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J. Biol. Chem., Vol. 279, Issue 8, 6576-6587, February 20, 2004

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Functional Dissection of Transcription Factor ZBRK1 Reveals Zinc Fingers with Dual Roles in DNA-binding and BRCA1-dependent Transcriptional Repression^*

Wei Tan, Lei Zheng, Wen-Hwa Lee, and Thomas G. Boyer¶

From the Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center, San Antonio, Texas 78245-3207 and the Department of Biological Chemistry, University of California, Irvine, California 92697-1700

The breast- and ovarian-specific tumor suppressor BRCA1 has been implicated in both activation and repression of gene transcription by virtue of its direct interaction with sequence-specific DNA-binding transcription factors. However, the mechanistic basis by which BRCA1 mediates the transcriptional activity of these regulatory proteins remains largely unknown. To clarify this issue, we have examined the functional interaction between BRCA1 and ZBRK1, a BRCA1-dependent KRAB eight zinc finger transcriptional repressor. We report here the identification and molecular characterization of a portable BRCA1-dependent transcriptional repression domain within ZBRK1 composed of zinc fingers 5-8 along with sequences in the unique ZBRK1 C terminus. This C-terminal repression domain functions in a BRCA1-, histone deacetylase-, and promoter-specific manner and is thus functionally distinguishable from the N-terminal KRAB repression domain in ZBRK1, which exhibits no BRCA1 dependence and broad promoter specificity. Significantly, we also find that the BRCA1-dependent transcriptional repression domain on ZBRK1 includes elements that modulate its sequence-specific DNA binding activity. These findings thus reveal the presence within ZBRK1 of functionally bipartite zinc fingers with dual roles in sequence-specific DNA-binding and BRCA1-dependent transcriptional repression. We discuss the implications of these findings for the role of BRCA1 as ZBRK1 co-repressor.

Received for publication, November 10, 2003 , and in revised form, November 26, 2003.

^* This work was supported by United States Army Department of Defense Grant DAMD17-02-1-0584 (to T. G. B.), United States Army Department of Defense Training Grant (to W. T.), and National Institutes of Health Grants CA94170, CA81020 (to W.-H. L.), and CA098301-01 (to T. G. B). 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.

^¶ To whom correspondence should be addressed: Dept. of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center, 15355 Lambda Dr., San Antonio, TX 78245-3207. Tel.: 210-567-7258; Fax: 210-567-7377; E-mail: boyer{at}uthscsa.edu.

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