A-to-I editing of coding and non-coding RNAs by ADARs

Adenosine deaminases acting on RNA (ADARs) convert adenosine to inosine in double-stranded RNA. This A-to-I editing occurs not only in protein-coding regions of mRNAs, but also frequently in non-coding regions that contain inverted Alu repeats. Editing of coding sequences can result in the expression of functionally altered proteins that are not encoded in the genome, whereas the significance of Alu editing remains largely unknown. Certain microRNA (miRNA) precursors are also edited, leading to reduced expression or altered function of mature miRNAs. Conversely, recent studies indicate that ADAR1 forms a complex with Dicer to promote miRNA processing, revealing a new function of ADAR1 in the regulation of RNA interference.

[1]  Fritz J Sedlazeck,et al.  Adenosine deaminases that act on RNA induce reproducible changes in abundance and sequence of embryonic miRNAs , 2012, Genome research.

[2]  Jack F Kirsch,et al.  Autoinhibition of human dicer by its internal helicase domain. , 2008, Journal of molecular biology.

[3]  T. Dawson,et al.  Regulation of alternative splicing by RNA editing , 1999, Nature.

[4]  A. Hatzigeorgiou,et al.  Redirection of Silencing Targets by Adenosine-to-Inosine Editing of miRNAs , 2007, Science.

[5]  T. Matise,et al.  Widespread RNA editing of embedded alu elements in the human transcriptome. , 2004, Genome research.

[6]  P. Seeburg,et al.  Liver Disintegration in the Mouse Embryo Caused by Deficiency in the RNA-editing Enzyme ADAR1* , 2004, Journal of Biological Chemistry.

[7]  Angela Gallo,et al.  A-to-I RNA editing: the "ADAR" side of human cancer. , 2012, Seminars in cell & developmental biology.

[8]  P. Seeburg,et al.  RNA editing in brain controls a determinant of ion flow in glutamate-gated channels , 1991, Cell.

[9]  S. Orkin,et al.  Corrigendum: ADAR1 is essential for the maintenance of hematopoiesis and suppression of interferon signaling , 2009, Nature Immunology.

[10]  T. Shimokawa,et al.  RNA editing of the GLI1 transcription factor modulates the output of Hedgehog signaling , 2013, RNA biology.

[11]  B. Bass,et al.  Inositol Hexakisphosphate Is Bound in the ADAR2 Core and Required for RNA Editing , 2005, Science.

[12]  Peter H. Seeburg,et al.  A-to-I RNA Editing: Effects on Proteins Key to Neural Excitability , 2012, Neuron.

[13]  M. Sakurai,et al.  Antagonistic and stimulative roles of ADAR1 in RNA silencing , 2013, RNA biology.

[14]  K. Nishikura,et al.  RNA Binding-independent Dimerization of Adenosine Deaminases Acting on RNA and Dominant Negative Effects of Nonfunctional Subunits on Dimer Functions* , 2007, Journal of Biological Chemistry.

[15]  Brent A. Shepherd,et al.  Effects of ADARs on small RNA processing pathways in C. elegans , 2012, Genome research.

[16]  C. Smith,et al.  Specific cleavage of hyper‐edited dsRNAs , 2001, The EMBO journal.

[17]  K. Wells,et al.  Modulation of RNA editing by functional nucleolar sequestration of ADAR2 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[18]  K. A. Lehmann,et al.  The importance of internal loops within RNA substrates of ADAR1. , 1999, Journal of molecular biology.

[19]  David Gacquer,et al.  Principles Governing A-to-I RNA Editing in the Breast Cancer Transcriptome , 2015, bioRxiv.

[20]  H. Ueda,et al.  Inosine cyanoethylation identifies A-to-I RNA editing sites in the human transcriptome. , 2010, Nature chemical biology.

[21]  R. Reenan,et al.  RNA editing in regulating gene expression in the brain. , 2008, Biochimica et biophysica acta.

