Site‐selective versus promiscuous A‐to‐I editing

RNA editing by adenosine deamination is acting on polymerase II derived transcripts in all metazoans. Adenosine‐to‐inosine (A‐to‐I) editing is mediated by the adenosine deaminase that acts on RNA (ADAR) enzymes. Two types of adenosine to inosine (A‐to‐I) RNA editing have been defined: site selective and hyper‐editing. Typically, in site selectively edited substrates, one or a few A‐to‐I sites are edited in double‐stranded RNA structures, frequently interrupted by single‐stranded bulges and loops. Hyper‐editing occurs in long stretches of duplex RNA where multiple adenosines are subjected to deamination. In this review, recent findings on editing within noncoding RNA as well as examples of site selective editing within coding regions are presented. We discuss how these two editing events have evolved and the structural differences between a site selective and hyper‐edited substrate. WIREs RNA 2011 2 761–771 DOI: 10.1002/wrna.89

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

[2]  S. Heinemann,et al.  Intron sequence directs RNA editing of the glutamate receptor subunit GluR2 coding sequence. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[3]  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.

[4]  Daniel Büring.  Binding. , 2021, Bulletin of the Medical Library Association.

[5]  M. Ohman.  A-to-I editing challenger or ally to the microRNA process. , 2007, Biochimie.

[6]  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.

[7]  Frédéric H.-T. Allain,et al.  The Solution Structure of the ADAR2 dsRBM-RNA Complex Reveals a Sequence-Specific Readout of the Minor Groove , 2010, Cell.

[8]  Eli Eisenberg,et al.  RNA editing level in the mouse is determined by the genomic repeat repertoire. , 2006, RNA.

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

[10]  B. Bass,et al.  Long RNA hairpins that contain inosine are present in Caenorhabditis elegans poly(A)+ RNA. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[11]  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.

[12]  François Major,et al.  Recognition and coupling of A-to-I edited sites are determined by the tertiary structure of the RNA , 2009, Nucleic acids research.

[13]  J. Itskovitz‐Eldor,et al.  Alu Sequences in Undifferentiated Human Embryonic Stem Cells Display High Levels of A-to-I RNA Editing , 2010, PloS one.

[14]  B. Bass,et al.  Evidence for auto-inhibition by the N terminus of hADAR2 and activation by dsRNA binding. , 2004, RNA.

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

[16]  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.

[17]  B. Bass,et al.  In vitro analysis of the binding of ADAR2 to the pre-mRNA encoding the GluR-B R/G site. , 2000, RNA.

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

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

[20]  B. Bass,et al.  Preferential selection of adenosines for modification by double‐stranded RNA adenosine deaminase. , 1994, The EMBO journal.

[21]  T. Gibson,et al.  Structure of the dsRNA binding domain of E. coli RNase III. , 1995, The EMBO journal.

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

[23]  R. Emeson,et al.  Glutamate receptor RNA editing in vitro by enzymatic conversion of adenosine to inosine , 1995, Science.

[24]  R. Reenan,et al.  Tuning of RNA editing by ADAR is required in Drosophila , 2005, The EMBO journal.

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

[26]  Aristotelis Tsirigos,et al.  Alu and B1 Repeats Have Been Selectively Retained in the Upstream and Intronic Regions of Genes of Specific Functional Classes , 2009, PLoS Comput. Biol..

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

[28]  Mats Ensterö,et al.  Large-scale mRNA sequencing determines global regulation of RNA editing during brain development. , 2009, Genome research.

[29]  B. Bass,et al.  A phylogenetic analysis reveals an unusual sequence conservation within introns involved in RNA editing. , 2000, RNA.

[30]  Roberto Cattaneo,et al.  RNA-specific Adenosine Deaminase ADAR1 Suppresses Measles Virus-induced Apoptosis and Activation of Protein Kinase PKR* , 2009, The Journal of Biological Chemistry.

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

[32]  E. Nevo,et al.  Adenosine-to-inosine RNA editing shapes transcriptome diversity in primates , 2010, Proceedings of the National Academy of Sciences.

[33]  Jochen C. Hartner,et al.  Specificity of ADAR-mediated RNA editing in newly identified targets. , 2008, RNA.

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

[35]  P. Beal,et al.  The binding selectivity of ADAR2's dsRBMs contributes to RNA-editing selectivity. , 2004, Chemistry & biology.

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

[37]  B. Bass,et al.  C. elegans and H. sapiens mRNAs with edited 3' UTRs are present on polysomes. , 2008, RNA.

[38]  M. Bycroft,et al.  Assignment of the backbone 1H,15N, 13C NMR resonances and secondary structure of a double‐stranded RNA binding domain from the Drosophila protein staufen , 1995, FEBS letters.

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

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

[41]  David Haussler,et al.  Editing modifies the GABAA receptor subunit α3 , 2007 .

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

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

[44]  J. Rosenthal,et al.  An extra double-stranded RNA binding domain confers high activity to a squid RNA editing enzyme. , 2009, RNA.

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

[46]  E. Eisenberg,et al.  Large-scale analysis of structural, sequence and thermodynamic characteristics of A-to-I RNA editing sites in human Alu repeats , 2010, BMC Genomics.

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

[48]  B. Bass,et al.  Purification of the Xenopus laevis double-stranded RNA adenosine deaminase. , 1994, The Journal of biological chemistry.

[49]  M. O’Connell,et al.  Cleavage of dsRNAs hyper-edited by ADARs occurs at preferred editing sites , 2005, Nucleic acids research.

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

[51]  B. Bass,et al.  RNA hairpins in noncoding regions of human brain and Caenorhabditis elegans mRNA are edited by adenosine deaminases that act on RNA , 2002, Proceedings of the National Academy of Sciences of the United States of America.

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

[53]  M. Carmo-Fonseca,et al.  SUMO-1 modification alters ADAR1 editing activity. , 2005, Molecular biology of the cell.

[54]  C. Samuel,et al.  Chimeric double-stranded RNA-specific adenosine deaminase ADAR1 proteins reveal functional selectivity of double-stranded RNA-binding domains from ADAR1 and protein kinase PKR. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[55]  T. Dawson,et al.  Structure and Sequence Determinants Required for the RNA Editing of ADAR2 Substrates* , 2004, Journal of Biological Chemistry.

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

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

[58]  Biochemical analysis and scanning force microscopy reveal productive and nonproductive ADAR2 binding to RNA substrates. , 2003, RNA.

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

[60]  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.

[61]  M. Mathews,et al.  Proteins binding to duplexed RNA: one motif, multiple functions. , 2000, Trends in biochemical sciences.

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

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

[64]  P. Beal,et al.  Selective binding by the RNA binding domain of PKR revealed by affinity cleavage. , 2001, Biochemistry.

[65]  A. Källman,et al.  ADAR2 A-->I editing: site selectivity and editing efficiency are separate events. , 2003, Nucleic acids research.