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Science 315 (5815): 1137-1140

Copyright © 2007 by the American Association for the Advancement of Science

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

Yukio Kawahara,1*{dagger} Boris Zinshteyn,1{dagger} Praveen Sethupathy,2 Hisashi Iizasa,1 Artemis G. Hatzigeorgiou,2,3 Kazuko Nishikura1*

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.

1 The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
2 Department of Genetics, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
3 Department of Computer and Information Science, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA.

{dagger} These authors contributed equally to this work.

* To whom correspondence should be addressed. E-mail: ykawahara{at} (Y.K.); kazuko{at} (K.N.)

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