[22]  S. Tsao,et al.  Perturbation of biogenesis and targeting of Epstein-Barr virus-encoded miR-BART3 microRNA by adenosine-to-inosine editing. , 2013, The Journal of general virology.

[23]  A. Scadden,et al.  Tudor-SN and ADAR1 are components of cytoplasmic stress granules. , 2012, RNA.

[24]  B. Sakmann,et al.  Determinants of ca2+ permeability in both TM1 and TM2 of high affinity kainate receptor channels: Diversity by RNA editing , 1993, Neuron.

[25]  Patrice Vitali,et al.  dsRNAs containing multiple IU pairs are sufficient to suppress interferon induction and apoptosis , 2013 .

[26]  C. Nusbaum,et al.  Mammalian microRNAs: experimental evaluation of novel and previously annotated genes. , 2010, Genes & development.

[27]  Brenda L Bass,et al.  Mutations in RNAi Rescue Aberrant Chemotaxis of ADAR Mutants , 2003, Science.

[28]  Edwin Sandanaraj,et al.  Attenuated adenosine-to-inosine editing of microRNA-376a* promotes invasiveness of glioblastoma cells. , 2012, The Journal of clinical investigation.

[29]  F. Locatelli,et al.  ADARs and the Balance Game between Virus Infection and Innate Immune Cell Response. , 2015, Current issues in molecular biology.

[30]  K. Nishikura,et al.  Dysregulated Editing of Serotonin 2C Receptor mRNAs Results in Energy Dissipation and Loss of Fat Mass , 2008, The Journal of Neuroscience.

[31]  John H Livingston,et al.  Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature , 2012, Nature Genetics.

[32]  R. Emeson,et al.  Regulation of serotonin-2C receptor G-protein coupling by RNA editing , 1997, Nature.

[33]  Axel Brennicke,et al.  RNA editing in plants and its evolution. , 2013, Annual review of genetics.

[34]  S. Maas,et al.  Identification of a selective nuclear import signal in adenosine deaminases acting on RNA , 2009, Nucleic acids research.

[35]  Sheila S. David,et al.  RNA editing changes the lesion specificity for the DNA repair enzyme NEIL1 , 2010, Proceedings of the National Academy of Sciences.

[36]  V. Kim,et al.  Regulation of microRNA biogenesis , 2014, Nature Reviews Molecular Cell Biology.

[37]  A. Scadden The RISC subunit Tudor-SN binds to hyper-edited double-stranded RNA and promotes its cleavage , 2005, Nature Structural &Molecular Biology.

[38]  M. Jantsch,et al.  RNA-Regulated Interaction of Transportin-1 and Exportin-5 with the Double-Stranded RNA-Binding Domain Regulates Nucleocytoplasmic Shuttling of ADAR1 , 2009, Molecular and Cellular Biology.

[39]  M. Carmo-Fonseca,et al.  Dynamic association of RNA-editing enzymes with the nucleolus , 2003, Journal of Cell Science.

[40]  R. Emeson,et al.  Editing of neurotransmitter receptor and ion channel RNAs in the nervous system. , 2012, Current topics in microbiology and immunology.

[41]  Yukio Kawahara,et al.  RNA editing of the microRNA‐151 precursor blocks cleavage by the Dicer–TRBP complex , 2007, EMBO reports.

[42]  D. Feldmeyer,et al.  Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2 , 2000, Nature.

[43]  Kol Jia Yong,et al.  A disrupted RNA editing balance mediated by ADARs (Adenosine DeAminases that act on RNA) in human hepatocellular carcinoma , 2013, Gut.

[44]  B. Bass,et al.  RNA editing by ADARs is important for normal behavior in Caenorhabditis elegans , 2002, The EMBO journal.

[45]  K. Nishikura,et al.  A third member of the RNA-specific adenosine deaminase gene family, ADAR3, contains both single- and double-stranded RNA binding domains. , 2000, RNA.

[46]  J. Schachter,et al.  A novel immune resistance mechanism of melanoma cells controlled by the ADAR1 enzyme , 2015, Oncotarget.

