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J. Biol. Chem., Vol. 281, Issue 34, 24236-24246, August 25, 2006

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BRCA1 Interacts with Poly(A)-binding Protein

IMPLICATION OF BRCA1 IN TRANSLATION REGULATION^*

Eva Dizin¹, Céline Gressier, Clémence Magnard², Hind Ray³, Didier Décimo, Théophile Ohlmann, and Nicole Dalla Venezia⁴

From the CNRS UMR 5201, Laboratoire de Génétique Moléculaire, Signalisation et Cancer, Université Claude Bernard Lyon I, Facultéde Médecine Rockefeller, 8 Avenue Rockefeller, 69373 Lyon cedex 08, France and INSERM, U 412, Ecole Normale Supérieure de Lyon, LaboRetro, Unité de Virologie Humaine, IFR 128, 46 Allée d'Italie, 69364 Lyon 07, France

BRCA1 has been implicated in a number of cellular processes, including transcription regulation, DNA damage repair, cell cycle control, and apoptosis. We identified poly(A)-binding protein 1 (PABP) as a novel BRCA1-interacting protein in a yeast two-hybrid screen and confirmed the interaction by in vitro assays and coimmunoprecipitation in mammalian cells. Endogenous interaction between BRCA1 and PABP was also observed. This interaction was abolished by BRCA1 cancer-associated mutations, suggesting that it may be physiologically relevant. Deletion mapping demonstrated that the RNA recognition motifs 1–4 region of PABP is required to mediate the interaction with BRCA1. To understand the biological function of the BRCA1-PABP complex, we sought to determine whether BRCA1 is a modulator of translation. We showed here that inhibition of endogenous BRCA1 using a small interfering RNA-based approach decreased protein synthesis. Conversely, overexpression of BRCA1 activated translation. Using a RNA transfection approach, we clearly showed that BRCA1 modulates translation, independently of any transcriptional activity. The data presented here suggest that BRCA1 modulates protein synthesis via its interaction with PABP, providing a novel mechanism by which BRCA1 may exert its tumor suppressor function.

Received for publication, March 7, 2006 , and in revised form, June 8, 2006.

^* The present work was supported by the Ligue Nationale Contre le Cancer, Comité Départemental du Rhône and Comité Départemental de la Haute-Savoie, and the Association pour la Recherche sur le Cancer. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of a fellowship from the French Ministry of Research.

² Current address: Yole Developpment, 45 Rue Sainte Geneviève, 69006 Lyon, France.

³ Recipient of a fellowship from the Association pour la Recherche sur le Cancer.

⁴ To whom correspondence should be addressed. Tel.: 33-478-777-213; Fax: 33-478-777-220; E-mail: dalla{at}rockefeller.univ-lyon1.fr.

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