Interaction between RNA interference and RNA editing pathways

Summary

Principal Investigator: Kazuko Nishikura
Abstract: DESCRIPTION (provided by applicant): One type of RNA editing involves the conversion of adenosine residues into inosine in double-stranded RNA (dsRNA) through the action of adenosine deaminase acting on RNA (ADAR). Three ADAR gene family members (ADAR1-3) have been identified in humans and rodents. When A I RNA editing occurs within a coding sequence, synthesis of proteins not directly encoded by the genome can result, as demonstrated with transcripts of glutamate receptor (GluR) ion channels and 5-HT2C serotonin receptors. However, the most common targets for A I editing are non-coding RNAs that contain inverted repeats of repetitive elements such as Alu and LINE located within introns and 3'UTRs. The biological significance of non-coding, repetitive RNA editing is largely unknown. The overall goal of this project is to better understand the biological significance of A I RNA editing. During the past 17 years, this grant has enabled us to clone ADAR1, the first identified member of the ADAR gene family. This in turn has led to the identification and cloning of ADAR2 and ADAR3. Furthermore, we have created an ADAR1-/- mutation in mice that causes widespread apoptosis and consequent embryonic lethal phenotypes. Our results suggest that ADAR1 is critically important for survival of numerous tissues by editing a currently unknown target dsRNA(s). During the current grant support period, we found that both ADAR1 and ADAR2 edit specific adenosine residues of certain miRNA precursor dsRNAs (pri-miRNAs). Editing of pri- miRNAs results in inhibition of their processing or expression of edited mature miRNAs that silence genes different from those targeted by unedited miRNAs. Our findings revealed a previously unknown role for A I RNA editing in miRNA-mediated gene silencing. Finally, our preliminary results indicate that ADAR1 associates with certain miRNA-induced silencing complex (miRISC) member proteins. Thus, our studies strongly indicate that the RNAi and RNA editing pathways interact in mammalian cells. Therefore, in the proposed work embodies in this application, we will focus our research efforts on this RNAi and RNA editing interaction as our main thrust. Specifically, we will determine: 1) the significance of certain miRNAs that are edited during embryonic development for regulation of apoptosis;2) the significance of A I editing of repetitive non-coding RNAs for control of endogenous siRNA (esiRNA) expression;and 3) the significance of ADAR1 interaction with the miRISC member proteins. PUBLIC HEALTH RELEVANCE: Recent studies indicate that mutations and mis-expression of miRNAs correlate with various human cancers. Certain miRNAs can function as tumor suppressors and oncogenes. Thus, the current grant proposal to investigate the effect of A&I editing of miRNAs and siRNAs has relevance to cancer biology. Our research focuses also on apoptosis, which is highly relevant to many human diseases including cancer.
Funding Period: 1991-07-01 - 2014-11-30
more information: NIH RePORT

Top Publications

  1. pmc Modulation of microRNA processing and expression through RNA editing by ADAR deaminases
    Weidong Yang
    The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA
    Nat Struct Mol Biol 13:13-21. 2006
  2. pmc Human endonuclease V is a ribonuclease specific for inosine-containing RNA
    Yoko Morita
    Graduate School of Engineering Science, Osaka University, 1 3 Machikaneyama, Toyonaka, Osaka 560 8531, Japan
    Nat Commun 4:2273. 2013
  3. pmc ADAR1 forms a complex with Dicer to promote microRNA processing and RNA-induced gene silencing
    Hiromitsu Ota
    The Wistar Institute, Philadelphia, PA 19104, USA
    Cell 153:575-89. 2013
  4. ncbi A-to-I editing of protein coding and noncoding RNAs
    Arka Mallela
    The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA
    Crit Rev Biochem Mol Biol 47:493-501. 2012
  5. pmc Elucidating the inosinome: global approaches to adenosine-to-inosine RNA editing
    Bjorn Erik Wulff
    The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA
    Nat Rev Genet 12:81-5. 2011
  6. pmc Substitutional A-to-I RNA editing
    Bjorn Erik Wulff
    Gene Expression and Regulation, The Wistar Institute, Philadelphia, PA, USA
    Wiley Interdiscip Rev RNA 1:90-101. 2010
  7. pmc Adenosine-to-inosine RNA editing
    Boris Zinshteyn
    The Wistar Institute, Gene Expression and Regulation, Philadelphia, PA 19104, USA
    Wiley Interdiscip Rev Syst Biol Med 1:202-9. 2009
  8. pmc Editing of Epstein-Barr virus-encoded BART6 microRNAs controls their dicer targeting and consequently affects viral latency
    Hisashi Iizasa
    The Wistar Institute, Philadelphia, Pennsylvania 19104, USA
    J Biol Chem 285:33358-70. 2010
  9. pmc Functional relevance of serotonin 2C receptor mRNA editing in antidepressant- and anxiety-like behaviors
    Cedric Mombereau
    Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    Neuropharmacology 59:468-73. 2010
  10. pmc Functions and regulation of RNA editing by ADAR deaminases
    Kazuko Nishikura
    Department of Gene Expression and Regulation, The Wistar Institute, Philadelphia, Pennsylvania 19104 4268, USA
    Annu Rev Biochem 79:321-49. 2010