[47]  J. Mendell,et al.  MicroRNAs in Stress Signaling and Human Disease , 2012, Cell.

[48]  I. Mian,et al.  A Z-DNA binding domain present in the human editing enzyme, double-stranded RNA adenosine deaminase. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[49]  M. Weiss,et al.  Stress-induced Apoptosis Associated with Null Mutation of ADAR1 RNA Editing Deaminase Gene* , 2004, Journal of Biological Chemistry.

[50]  HaroldC. Smith,et al.  Functions and regulation of the APOBEC family of proteins. , 2012, Seminars in cell & developmental biology.

[51]  Ramana V. Davuluri,et al.  ADAR1 Forms a Complex with Dicer to Promote MicroRNA Processing and RNA-Induced Gene Silencing , 2013, Cell.

[52]  Zuo Zhang,et al.  The Fate of dsRNA in the Nucleus A p54nrb-Containing Complex Mediates the Nuclear Retention of Promiscuously A-to-I Edited RNAs , 2001, Cell.

[53]  P. Seeburg,et al.  Modulation of microRNA processing and expression through RNA editing by ADAR deaminases , 2006, Nature Structural &Molecular Biology.

[54]  W. I. Mohamed,et al.  A bimodular nuclear localization signal assembled via an extended double-stranded RNA-binding domain acts as an RNA-sensing signal for transportin 1 , 2014, Proceedings of the National Academy of Sciences.

[55]  G. Church,et al.  Genome-Wide Identification of Human RNA Editing Sites by Parallel DNA Capturing and Sequencing , 2009, Science.

[56]  Wenwei Zhang,et al.  Comprehensive analysis of RNA-Seq data reveals extensive RNA editing in a human transcriptome , 2012, Nature Biotechnology.

[57]  R. Emeson,et al.  Altered RNA Editing in Mice Lacking ADAR2 Autoregulation , 2006, Molecular and Cellular Biology.

[58]  C. Samuel,et al.  ADARs: viruses and innate immunity. , 2012, Current topics in microbiology and immunology.

[59]  Shahar Alon,et al.  Modulation of microRNA editing, expression and processing by ADAR2 deaminase in glioblastoma , 2014, Genome Biology.

[60]  T. Horikawa,et al.  Ten novel mutations of the ADAR1 gene in Japanese patients with dyschromatosis symmetrica hereditaria. , 2007, The Journal of investigative dermatology.

[61]  R. Braun,et al.  Distribution of Tenr, an RNA-binding protein, in a lattice-like network within the spermatid nucleus in the mouse. , 1995, Biology of reproduction.

[62]  K. Nishikura Functions and regulation of RNA editing by ADAR deaminases. , 2010, Annual review of biochemistry.

[63]  Zuo Zhang,et al.  Vigilins Bind to Promiscuously A-to-I-Edited RNAs and Are Involved in the Formation of Heterochromatin , 2005, Current Biology.

[64]  P. Seeburg,et al.  RNA editing of AMPA receptor subunit GluR-B: A base-paired intron-exon structure determines position and efficiency , 1993, Cell.

[65]  A. Lin,et al.  c-Jun Amino-Terminal Kinase-1 Mediates Glucose-Responsive Upregulation of the RNA Editing Enzyme ADAR2 in Pancreatic Beta-Cells , 2012, PloS one.

[66]  T. Cheng,et al.  ADAR1 is required for hematopoietic progenitor cell survival via RNA editing , 2009, Proceedings of the National Academy of Sciences.

[67]  J. E. Smith,et al.  A double-stranded RNA unwinding activity introduces structural alterations by means of adenosine to inosine conversions in mammalian cells and Xenopus eggs. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[68]  Brigitta B. Gundersen,et al.  Functional relevance of serotonin 2C receptor mRNA editing in antidepressant- and anxiety-like behaviors , 2010, Neuropharmacology.

[69]  Michael Q. Zhang,et al.  Regulating Gene Expression through RNA Nuclear Retention , 2005, Cell.

