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J. Biol. Chem., Vol. 281, Issue 13, 8317-8320, March 31, 2006

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Direct Stimulation of Transcription Initiation by BRCA1 Requires Both Its Amino and Carboxyl Termini^*

Andrew A. Horwitz, Satish Sankaran, and Jeffrey D. Parvin¹

From the Program in Biology and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts 02115 and the Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115

Published experiments suggest that BRCA1 interaction with RNAPII and regulation of a number of target genes may be central to its role as a tumor suppressor. Previous in vivo and in vitro work has implicated the carboxyl terminus of BRCA1 in transcriptional stimulation, but the mechanism of action remains unknown, and whether the full-length protein stimulates transcription is controversial. BRCA1 interacts with a number of enhancer-binding transcriptional activators, suggesting that these factors recruit BRCA1 to promoters, where it stimulates RNA synthesis. To investigate whether BRCA1 has intrinsic transcriptional activity, we established a fully purified transcription assay. We demonstrate here that BRCA1 stimulates transcription initiation across a range of promoters. Both the amino and carboxyl termini of BRCA1 are required for this activity, but the BRCA1-binding partner, BARD1, is not. Our data support a model whereby BRCA1 stabilizes productive preinitiation complexes and thus stimulates transcription.

Received for publication, December 21, 2005 , and in revised form, January 27, 2006.

^* This work was supported by a predoctoral fellowship from the Department of Defense Breast Cancer Research Program (to A. A. H.), a postdoctoral fellowship from the Komen Foundation (to S. S.), and National Institutes of Health Research Grant CA90281 (to J. D. P.). 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 To whom correspondence should be addressed. E-mail: jparvin{at}rics.bwh.harvard.edu.

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