Editor meets silencer: crosstalk between RNA editing and RNA interference

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.

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

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

[3]  Colleen M Niswender,et al.  RNA Editing of the Human Serotonin 5-HT2C Receptor: Alterations in Suicide and Implications for Serotonergic Pharmacotherapy , 2001, Neuropsychopharmacology.

[4]  V. Kim.  MicroRNA biogenesis: coordinated cropping and dicing , 2005, Nature Reviews Molecular Cell Biology.

[5]  R. Martienssen,et al.  RNA interference and heterochromatin in the fission yeast Schizosaccharomyces pombe. , 2005, Trends in genetics : TIG.

[6]  K. Nishikura,et al.  Editing of glutamate receptor B subunit ion channel RNAs by four alternatively spliced DRADA2 double-stranded RNA adenosine deaminases , 1997, Molecular and cellular biology.

[7]  R. Sorek,et al.  Is abundant A-to-I RNA editing primate-specific? , 2004, Trends in genetics : TIG.

[8]  K. Nishikura,et al.  Altered G Protein‐Coupling Functions of RNA Editing Isoform and Splicing Variant Serotonin2C Receptors , 2000, Journal of neurochemistry.

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

[10]  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.

[11]  H. Vaucheret,et al.  RNA Silencing in Plants--Defense and Counterdefense , 2001, Science.

[12]  P. Seeburg,et al.  Regulation of ion channel/neurotransmitter receptor function by RNA editing , 2003, Current Opinion in Neurobiology.

[13]  N. Lau,et al.  Characterization of the piRNA Complex from Rat Testes , 2006, Science.

[14]  A. Lohan,et al.  Methods for analysis of mitochondrial tRNA editing in Acanthamoeba castellanii. , 2004, Methods in molecular biology.

[15]  Anton J. Enright,et al.  RNA editing of human microRNAs , 2006, Genome Biology.

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

[17]  Ali Shilatifard,et al.  Chromatin modifications by methylation and ubiquitination: implications in the regulation of gene expression. , 2006, Annual review of biochemistry.

[18]  K. Nishikura,et al.  Mutagenic Analysis of Double-stranded RNA Adenosine Deaminase, a Candidate Enzyme for RNA Editing of Glutamate-gated Ion Channel Transcripts (*) , 1995, The Journal of Biological Chemistry.

[19]  Victoria Arango,et al.  Altered Editing of Serotonin 2C Receptor Pre-mRNA in the Prefrontal Cortex of Depressed Suicide Victims , 2002, Neuron.

[20]  D. Bartel.  MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[21]  B. Bass,et al.  Inosine exists in mRNA at tissue‐specific levels and is most abundant in brain mRNA , 1998, The EMBO journal.

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

[23]  M. O’Connell,et al.  Adenosine deaminases acting on RNA (ADARs): RNA-editing enzymes , 2004, Genome Biology.

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

[25]  Weida Huang,et al.  High doses of siRNAs induce eri-1 and adar-1 gene expression and reduce the efficiency of RNA interference in the mouse. , 2005, The Biochemical journal.

[26]  Brenda L Bass,et al.  RNA editing by adenosine deaminases that act on RNA. , 2002, Annual review of biochemistry.

[27]  C. Schmauss.  Regulation of serotonin 2C receptor pre-mRNA editing by serotonin. , 2005, International review of neurobiology.

[28]  G. Hannon.  RNA interference : RNA , 2002 .

[29]  S. Batalov,et al.  Antisense Transcription in the Mammalian Transcriptome , 2005, Science.

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

[31]  W. Filipowicz,et al.  Post-transcriptional gene silencing by siRNAs and miRNAs. , 2005, Current opinion in structural biology.

[32]  K. Nishikura,et al.  ADAR gene family and A-to-I RNA editing: diverse roles in posttranscriptional gene regulation. , 2005, Progress in nucleic acid research and molecular biology.

[33]  A. Fire,et al.  Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans , 1998, Nature.

[34]  W. Keller,et al.  tadA, an essential tRNA‐specific adenosine deaminase from Escherichia coli , 2002, The EMBO journal.

[35]  Y. Nie,et al.  Widespread inosine‐containing mRNA in lymphocytes regulated by ADAR1 in response to inflammation , 2003, Immunology.

[36]  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.

[37]  Ronald H. A. Plasterk,et al.  Transposon silencing in the Caenorhabditis elegans germ line by natural RNAi , 2003, Nature.

[38]  S C Schultz,et al.  Molecular basis of double‐stranded RNA‐protein interactions: structure of a dsRNA‐binding domain complexed with dsRNA , 1998, The EMBO journal.

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

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

[41]  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.

[42]  K. Nishikura,et al.  ADAR1 RNA Deaminase Limits Short Interfering RNA Efficacy in Mammalian Cells* , 2005, Journal of Biological Chemistry.

[43]  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.

[44]  G. Szittya,et al.  Size Selective Recognition of siRNA by an RNA Silencing Suppressor , 2003, Cell.

[45]  C. Samuel,et al.  Human RNA-specific adenosine deaminase (ADAR1) gene specifies transcripts that initiate from a constitutively active alternative promoter. , 2000, Gene.

[46]  D. Bentley,et al.  Rules of engagement: co-transcriptional recruitment of pre-mRNA processing factors. , 2005, Current opinion in cell biology.

[47]  Gary Ruvkun,et al.  A conserved siRNA-degrading RNase negatively regulates RNA interference in C. elegans , 2004, Nature.