[70]  Jun Zhang,et al.  ADAR1 is required for differentiation and neural induction by regulating microRNA processing in a catalytically independent manner , 2015, Cell Research.

[71]  J. Kjems,et al.  CRM1 Mediates the Export of ADAR1 through a Nuclear Export Signal within the Z-DNA Binding Domain , 2001, Molecular and Cellular Biology.

[72]  J. Issa,et al.  Enrichment for Histone H3 Lysine 9 Methylation at Alu Repeats in Human Cells* , 2003, Journal of Biological Chemistry.

[73]  Zipora Y. Fligelman,et al.  Systematic identification of abundant A-to-I editing sites in the human transcriptome , 2004, Nature Biotechnology.

[74]  Ayelet T. Lamm,et al.  Competition between ADAR and RNAi pathways for an extensive class of RNA targets , 2011, Nature Structural &Molecular Biology.

[75]  S. Heinemann,et al.  Generation and Analysis of GluR5(Q636R) Kainate Receptor Mutant Mice , 1999, The Journal of Neuroscience.

[76]  P. Silver,et al.  A genome-wide in situ hybridization map of RNA-binding proteins reveals anatomically restricted expression in the developing mouse brain , 2005, BMC Developmental Biology.

[77]  Joshua J C Rosenthal,et al.  The emerging role of RNA editing in plasticity , 2015, The Journal of Experimental Biology.

[78]  T Kuner,et al.  Control of kinetic properties of AMPA receptor channels by nuclear RNA editing. , 1994, Science.

[79]  F. Nielsen,et al.  Dimerization of ADAR2 is mediated by the double-stranded RNA binding domain. , 2006, RNA.

[80]  I. Gromova,et al.  Human BLCAP transcript: new editing events in normal and cancerous tissues , 2009, International journal of cancer.

[81]  K. Nishikura,et al.  Human endonuclease V is a ribonuclease specific for inosine-containing RNA , 2013, Nature Communications.

[82]  Jin Billy Li,et al.  Accurate identification of human Alu and non-Alu RNA editing sites , 2012, Nature Methods.

[83]  Richard Wooster,et al.  A survey of RNA editing in human brain. , 2004, Genome research.

[84]  B. Bass Double-Stranded RNA as a Template for Gene Silencing , 2000, Cell.

[85]  S. Heinemann,et al.  Ca2+ permeability of unedited and edited versions of the kainate selective glutamate receptor GluR6. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[86]  C. Croce,et al.  miRNAs, Cancer, and Stem Cell Division , 2005, Cell.

[87]  Erez Y. Levanon,et al.  A genome-wide map of hyper-edited RNA reveals numerous new sites , 2014, Nature Communications.

[88]  Eli Eisenberg,et al.  Elevated RNA Editing Activity Is a Major Contributor to Transcriptomic Diversity in Tumors. , 2015, Cell reports.

[89]  R. Emeson,et al.  Functions and mechanisms of RNA editing. , 2000, Annual review of genetics.

[90]  P. Seeburg,et al.  RED2, a Brain-specific Member of the RNA-specific Adenosine Deaminase Family* , 1996, The Journal of Biological Chemistry.

[91]  Y. Yoshida,et al.  Ca2+-Permeable AMPA Receptors Regulate Growth of Human Glioblastoma via Akt Activation , 2007, The Journal of Neuroscience.

[92]  Wenjing Zhang,et al.  Origins and evolution of ADAR‐mediated RNA editing , 2009, IUBMB life.

[93]  Brenda L. Bass,et al.  An unwinding activity that covalently modifies its double-stranded RNA substrate , 1988, Cell.

[94]  Alexander Rich,et al.  Widespread A-to-I RNA Editing of Alu-Containing mRNAs in the Human Transcriptome , 2004, PLoS biology.

[95]  A. Scadden Inosine-Containing dsRNA Binds a Stress-Granule-like Complex and Downregulates Gene Expression In trans , 2007, Molecular cell.

