A‐to‐I RNA Editing and Human Genetic Disease

Abstract

The regulation of when, where and how genomic information is utilised in cells and organisms is just as important for normal physiology as the deoxyribonucleic acid sequence itself. One important molecular tool at the disposal of eukaryotic cells is the process of ribonucleic acid (RNA) editing, which involves the recoding of genomically specified sequences within primary RNA transcripts. One kind of RNA editing, A‐to‐I modification, turns out to regulate the expression and function of various genes as well as enhance the functional and phenotypic diversity within the transcriptome and proteome. Recent insights on the A‐to‐I RNA‐editing machinery and the discovery of many additional editing targets, especially within mammalian species, underscore the importance of editing for normal physiology and also uncover strong links to human genetic diseases. Harnessing that knowledge could lead to approaches for treating RNA editing‐related disorders or even to the development of RNA‐directed gene therapy technologies.

Key Concepts:

  • RNA editing regulates protein function.

  • RNA editing diversifies the transcriptome and proteome.

  • ADARs mediate A‐to‐I RNA editing.

  • Important editing sites include many noncoding RNAs.

  • Some editing events are essential for survival.

  • Many editing sites await functional characterisation.

  • Deregulation of RNA editing can lead to disease.

Keywords: RNA editing; inosine; adenosine deaminase; epilepsy; cancer; neurological disorder; autoimmune disease; gene therapy

Figure 1.

Landscape of A‐to‐I RNA editing occurrence and impact. RNA editing is not random; despite the small representation of protein coding and other gene sequences within the human genome, editing is concentrated in transcribed exons, introns and transcribed repetitive sequences. When looking at the functional implications of editing, the evidence for positive selection of RNA editing events is evident from the high prevalence of editing sites in sequences that influence gene expression and function (mainly in introns, miRNA exons and protein exons). (a) Relative amounts of sequence types within the human genome. (b) Distribution of known editing sites among different types of sequences. (c) Distribution of functional roles of RNA editing across different sequence types.

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References

Aphasizhev R and Aphasizheva I (2011) Uridine insertion/deletion editing in trypanosomes: a playground for RNA‐guided information transfer. Wiley Interdisciplinary Reviews RNA 2: 669–685.

Athanasiadis A (2012) Zalpha‐domains: at the intersection between RNA editing and innate immunity. Seminars in Cell and Developmental Biology 23: 275–280.

Barraud P and Allain FH (2012) ADAR proteins: double‐stranded RNA and Z‐DNA binding domains. Current Topics in Microbiology and Immunology 353: 35–60.

Bhogal B, Jepson JE, Savva YA et al. (2011) Modulation of dADAR‐dependent RNA editing by the Drosophila fragile X mental retardation protein. Nature Neuroscience 14: 1517–1524.

Brusa R, Zimmermann F, Koh DS et al. (1995) Early‐onset epilepsy and postnatal lethality associated with an editing‐deficient GluR‐B allele in mice. Science (New York) 270: 1677–1680.

Cenci C, Barzotti R, Galeano F et al. (2008) Down‐regulation of RNA editing in pediatric astrocytomas: ADAR2 editing activity inhibits cell migration and proliferation. Journal of Biological Chemistry 283: 7251–7260.

Chen L, Li Y, Lin CH et al. (2013) Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma. Nature Medicine 19: 209–216.

Chen LL and Carmichael GG (2008) Gene regulation by SINES and inosines: biological consequences of A‐to‐I editing of Alu element inverted repeats. Cell Cycle 7: 3294–3301.

Colina C, Palavicini JP, Srikumar D, Holmgren M and Rosenthal JJ (2010) Regulation of Na+/K+ ATPase transport velocity by RNA editing. PLoS Biology 8: e1000540.

Desterro JM, Keegan LP, Jaffray E et al. (2005) SUMO‐1 modification alters ADAR1 editing activity. Molecular Bology of the Cell 16: 5115–5126.

Galeano F, Leroy A, Rossetti C et al. (2010) Human BLCAP transcript: new editing events in normal and cancerous tissues. International Journal of Cancer Journal International du Cancer 127: 127–137.

George CX, Gan Z, Liu Y and Samuel CE (2011) Adenosine deaminases acting on RNA, RNA editing, and interferon action. Journal of Interferon and Cytokine Research 31: 99–117.

Greenberger S, Levanon EY, Paz‐Yaacov N et al. (2010) Consistent levels of A‐to‐I RNA editing across individuals in coding sequences and non‐conserved Alu repeats. BMC Genomics 11: 608.

