformatic screen for novel A–I RNA editing sites reveals recoding editing in BC10. Bioinformatics 21, 2590–2595 (2005). References 70 and 71 report that A→I editing of protein-coding regions is exceptionally rare, as demonstrated by a genome-wide screening strategy.

    Article  CAS  PubMed  Google Scholar 

  72. Eisenberg, E. et al. Is abundant A-to-I RNA editing primate-specific? Trends Genet. 21, 77–81 (2005).

    Article  CAS  PubMed  Google Scholar 

  73. Katayama, S. et al. Antisense transcription in the mammalian transcriptome. Science 309, 1564–1566 (2005).

    Article  PubMed  Google Scholar 

  74. Chen, J., Sun, M., Hurst, L. D., Carmichael, G. G. & Rowley, J. D. Genome-wide analysis of coordinate expression and evolution of human cis-encoded sense–antisense transcripts. Trends Genet. 21, 326–329 (2005).

    Article  CAS  PubMed  Google Scholar 

  75. Neeman, Y., Dahary, D., Levanon, E. Y., Sorek, R. & Eisenberg, E. Is there any sense in antisense editing? Trends Genet. 21, 544–547 (2005).

    Article  CAS  PubMed  Google Scholar 

  76. Kawahara, Y. & Nishikura, K. Extensive adenosine-to-inosine editing detected in Alu repeats of antisense RNAs reveals scarcity of sense–antisense duplex formation. FEBS Lett. 580, 2301–2305 (2006). References 75 and 76 show that antisense RNA is extensively edited, but only in regions containing an inverted Alu repeat dsRNA, showing that the formation of sense–antisense intermolecular dsRNAs is very rare.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Rueter, S. M., Dawson, T. R. & Emeson, R. B. Regulation of alternative splicing by RNA editing. Nature 399, 75–80 (1999).

    Article  CAS  PubMed  Google Scholar 

  78. Sorek, R. et al. Minimal conditions for exonization of intronic sequences: 5′ splice site formation in Alu exons. Mol. Cell 14, 221–231 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Zhang, Z. & Carmichael, G. G. The fate of dsRNA in the nucleus: a p54nrb-containing complex mediates the nuclear retention of promiscuously A-to-I edited RNAs. Cell 106, 465–475 (2001).

    Article  CAS  PubMed  Google Scholar 

  81. Prasanth, K. V. et al. Regulating gene expression through RNA nuclear retention. Cell 123, 249–263 (2005). Reports that A→I editing of SINE repeats located in the 3′ UTR might regulate nuclear retention and the release of cationic amino-acid transporter-2 mRNAs.

    Article  CAS  PubMed  Google Scholar 

  82. Scadden, A. D. & Smith, C. W. Specific cleavage of hyper-edited dsRNAs. EMBO J. 20, 4243–4252 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Scadden, A. D. The RISC subunit Tudor-SN binds to hyper-edited double-stranded RNA and promotes its cleavage. Nature Struct. Mol. Biol. 12, 489–496 (2005). Reports that Tudor-SN, previously identified as a RISC-associated protein, is a ribonuclease specific for inosine-containing dsRNAs, revealing a mechanistic connection between RNAi and RNA-editing pathways.

    Article  CAS  Google Scholar 

  84. Tong, X., Drapkin, R., Yalamanchili, R., Mosialos, G. & Kieff, E. The Epstein–Barr virus nuclear protein 2 acidic domain forms a complex with a novel cellular coactivator that can interact with TFIIE. Mol. Cell. Biol. 15, 4735–4744 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Wang, Q., Zhang, Z., Blackwell, K. & Carmichael, G. G. Vigilins bind to promiscuously A-to-I-edited RNAs and are involved in the formation of heterochromatin. Curr. Biol. 15, 384–391 (2005). Vigilin in complex with ADAR1 binds to inosine-containing RNAs, revealing a possible role for A→I editing in the heterochomatic gene-silencing mechanism.

    Article  CAS  PubMed  Google Scholar 

  86. Martienssen, R. A., Zaratiegui, M. & Goto, D. B. RNA interference and heterochromatin in the fission yeast Schizosaccharomyces pombe. Trends Genet. 21, 450–456 (2005).

    Article  CAS  PubMed  Google Scholar 

  87. Shilatifard, A. Chromatin modifications by methylation and ubiquitination: implications in the regulation of gene expression. Annu. Rev. Biochem. (2006).

  88. Aravin, A. A. et al. The small RNA profile during Drosophila melanogaster development. Dev. Cell 5, 337–350 (2003).

    Article  CAS  PubMed  Google Scholar 

  89. Sijen, T. & Plasterk, R. H. Transposon silencing in the Caenorhabditis elegans germ line by natural RNAi. Nature 426, 310–314 (2003).

    Article  CAS  PubMed  Google Scholar 

  90. Aravin, A. & Tuschl, T. Identification and characterization of small RNAs involved in RNA silencing. FEBS Lett. 579, 5830–5840 (2005).