[96]  P. Seeburg,et al.  Induced Loss of ADAR2 Engenders Slow Death of Motor Neurons from Q/R Site-Unedited GluR2 , 2010, The Journal of Neuroscience.

[97]  K. A. Lehmann,et al.  Double-stranded RNA adenosine deaminases ADAR1 and ADAR2 have overlapping specificities. , 2000, Biochemistry.

[98]  C. Samuel,et al.  Human RNA-specific adenosine deaminase ADAR1 transcripts possess alternative exon 1 structures that initiate from different promoters, one constitutively active and the other interferon inducible. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[99]  Jin Billy Li,et al.  Edinburgh Research Explorer Identifying Rna Editing Sites Using Rna Sequencing Data Alone , 2022 .

[100]  K. Nishikura,et al.  Substrate specificity of the dsRNA unwinding/modifying activity. , 1991, The EMBO journal.

[101]  C. Samuel,et al.  Expression and regulation by interferon of a double-stranded-RNA-specific adenosine deaminase from human cells: evidence for two forms of the deaminase , 1995, Molecular and cellular biology.

[102]  Emery N. Brown,et al.  Comparative RNA Editing in Autistic and Neurotypical Cerebella , 2012, Molecular Psychiatry.

[103]  M. O’Connell,et al.  RNA editing by mammalian ADARs. , 2011, Advances in genetics.

[104]  P. L. Peng,et al.  ADAR2-Dependent RNA Editing of AMPA Receptor Subunit GluR2 Determines Vulnerability of Neurons in Forebrain Ischemia , 2006, Neuron.

[105]  P. Seeburg,et al.  A mammalian RNA editing enzyme , 1996, Nature.

[106]  M. Hallegger,et al.  Nucleocytoplasmic distribution of human RNA-editing enzyme ADAR1 is modulated by double-stranded RNA-binding domains, a leucine-rich export signal, and a putative dimerization domain. , 2002, Molecular biology of the cell.

[107]  Helene Wahlstedt,et al.  Adenosine-to-Inosine RNA Editing Affects Trafficking of the γ-Aminobutyric Acid Type A (GABAA) Receptor* , 2010, The Journal of Biological Chemistry.

[108]  A. Hatzigeorgiou,et al.  Editing of Epstein-Barr Virus-encoded BART6 MicroRNAs Controls Their Dicer Targeting and Consequently Affects Viral Latency* , 2010, The Journal of Biological Chemistry.

[109]  G. Carmichael,et al.  Alu element‐mediated gene silencing , 2008, The EMBO journal.

[110]  John M. Murray,et al.  Requirement of Dimerization for RNA Editing Activity of Adenosine Deaminases Acting on RNA* , 2003, The Journal of Biological Chemistry.

[111]  Izumi V. Hinkson,et al.  RNA Editing of Androgen Receptor Gene Transcripts in Prostate Cancer Cells* , 2008, Journal of Biological Chemistry.

[112]  G. Carmichael,et al.  On the mechanism of induction of heterochromatin by the RNA-binding protein vigilin. , 2008, RNA.

[113]  Leilei Chen,et al.  Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma , 2013, Nature Medicine.

[114]  Brenda L. Bass,et al.  A developmentally regulated activity that unwinds RNA duplexes , 1987, Cell.

[115]  Ichiro Kanazawa,et al.  Glutamate receptors: RNA editing and death of motor neurons , 2004, Nature.

[116]  M. O’Connell,et al.  Editing independent effects of ADARs on the miRNA/siRNA pathways , 2009, The EMBO journal.

[117]  Kazuko Nishikura,et al.  Adenosine-to-inosine RNA editing and human disease , 2013, Genome Medicine.

[118]  Leng Han,et al.  The Genomic Landscape and Clinical Relevance of A-to-I RNA Editing in Human Cancers. , 2015, Cancer cell.

[119]  Eli Eisenberg,et al.  RNA-editing-mediated exon evolution , 2007, Genome Biology.

[120]  Shahar Alon,et al.  Systematic identification of edited microRNAs in the human brain , 2012, Genome research.