Greger IH, Akamine P, Khatri L and Ziff EB (2006) Developmentally regulated, combinatorial RNA processing modulates AMPA receptor biogenesis. Neuron 51: 85–97.

Hartner JC, Schmittwolf C, Kispert A et al. (2004) Liver disintegration in the mouse embryo caused by deficiency in the RNA‐editing enzyme ADAR1. Journal of Biological Chemistry 279: 4894–4902.

Heale BS, Keegan LP, McGurk L et al. (2009) Editing independent effects of ADARs on the miRNA/siRNA pathways. EMBO Journal 28: 3145–3156.

Herbert A, Lowenhaupt K, Spitzner J et al. (1995) Chicken double‐stranded RNA adenosine deaminase has apparent specificity for Z‐DNA. Proceedings of the National Academy of Sciences of the USA 92: 7550–7554.

Hideyama T, Yamashita T, Aizawa H et al. (2011) Profound downregulation of the RNA editing enzyme ADAR2 in ALS spinal motor neurons. Neurobiology of Disease 45(3): 1121–1128.

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

Hogg M, Paro S, Keegan LP and O'Connell MA (2011) RNA editing by mammalian ADARs. Advances in Genetics 73: 87–120.

Hood JL and Emeson RB (2012) Editing of neurotransmitter receptor and ion channel RNAs in the nervous system. Current Topics in Microbiology and Immunology 353: 61–90.

Horsch M, Seeburg PH, Adler T et al. (2011) Requirement of the RNA‐editing enzyme ADAR2 for normal physiology in mice. Journal of Biological Chemistry 286: 18614–18622.

Iizasa H and Nishikura K (2009) A new function for the RNA‐editing enzyme ADAR1. Nature Immunology 10: 16–18.

Jepson JE, Savva YA, Yokose C et al. (2011) Engineered alterations in RNA editing modulate complex behavior in Drosophila: regulatory diversity of adenosine deaminase acting on RNA (ADAR) targets. Journal of Biological Chemistry 286: 8325–8337.

Kask K, Zamanillo D, Rozov A et al. (1998) The AMPA receptor subunit GluR‐B in its Q/R site‐unedited form is not essential for brain development and function. Proceedings of the National Academy of Sciences of the USA 95: 13777–13782.

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

Knoop V (2011) When you can't trust the DNA: RNA editing changes transcript sequences. Cellular and Molecular Life Sciences 68: 567–586.

Laxminarayana D, Khan IU and Kammer G (2002) Transcript mutations of the alpha regulatory subunit of protein kinase A and up‐regulation of the RNA‐editing gene transcript in lupus T lymphocytes. Lancet 360: 842–849.

Levanon EY, Hallegger M, Kinar Y et al. (2005) Evolutionarily conserved human targets of adenosine to inosine RNA editing. Nucleic Acids Research 33: 1162–1168.

Li JB, Levanon EY, Yoon JK et al. (2009) Genome‐wide identification of human RNA editing sites by parallel DNA capturing and sequencing. Science (New York) 324: 1210–1213.

Li M, Yang L, Li C et al. (2010) Mutational spectrum of the ADAR1 gene in dyschromatosis symmetrica hereditaria. Archives of Dermatological Research 302: 469–476.

Maas S (2012) Posttranscriptional recoding by RNA editing. Advances in Protein Chemistry and Structural Biology 86: 193–224.

Maas S, Kawahara Y, Tamburro KM and Nishikura K (2006) A‐to‐I RNA editing and human disease. RNA Biology 3: 1–9.

Maas S, Patt S, Schrey M and Rich A (2001) Underediting of glutamate receptor GluR‐B mRNA in malignant gliomas. Proceedings of the National Academy of Sciences of the USA 98: 14687–14692.

Mallela A and Nishikura K (2012) A‐to‐I editing of protein coding and noncoding RNAs. Critical Reviews in Biochemistry and Molecular Biology 47: 493–501.

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

Morabito MV, Abbas AI, Hood JL et al. (2010) Mice with altered serotonin 2C receptor RNA editing display characteristics of Prader-Willi syndrome. Neurobiology of Disease 39: 169–180.

Paris Z, Fleming IM and Alfonzo JD (2012) Determinants of tRNA editing and modification: avoiding conundrums, affecting function. Seminars in Cell and Developmental Biology 23: 269–274.

Paro S, Li X, O'Connell MA et al. (2012) Regulation and functions of ADAR in Drosophila. Current Topics in Microbiology and Immunology 353: 221–236.

