title: Redirection of silencing targets by adenosine-to-inosine editing of miRNAs.
abstract: 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.
authors.affiliation: Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA. ykawahara@wistar.org
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kawahara
authors.forename: Boris
authors.initials: B
authors.lastname: Zinshteyn
authors.forename: Praveen
authors.initials: P
authors.lastname: Sethupathy
authors.forename: Hisashi
authors.initials: H
authors.lastname: Iizasa
authors.forename: Artemis G
authors.initials: AG
authors.lastname: Hatzigeorgiou
authors.forename: Kazuko
authors.initials: K
authors.lastname: Nishikura
mesh_terms: D020413:3' Untranslated Regions; D000241:Adenosine / Q000378:metabolism*; D000243:Adenosine Deaminase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007288:Inosine / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009928:Organ Specificity; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017393:RNA Editing; D034622:RNA Interference; D016601:RNA-Binding Proteins; D012268:Ribose-Phosphate Pyrophosphokinase / Q000235:genetics / Q000378:metabolism; D014527:Uric Acid / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D035683:MicroRNAs; D016601:RNA-Binding Proteins; D014527:Uric Acid; D007288:Inosine; C441620:Ttk protein, mouse; D017346:Protein Serine-Threonine Kinases; D012268:Ribose-Phosphate Pyrophosphokinase; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase; D000241:Adenosine