    Article  CAS  PubMed  Google Scholar 

  91. Matzke, M. A. & Birchler, J. A. RNAi-mediated pathways in the nucleus. Nature Rev. Genet. 6, 24–35 (2005).

    Article  CAS  PubMed  Google Scholar 

  92. Watanabe, T. et al. Identification and characterization of two novel classes of small RNAs in the mouse germline: retrotransposon-derived siRNAs in oocytes and germline small RNAs in testes. Genes Dev. 20, 1732–1743 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Saccomanno, L. & Bass, B. L. The cytoplasm of Xenopus oocytes contains a factor that protects double-stranded RNA from adenosine-to-inosine modification. Mol. Cell. Biol. 14, 5425–5432 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Saunders, L. R. & Barber, G. N. The dsRNA binding protein family: critical roles, diverse cellular functions. FASEB J. 17, 961–983 (2003).

    Article  CAS  PubMed  Google Scholar 

  95. Scadden, A. D. & Smith, C. W. RNAi is antagonized by A→I hyper-editing. EMBO Rep. 2, 1107–1111 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Vance, V. & Vaucheret, H. RNA silencing in plants-defense and counterdefense. Science 292, 2277–2280 (2001).

    Article  CAS  PubMed  Google Scholar 

  97. Kennedy, S., Wang, D. & Ruvkun, G. A conserved siRNA-degrading RNase negatively regulates RNA interference in C. elegans. Nature 427, 645–649 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. Vargason, J. M., Szittya, G., Burgyan, J. & Tanaka Hall, T. M. Size selective recognition of siRNA by an RNA silencing suppressor. Cell 115, 799–811 (2003).

    Article  CAS  PubMed  Google Scholar 

  99. Ye, K., Malinina, L. & Patel, D. J. Recognition of small interfering RNA by a viral suppressor of RNA silencing. Nature 426, 874–878 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Hong, J. et al. High doses of siRNAs induce eri-1 and adar-1 gene expression and reduce the efficiency of RNA interference in the mouse. Biochem. J. 390, 675–679 (2005). Reports the induction of ADAR-1 and ERI-1, an siRNA-specific ribonuclease and an RNAi suppressor, respectively, by high concentrations of siRNA. This indicates the presence of a feedback mechanism.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Aravin, A. et al. A novel class of small RNAs bind to MILI protein in mouse testes. Nature 442, 203–207 (2006).

    Article  CAS  PubMed  Google Scholar 

  102. Girard, A., Sachidanandam, R., Hannon, G. J. & Carmell, M. A. A germline-specific class of small RNAs binds mammalian Piwi proteins. Nature 442, 199–202 (2006).

    Article  PubMed  Google Scholar 

  103. Lau, N. C. et al. Characterization of the piRNA complex from rat testes. Science 313, 363–367 (2006).

    Article  CAS  PubMed  Google Scholar 

  104. Byrne, E. M., Stout, A. & Gott, J. M. Editing site recognition and nucleotide insertion are separable processes in Physarum mitochondria. EMBO J. 21, 6154–6161 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Gott, J. M., Parimi, N. & Bundschuh, R. Discovery of new genes and deletion editing in Physarum mitochondria enabled by a novel algorithm for finding edited mRNAs. Nucleic Acids Res. 33, 5063–5072 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Barth, C., Greferath, U., Kotsifas, M. & Fisher, P. R. Polycistronic transcription and editing of the mitochondrial small subunit (SSU) ribosomal RNA in Dictyostelium discoideum. Curr. Genet. 36, 55–61 (1999).

    Article  CAS  PubMed  Google Scholar 

  107. Navaratnam, N. & Sarwar, R. An overview of cytidine deaminases. Int. J. Hematol. 83, 195–200 (2006).

    Article  CAS  PubMed  Google Scholar 

  108. Lohan, A. J. & Gray, M. W. Methods for analysis of mitochondrial tRNA editing in Acanthamoeba castellanii. Methods Mol. Biol. 265, 315–331 (2004).

    CAS  PubMed  Google Scholar 

  109. Wolf, J., Gerber, A. P. & Keller, W. tadA, an essential tRNA-specific adenosine deaminase from Escherichia coli. EMBO J. 21, 3841–3851 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Gerber, A. P. & Keller, W. RNA editing by base deamination: more enzymes, more targets, new mysteries. Trends Biochem. Sci. 26, 376–384 (2001).

    Article  CAS  PubMed  Google Scholar 

  111. Greger, I. H., Khatri, L., Kong, X. & Ziff, E. B. AMPA receptor tetramerization is mediated by Q/R editing. Neuron 40, 763–774 (2003).

    Article  CAS  PubMed  Google Scholar 

  112. Nishikura, K. Editing the message from A to I. Nature Biotechnol. 22, 962–963 (2004).

    Article  CAS  Google Scholar 

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Acknowledgements

I am grateful to J. M. Gott, H. H. Kazazian, J. M. Murray and also members of my laboratory, especially L. Valente and Y. Kawahara, for their comments and suggestions. This work was supported in part by grants from the US National Institutes of Health, Juvenile Diabetes Research Foundation and the Commonwealth Universal Research Enhancement Program of the Pennsylvania Department of Health.