Research Grants

  1. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013

Detail Information

Publications19

  1. pmc Modulation of microRNA processing and expression through RNA editing by ADAR deaminases
    Weidong Yang
    The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA
    Nat Struct Mol Biol 13:13-21. 2006
    ..Consequently, mature miRNA-142 expression levels increased substantially in ADAR1 null or ADAR2 null mice. Our results demonstrate a new function of RNA editing in the control of miRNA biogenesis...
  2. pmc Human endonuclease V is a ribonuclease specific for inosine-containing RNA
    Yoko Morita
    Graduate School of Engineering Science, Osaka University, 1 3 Machikaneyama, Toyonaka, Osaka 560 8531, Japan
    Nat Commun 4:2273. 2013
    ..These results demonstrate that hEndoV controls the fate of inosine-containing RNA in humans. ..
  3. pmc ADAR1 forms a complex with Dicer to promote microRNA processing and RNA-induced gene silencing
    Hiromitsu Ota
    The Wistar Institute, Philadelphia, PA 19104, USA
    Cell 153:575-89. 2013
    ..As expected, the expression of miRNAs is globally inhibited in ADAR1(-/-) mouse embryos, which, in turn, alters the expression of their target genes and might contribute to their embryonic lethal phenotype...
  4. ncbi A-to-I editing of protein coding and noncoding RNAs
    Arka Mallela
    The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA
    Crit Rev Biochem Mol Biol 47:493-501. 2012
    ..Such editing has a wide range of physiological effects, including modification of targets in the brain and in disease states...
  5. pmc Elucidating the inosinome: global approaches to adenosine-to-inosine RNA editing
    Bjorn Erik Wulff
    The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA
    Nat Rev Genet 12:81-5. 2011
    ..This Progress article reviews some of these recent global studies and their results...
  6. pmc Substitutional A-to-I RNA editing
    Bjorn Erik Wulff
    Gene Expression and Regulation, The Wistar Institute, Philadelphia, PA, USA
    Wiley Interdiscip Rev RNA 1:90-101. 2010
    ..This includes microRNAs, small interfering RNAs, viral RNAs, and messenger RNAs with potential for recoding events and splice site modifications...
  7. pmc Adenosine-to-inosine RNA editing
    Boris Zinshteyn
    The Wistar Institute, Gene Expression and Regulation, Philadelphia, PA 19104, USA
    Wiley Interdiscip Rev Syst Biol Med 1:202-9. 2009
    ..The vast majority of editing sites are in noncoding sequences. This includes microRNAs, as well as the introns and 3' untranslated regions of messenger RNAs, which play important roles in the RNA-mediated regulation of gene expression...
  8. pmc Editing of Epstein-Barr virus-encoded BART6 microRNAs controls their dicer targeting and consequently affects viral latency
    Hisashi Iizasa
    The Wistar Institute, Philadelphia, Pennsylvania 19104, USA
    J Biol Chem 285:33358-70. 2010
    ..Mutation and A-to-I editing appear to be adaptive mechanisms that antagonize miR-BART6 activities...
  9. pmc Functional relevance of serotonin 2C receptor mRNA editing in antidepressant- and anxiety-like behaviors
    Cedric Mombereau
    Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    Neuropharmacology 59:468-73. 2010
    ..These data constitute the first in vivo demonstration of a role for 5-HT(2C)R mRNA editing in anxiety- and depression-related behaviors...
  10. pmc Functions and regulation of RNA editing by ADAR deaminases
    Kazuko Nishikura
    Department of Gene Expression and Regulation, The Wistar Institute, Philadelphia, Pennsylvania 19104 4268, USA
    Annu Rev Biochem 79:321-49. 2010
