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J. Biol. Chem., Vol. 279, Issue 53, 55153-55160, December 31, 2004

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Tetrameric Oligomerization Mediates Transcriptional Repression by the BRCA1-dependent Kruppel-associated Box-Zinc Finger Protein ZBRK1^*

Wei Tan, Seokjoong Kim, and Thomas G. Boyer

From the Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245-3207

The Kruppel-associated box (KRAB)-zinc finger protein ZBRK1 has been implicated in the transcriptional regulation of DNA damage-response genes that function in cell growth control and survival. Recently, we described a novel BRCA1-dependent C-terminal transcriptional repression domain (CTRD) within ZBRK1, the mode of repression of which is functionally distinguishable from that of the N-terminal KRAB repression domain within ZBRK1. The identification of BRCA1 binding-competent but repression-defective CTRD mutants further revealed that BRCA1 binding is necessary, but not sufficient, for ZBRK1 CTRD function. During an unbiased search for possible co-regulators of the CTRD, we identified ZBRK1 itself, suggesting that ZBRK1 can oligomerize through its CTRD. Herein we explore the physical and functional requirements for ZBRK1 oligomerization in ZBRK1-directed transcriptional repression. Protein interaction analyses confirmed that ZBRK1 can homo-oligomerize both in vitro and in vivo and further mapped the ZBRK1 oligomerization domain to the CTRD C terminus. Biochemical analyses, including protein cross-linking and gel filtration chromatography, revealed that ZBRK1 homo-oligomers exist as tetramers in solution. Functionally, ZBRK1 oligomerization facilitates ZBRK1-directed transcriptional repression through ZBRK1 response elements; requirements for oligomerization-dependent repression include the ZBRK1 CTRD and KRAB repression domains but not the DNA binding activity of ZBRK1. These observations suggest that higher order oligomers of ZBRK1 may assemble on target ZBRK1 response elements through both protein-DNA and CTRD-dependent protein-protein interactions. These findings thus reveal an unanticipated dual function for ZBRK1 in both DNA binding-dependent and -independent modes of transcriptional repression and further establish the CTRD as a novel protein interaction surface responsible for directing homotypic and heterotypic interactions necessary for ZBRK1-directed transcriptional repression.

Received for publication, September 22, 2004 , and in revised form, October 5, 2004.

^* This work was supported by United States Army Department of Defense Grant DAMD17-02-1-0584, National Institutes of Health Grant CA098301-01 (to T. G. B.), and United States Army Department of Defense Predoctoral Fellowship DAMD17-03-1-0259 (to W. T.). 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 Inst. of Biotechnology, University of Texas Health Science Center at San Antonio, 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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