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  1. Department of Gene Expression and Regulation, The Wistar Institute, 3601 Spruce Street, Philadelphia, 19104-4268, Pennsylvania, USA

    Kazuko Nishikura

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A→I RNA editing

Pfam — ADAR domain structure

Pfam — double-stranded RNA-binding proteins

RNA editing

Glossary

ADAR

An adenosine deaminase that catalyses an RNA-editing reaction whereby an adenosine is converted to an inosine.

Alu repeat

A dispersed, moderately repetitive DNA sequence found in the human genome with ∼1.4 million copies. The sequence is ∼300 base pairs long. The name Alu comes from the restriction endonuclease (AluI) that cleaves the sequence.

LINE

A long interspersed element (LINE) sequence that is typically used for non-long terminal repeat retrotransposons.

Non-coding RNA

RNA that is transcribed from DNA, but that is not translated into protein. Introns, 5′ and 3′ untranslated regions of mRNA, antisense transcripts (RNAs transcribed from the antisense strand of DNA), siRNA, miRNA, RNAs transcribed from repetitive sequences, tRNA, rRNA, small nuclear (sn)RNA and small nucleolar (sno)RNA are all non-coding RNAs.

Retrotransposon

A mobile genetic element; its DNA is transcribed into RNA, which is reverse-transcribed into DNA and then is inserted into a new location in the genome.

RNA interference

(RNAi). A post-transcriptional gene-silencing process in which double-stranded (ds)RNA triggers the degradation of homologous mRNA. Degradation of the target mRNA is induced by siRNAs that are derived from long dsRNA.

Small interfering RNA

(siRNA). A small (19–23 base pair) non-coding double-stranded (ds)RNA that is processed from a longer dsRNA. Such non-coding RNAs hybridize with mRNA targets, and confer target specificity to the silencing complexes in which they reside.

microRNA

(miRNA). A small (19–23 nucleotide) single-stranded RNA that is processed from a precursor that consists of a short double-stranded (ds)RNA region, internal loops or bulges, and a loop. miRNAs have an essential role in suppressing translation or in the degradation of a target mRNA by the miRNA-mediated RNA-interference mechanism.

RNase III family

A group of double-stranded (ds)RNA-specific endonucleases that cleave dsRNA into short fragments with a 3′ overhang and a recessed 5′ phosphate on each strand. Drosha and Dicer, which are essential for RNA interference, belong to this family.

RNA-induced silencing complex

(RISC). This complex, which contains siRNAs and protein factors, such as AGO2, mediates the degradation of target mRNAs with high sequence complementarity to the siRNA. A similar complex that contains miRNA instead of siRNA (miRISC) suppresses the translation of target mRNAs with partial complementarity to the miRNA.

Deamination

The chemical process that replaces a primary amino group by a hydroxyl group, resulting in the conversion of one nucleoside to another.

Double-stranded RNA-binding domain

(dsRBD). This compact (∼65 amino acids) domain with an α–β–β–β–α structure makes direct contact with the dsRNA. Proteins that function on dsRNAs contain a single or multiple dsRBDs.

Inositol hexakisphosphate

(IP6). A phospholipid that is widely distributed throughout the animal kingdom and is affiliated with a wide-ranging array of important physiological activities.

Z-DNA

A left-handed DNA form that is different from the A and B forms and that is believed to be involved in specific biological functions.

Expressed sequence tag

(EST). A single-pass, short read of complementary DNA that is generated from a transcribed region of the genome.

Single nucleotide polymorphism

(SNP). Typically a bi-allelic base-pair substitution, which is the most common form of genetic polymorphism.

SINE

Short interspersed, repetitive sequences, such as Alu elements, generated by retrotransposition.

Nuclear speckle

An irregularly shaped nuclear organelle that can be visualized by immunofluorescence microscopy using anti-splicing-factor antibodies. Usually, ∼25–50 speckles are present in the interphase mammalian nucleus, and they are thought to constitute storage and/or assembly sites for certain splicing factors.

rasiRNA

(repeat-associated siRNA). siRNA derived from repetitive sequences such as Alu or LINE retrotransposon elements or centromeric repeat sequences.

Wobble base pair

Non-G·C, A·U pairing, such as the thermodynamically less stable G·U, I·U pairing. Wobble base pairs, like Watson–Crick pairs, participate in forming helical regions in RNA folding.

piRNA

An siRNA-like, small non-coding RNA (26–30 nucleotides) that was identified as an RNA component that is complexed with Piwi-family proteins in testes.

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Nishikura, K. Editor meets silencer: crosstalk between RNA editing and RNA interference. Nat Rev Mol Cell Biol 7, 919–931 (2006). https://doi.org/10.1038/nrm2061

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  • DOI: https://doi.org/10.1038/nrm2061

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