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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Molecular Genetics B Study Section (MGB)
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Bender, Michael T
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Wistar Institute
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Nishikura, Kazuko (2017) Oesophageal cancer: RNA editing of SLC22A3 mRNAs: causative relevance to familial ESCC? Nat Rev Gastroenterol Hepatol 14:569-570
Sakurai, Masayuki; Shiromoto, Yusuke; Ota, Hiromitsu et al. (2017) ADAR1 controls apoptosis of stressed cells by inhibiting Staufen1-mediated mRNA decay. Nat Struct Mol Biol 24:534-543
Tan, Meng How; Li, Qin; Shanmugam, Raghuvaran et al. (2017) Dynamic landscape and regulation of RNA editing in mammals. Nature 550:249-254
Song, Chunzi; Sakurai, Masayuki; Shiromoto, Yusuke et al. (2016) Functions of the RNA Editing Enzyme ADAR1 and Their Relevance to Human Diseases. Genes (Basel) 7:
Miyake, Kotaro; Ohta, Toshio; Nakayama, Hisako et al. (2016) CAPS1 RNA Editing Promotes Dense Core Vesicle Exocytosis. Cell Rep 17:2004-2014
Nishikura, Kazuko (2016) A-to-I editing of coding and non-coding RNAs by ADARs. Nat Rev Mol Cell Biol 17:83-96
Gumireddy, Kiranmai; Li, Anping; Kossenkov, Andrew V et al. (2016) The mRNA-edited form of GABRA3 suppresses GABRA3-mediated Akt activation and breast cancer metastasis. Nat Commun 7:10715
Watanabe, Yoshihisa; Yoshimoto, Kanji; Tatebe, Harutsugu et al. (2014) Enhancement of alcohol drinking in mice depends on alterations in RNA editing of serotonin 2C receptors. Int J Neuropsychopharmacol 17:739-51
Ota, Hiromitsu; Sakurai, Masayuki; Gupta, Ravi et al. (2013) ADAR1 forms a complex with Dicer to promote microRNA processing and RNA-induced gene silencing. Cell 153:575-89
Nishikura, Kazuko; Sakurai, Masayuki; Ariyoshi, Kantaro et al. (2013) Antagonistic and stimulative roles of ADAR1 in RNA silencing. RNA Biol 10:1240-7

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