[121]  Aamira Tariq,et al.  Transcript Diversification in the Nervous System: A to I RNA Editing in CNS Function and Disease Development , 2012, Front. Neurosci..

[122]  J. Kjems,et al.  CRM 1 Mediates the Export of ADAR 1 through a Nuclear Export Signal within the Z-DNA Binding Domain , 2001 .

[123]  Xinshu Xiao,et al.  Genomic Analysis of ADAR1 Binding and its Involvement in Multiple RNA Processing Pathways , 2015, Nature Communications.

[124]  R. Aphasizhev,et al.  Mitochondrial RNA processing in trypanosomes. , 2011, Research in microbiology.

[125]  Erez Y. Levanon,et al.  Evolutionarily conserved human targets of adenosine to inosine RNA editing , 2005, Nucleic acids research.

[126]  Robert A. Martienssen,et al.  RNA interference in the nucleus: roles for small RNAs in transcription, epigenetics and beyond , 2013, Nature Reviews Genetics.

[127]  G. Del Sal,et al.  Pin1 and WWP2 regulate GluR2 Q/R site RNA editing by ADAR2 with opposing effects , 2011, The EMBO journal.

[128]  B. Roth,et al.  Mice with altered serotonin 2C receptor RNA editing display characteristics of Prader–Willi syndrome , 2010, Neurobiology of Disease.

[129]  P. Seeburg,et al.  RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself , 2015, Science.

[130]  F. Allain,et al.  Structure and specific RNA binding of ADAR2 double-stranded RNA binding motifs. , 2006, Structure.

[131]  G. Carmichael,et al.  Altered nuclear retention of mRNAs containing inverted repeats in human embryonic stem cells: functional role of a nuclear noncoding RNA. , 2009, Molecular cell.

[132]  Ding‐Shinn Chen,et al.  ADAR2-Mediated Editing of miR-214 and miR-122 Precursor and Antisense RNA Transcripts in Liver Cancers , 2013, PloS one.

[133]  Yiannis A. Savva,et al.  RNA editing regulates transposon-mediated heterochromatic gene silencing , 2013, Nature Communications.

[134]  K. Nishikura,et al.  Molecular cloning of cDNA for double-stranded RNA adenosine deaminase, a candidate enzyme for nuclear RNA editing. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[135]  T. Billiar,et al.  Adenosine Deaminase Acting on RNA 1 Limits RIG-I RNA Detection and Suppresses IFN Production Responding to Viral and Endogenous RNAs , 2014, The Journal of Immunology.

[136]  Chris P. Ponting,et al.  The RNA-Editing Enzyme ADAR1 Controls Innate Immune Responses to RNA , 2014, Cell reports.

[137]  Jens Lagergren,et al.  A-to-I editing of microRNAs in the mammalian brain increases during development , 2012, Genome research.

[138]  A. Scadden,et al.  Proteins that contain a functional Z-DNA-binding domain localize to cytoplasmic stress granules , 2013, Nucleic acids research.

[139]  Joshua J C Rosenthal,et al.  Control of human potassium channel inactivation by editing of a small mRNA hairpin , 2004, Nature Structural &Molecular Biology.

[140]  K. Nishikura,et al.  Editor meets silencer: crosstalk between RNA editing and RNA interference , 2006, Nature Reviews Molecular Cell Biology.

[141]  Eli Eisenberg,et al.  A-to-I RNA editing occurs at over a hundred million genomic sites, located in a majority of human genes , 2014, Genome research.

[142]  G. Chawla,et al.  ADAR mediates differential expression of polycistronic microRNAs , 2014, Nucleic acids research.

[143]  Molly Megraw,et al.  Frequency and fate of microRNA editing in human brain , 2008, Nucleic acids research.

[144]  J. Wettengel,et al.  Optimal guideRNAs for re-directing deaminase activity of hADAR1 and hADAR2 in trans , 2014, Nucleic acids research.

[145]  C. Sander,et al.  Identification of microRNAs of the herpesvirus family , 2005, Nature Methods.