Paz N, Levanon EY, Amariglio N et al. (2007) Altered adenosine‐to‐inosine RNA editing in human cancer. Genome Research 17: 1586–1595.

Peng PL, Zhong X, Tu W et al. (2006) ADAR2-dependent RNA editing of AMPA receptor subunit GluR2 determines vulnerability of neurons in forebrain ischemia. Neuron 49: 719–733.

Rice GI, Kasher PR, Forte GM et al. (2012) Mutations in ADAR1 cause Aicardi–Goutieres syndrome associated with a type I interferon signature. Nature Genetics 44: 1243–1248.

Rosenthal JJ and Seeburg PH (2012) A‐to‐I RNA editing: effects on proteins key to neural excitability. Neuron 74: 432–439.

Savva YA, Rieder LE and Reenan RA (2012) The ADAR protein family. Genome Biology 13: 252.

Sie CG, Hesler S, Maas S and Kuchka M (2012) IGFBP7's susceptibility to proteolysis is altered by A‐to‐I RNA editing of its transcript. FEBS Letters 586: 2313–2317.

Silberberg G, Lundin D, Navon R and Ohman M (2012) Deregulation of the A‐to‐I RNA editing mechanism in psychiatric disorders. Human Molecular Genetics 21: 311–321.

Silberberg G and Ohman M (2011) The edited transcriptome: novel high throughput approaches to detect nucleotide deamination. Current Opinion in Genetics & Development 21: 401–406.

Smith HC, Bennett RP, Kizilyer A, McDougall WM and Prohaska KM (2012) Functions and regulation of the APOBEC family of proteins. Seminars in Cell and Developmental Biology 23: 258–268.

Sommer B, Kohler M, Sprengel R and Seeburg PH (1991) RNA editing in brain controls a determinant of ion flow in glutamate‐gated channels. Cell 67: 11–19.

Tariq A and Jantsch MF (2012) Transcript diversification in the nervous system: a to I RNA editing in CNS function and disease development. Frontiers in Neuroscience 6: 99.

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

Warf MB, Shepherd BA, Johnson WE and Bass BL (2012) Effects of ADARs on small RNA processing pathways in C. elegans. Genome Research 22: 1488–1498.

Wright A and Vissel B (2012) The essential role of AMPA receptor GluR2 subunit RNA editing in the normal and diseased brain. Frontiers in Molecular Neuroscience 5: 34.

Wulff BE and Nishikura K (2012) Modulation of microRNA expression and function by ADARs. Current Topics in Microbiology and Immunology 353: 91–109.

Wulff BE, Sakurai M and Nishikura K (2011) Elucidating the inosinome: global approaches to adenosine‐to‐inosine RNA editing. Nature Reviews Genetics 12: 81–85.

Yang JH, Luo X, Nie Y et al. (2003) Widespread inosine‐containing mRNA in lymphocytes regulated by ADAR1 in response to inflammation. Immunology 109: 15–23.

Further Reading

Athanasiadis A (2012) Zalpha‐domains: at the intersection between RNA editing and innate immunity. Seminars in Cell and Developmental Biology 23: 275–280.

Galeano F, Tomaselli S, Locatelli F and Gallo A (2012) A‐to‐I RNA editing: the “ADAR” side of human cancer. Seminars in Cell and Developmental Biology 23: 244–250.

Gommans WM (2012) A‐to‐I editing of microRNAs: regulating the regulators? Seminars in Cell and Developmental Biology 23: 251–257.

Gommans WM, Mullen SP and Maas S (2009) RNA editing: a driving force for adaptive evolution? BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology 31: 1137–1145.

Gray MW (2012) Evolutionary origin of RNA editing. Biochemistry 51: 5235–5242.

Maas S (2010) Gene regulation through RNA editing. Discovery Medicine 10: 379–386.

Maas S (ed.) (2013) RNA Editing: Current Research and Future Trends Norfolk, UK: Caister Academic Press.

Rieder LE and Reenan RA (2012) The intricate relationship between RNA structure, editing, and splicing. Seminars in Cell and Developmental Biology 23: 281–288.

Singh M (2012) Dysregulated A to I RNA editing and non‐coding RNAs in neurodegeneration. Frontiers in Genetics 3: 326.

Wahlstedt H and Ohman M (2011) Site‐selective versus promiscuous A‐to‐I editing. Wiley Interdisciplinary Reviews RNA 2: 761–771.

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Maas, Stefan(Sep 2013) A‐to‐I RNA Editing and Human Genetic Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024625]