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J. Biol. Chem., Vol. 281, Issue 30, 21119-21130, July 28, 2006

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The BRCA1 COOH-terminal Region Acts as an RNA Polymerase II Carboxyl-terminal Domain Kinase Inhibitor That Modulates p21^WAF1/CIP1 Expression^*

From the Département de Biologie, Faculté des Sciences, Université de Sherbrooke, Sherbrooke, Québec J1K 2R1, Canada

BRCA1 is involved both in positive and negative regulation of gene activity as well as in numerous other processes, such as DNA damage response and repair. We recently reported that BRCA1 inhibits RNA polymerase II carboxyl-terminal domain (CTD) phosphorylation by TFIIH and decreases serine 5 phosphorylation levels when introduced into a BRCA1^-/- cell line. Regulation of CTD phosphorylation is crucial for proper gene expression and response to cellular stresses, such as DNA damage and transcription arrest. A key player in this process, P-TEFb, phosphorylates the CTD on serine 2 of transcriptionally engaged RNA polymerase II, and its kinase activity was shown to be up-regulated when cells are exposed to transcriptional stress such as UV irradiation. Here, we investigate the effect of BRCA1 on serine 2 phosphorylation and UV-activated P-TEFb kinase activity. We now show that BRCA1 inhibits immunoprecipitated P-TEFb kinase activity from UV-irradiated cells and preferentially decreases UV-induced serine 2 phosphorylation of soluble, rather than chromatin-bound, RNAPII. We further show that BRCA1 rescues the UV-mediated inhibition of transcriptional activity from nuclear extracts and stimulates endogenous p21 gene expression upon UV irradiation, a function that is dependent of the inhibition of CTD kinase activity. Our results suggest that BRCA1 could act as a CTD kinase inhibitor and, as such, contribute to the regulation of p21 gene expression.

Received for publication, January 24, 2006 , and in revised form, May 30, 2006.

^* This work was supported by the Cancer Research Society Inc. of Canada (to L. G.). 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 studentship from the National Cancer Institute of Canada, supported by the Terry Fox Foundation.

² To whom correspondence should be addressed. Tel.: 819-821-8000 (ext. 2081); Fax: 819-821-8049; E-mail: Luc.Gaudreau{at}USherbrooke.ca.

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