    ..Here, I review the recent findings that indicate new functions for A-->I editing in the regulation of noncoding RNAs and for interactions between RNA editing and RNA interference mechanisms...
  11. pmc A new function for the RNA-editing enzyme ADAR1
    Hisashi Iizasa
    Department of Gene Expression and Regulation, Wistar Institute, Philadelphia, Pennsylvania 19104, USA
    Nat Immunol 10:16-8. 2009
    ..ADAR1 catalyzes the deamination of adenosine to inosine in double-stranded RNA. This RNA-editing enzyme is now shown to be involved in hematopoiesis, where it acts to suppress interferon signaling and to block premature apoptosis...
  12. pmc Dysregulated editing of serotonin 2C receptor mRNAs results in energy dissipation and loss of fat mass
    Yukio Kawahara
    The Wistar Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    J Neurosci 28:12834-44. 2008
    ..Our results highlight the importance of regulated 5-HT(2C)R mRNA editing, because dysregulation could result in the pathological consequences such as growth retardation seen in VGV mice...
  13. pmc Frequency and fate of microRNA editing in human brain
    Yukio Kawahara
    The Wistar Institute
    Nucleic Acids Res 36:5270-80. 2008
    ..Our studies predict that approximately 16% of human pri-miRNAs are subject to A-->I editing and, thus, miRNA editing could have a large impact on the miRNA-mediated gene silencing...
  14. pmc RNA binding-independent dimerization of adenosine deaminases acting on RNA and dominant negative effects of nonfunctional subunits on dimer functions
    Louis Valente
    Department of Gene Expression and Regulation, Wistar Institute, Philadelphia, Pennsylvania 19104, USA
    J Biol Chem 282:16054-61. 2007
    ....
  15. pmc Redirection of silencing targets by adenosine-to-inosine editing of miRNAs
    Yukio Kawahara
    Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA
    Science 315:1137-40. 2007
    ....
  16. pmc Editor meets silencer: crosstalk between RNA editing and RNA interference
    Kazuko Nishikura
    The Wistar Institute, Department of Gene Expression and Regulation, 3601 Spruce Street, Philadelphia, Pennsylvania 19104 4268, USA
    Nat Rev Mol Cell Biol 7:919-31. 2006
    ..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...
  17. pmc A-to-I RNA editing and human disease
    Stefan Maas
    Department of Biological Sciences, Lehigh University, Bethlehem, Pennsylvania 18015, USA
    RNA Biol 3:1-9. 2006
    ..Here we review the recent knowledge on where disturbances in A-to-I RNA editing have been correlated with human disease phenotypes...
  18. pmc Extensive adenosine-to-inosine editing detected in Alu repeats of antisense RNAs reveals scarcity of sense-antisense duplex formation
    Yukio Kawahara
    The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA
    FEBS Lett 580:2301-5. 2006
    ..Our findings imply that sense and antisense RNAs form two separate intramolecular double-stranded RNAs consisting of inversely oriented Alu repeats, but rarely form intermolecular duplexes...
  19. pmc Antagonistic and stimulative roles of ADAR1 in RNA silencing
    Kazuko Nishikura
    The Wistar Institute Philadelphia, PA USA
    RNA Biol 10:1240-7. 2013
    ..Expression of miRNAs is globally inhibited in ADAR1-null mouse embryos, which, in turn, alters expression of their target genes and may contribute to their embryonic lethal phenotype. ..

Research Grants30

  1. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013
    ..Through all of its activities, the Center improves communication, promotes collaboration, develops careers and generally enriches the intellectual climate for digestive disease research. ..