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M312270200v1
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Papers In Press, published online ahead of print December 2, 2003
J. Biol. Chem, 10.1074/jbc.M312270200
Submitted on November 10, 2003
Revised on November 26, 2003
Accepted on December 2, 2003

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

Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78245

Corresponding Author: boyer{at}uthscsa.edu

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 comprised 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 dependency 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.


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