[48]  Yukio Kawahara,et al.  A-to-I RNA Editing and Human Disease , 2006, RNA biology.

[49]  C. Sander,et al.  A novel class of small RNAs bind to MILI protein in mouse testes , 2006, Nature.

[50]  D. Marks,et al.  The small RNA profile during Drosophila melanogaster development. , 2003, Developmental cell.

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

[52]  L. Hurst,et al.  Genome-wide analysis of coordinate expression and evolution of human cis-encoded sense-antisense transcripts. , 2005, Trends in genetics : TIG.

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

[54]  L. Malinina,et al.  Recognition of small interfering RNA by a viral suppressor of RNA silencing , 2003, Nature.

[55]  R. Sorek,et al.  Is there any sense in antisense editing? , 2005, Trends in genetics : TIG.

[56]  Henry Mirsky,et al.  RNA editing of a miRNA precursor. , 2004, RNA.

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

[58]  Tamio Suzuki,et al.  Mutations of the RNA-specific adenosine deaminase gene (DSRAD) are involved in dyschromatosis symmetrica hereditaria. , 2003, American journal of human genetics.

[59]  Phillip D Zamore,et al.  microPrimer: the biogenesis and function of microRNA , 2005, Development.

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

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

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

[63]  B. Bass,et al.  The role of RNA editing by ADARs in RNAi. , 2002, Molecular cell.

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

[65]  E. Kieff,et al.  The Epstein-Barr virus nuclear protein 2 acidic domain forms a complex with a novel cellular coactivator that can interact with TFIIE , 1995, Molecular and cellular biology.

[66]  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.

[67]  R. Reenan,et al.  Nervous System Targets of RNA Editing Identified by Comparative Genomics , 2003, Science.

[68]  R. Reenan,et al.  A-to-I Pre-mRNA Editing in Drosophila Is Primarily Involved in Adult Nervous System Function and Integrity , 2000, Cell.

[69]  J. Gott,et al.  Editing site recognition and nucleotide insertion are separable processes in Physarum mitochondria , 2002, The EMBO journal.

[70]  Dan Graur,et al.  Minimal conditions for exonization of intronic sequences: 5' splice site formation in alu exons. , 2004, Molecular cell.

[71]  P. Fisher,et al.  Polycistronic transcription and editing of the mitochondrial small subunit (SSU ) ribosomal RNA in Dictyostelium discoideum , 1999, Current Genetics.

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

[73]  R. Reenan.  The RNA world meets behavior: A-->I pre-mRNA editing in animals. , 2001, Trends in genetics : TIG.

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

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

[76]  R. Reenan,et al.  The mlenapts RNA Helicase Mutation in Drosophila Results in a Splicing Catastrophe of the para Na+ Channel Transcript in a Region of RNA Editing , 2000, Neuron.

[77]  G. Barber,et al.  The dsRNA binding protein family: critical roles, diverse cellular functions , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

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

[79]  T. Tuschl,et al.  Mechanisms of gene silencing by double-stranded RNA , 2004, Nature.

[80]  W. Keller,et al.  Two forms of human double-stranded RNA-specific editase 1 (hRED1) generated by the insertion of an Alu cassette. , 1997, RNA.

[81]  Dan Graur,et al.  kinase localization of a novel catalytic subunit of casein Translated Alu sequence determines nuclear , 2002 .

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

[83]  Ralf Bundschuh,et al.  Discovery of new genes and deletion editing in Physarum mitochondria enabled by a novel algorithm for finding edited mRNAs , 2005, Nucleic acids research.

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

[85]  B. Bass,et al.  RNA editing of hepatitis delta virus antigenome by dsRNA-adenosine deaminase , 1996, Nature.

[86]  Thomas Tuschl,et al.  Identification and characterization of small RNAs involved in RNA silencing , 2005, FEBS letters.

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

[88]  K. Nishikura.  Editing the message from A to I , 2004, Nature Biotechnology.

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

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

[91]  Christopher W. J. Smith,et al.  RNAi is antagonized by A→I hyper‐editing , 2001, EMBO reports.

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

[93]  N. Navaratnam,et al.  An Overview of Cytidine Deaminases , 2006, International journal of hematology.

[94]  James A. Birchler,et al.  RNAi-mediated pathways in the nucleus , 2005, Nature Reviews Genetics.

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

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

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

[98]  Toshiaki Watanabe,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. , 2006, Genes & development.

[99]  K. Nishikura,et al.  Requirement of the RNA editing deaminase ADAR1 gene for embryonic erythropoiesis. , 2000, Science.

[100]  I. Greger,et al.  AMPA Receptor Tetramerization Is Mediated by Q/R Editing , 2003, Neuron.

[101]  K. Nishikura,et al.  Extensive adenosine‐to‐inosine editing detected in Alu repeats of antisense RNAs reveals scarcity of sense–antisense duplex formation , 2006, FEBS letters.

[102]  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.

[103]  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.

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

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

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

[107]  D. Melton,et al.  Antisense RNA injections in fertilized frog eggs reveal an RNA duplex unwinding activity , 1987, Cell.

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

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

[110]  Daniel R. Clutterbuck,et al.  A bioinformatic screen for novel A-I RNA editing sites reveals recoding editing in BC10 , 2005, Bioinform..

[111]  W. Keller,et al.  RNA editing by base deamination: more enzymes, more targets, new mysteries. , 2001, Trends in biochemical sciences.

[112]  Ravi Sachidanandam,et al.  A germline-specific class of small RNAs binds mammalian Piwi proteins , 2006, Nature.