Redirection of Silencing Targets by Adenosine-to-Inosine Editing of miRNAs

• Published in: Science (American Association for the Advancement of Science) Vol. 315; no. 5815; pp. 1137 - 1140
• Main Authors: Kawahara, Yukio, Zinshteyn, Boris, Sethupathy, Praveen, Iizasa, Hisashi, Hatzigeorgiou, Artemis G, Nishikura, Kazuko
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 23.02.2007; The American Association for the Advancement of Science
• Subjects: 3' Untranslated Regions; Adenosine; Adenosine - metabolism; Adenosine Deaminase - genetics; Adenosine Deaminase - metabolism; Animals; Base Sequence; Biochemistry; Brain - metabolism; Complementary DNA; Embryos; Gene expression; Gene expression regulation; gene silencing; Genes; HeLa Cells; Humans; hybridization; Inosine - metabolism; Liver; Liver - metabolism; Mice; MicroRNA; MicroRNAs - chemistry; MicroRNAs - genetics; MicroRNAs - metabolism; Molecular Sequence Data; Nucleic Acid Conformation; Organ Specificity; Protein isoforms; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Repression; Ribonucleic acid; Ribose-Phosphate Pyrophosphokinase - genetics; Ribose-Phosphate Pyrophosphokinase - metabolism; RNA; RNA Editing; RNA Interference; RNA-Binding Proteins; uric acid; Uric Acid - metabolism
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.1138050

Primary transcripts of certain microRNA (miRNA) genes are subject to RNA editing that converts adenosine to inosine. However, the importance of miRNA editing remains largely undetermined. Here we report that tissue-specific adenosine-to-inosine editing of miR-376 cluster transcripts leads to predominant expression of edited miR-376 isoform RNAs. One highly edited site is positioned in the middle of the 5'-proximal half "seed" region critical for the hybridization of miRNAs to targets. We provide evidence that the edited miR-376 RNA silences specifically a different set of genes. Repression of phosphoribosyl pyrophosphate synthetase 1, a target of the edited miR-376 RNA and an enzyme involved in the uric-acid synthesis pathway, contributes to tight and tissue-specific regulation of uric-acid levels, revealing a previously unknown role for RNA editing in miRNA-mediated gene silencing.