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J. Biol. Chem., Vol. 278, Issue 38, 35979-35987, September 19, 2003

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M Phase-specific Phosphorylation of BRCA2 by Polo-like Kinase 1 Correlates with the Dissociation of the BRCA2-P/CAF Complex^*

Horng-Ru Lin  , Nicholas S. Y. Ting  ¶, Jun Qin || and Wen-Hwa Lee  **

From the Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center, San Antonio, Texas 78245 and the ^||Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030

BRCA2 is a breast tumor susceptibility gene encoding a 390-kDa protein with functions in maintaining genomic stability and cell cycle progression. Evidence has been accumulated to support the concept that BRCA2 has a critical role in homologous recombination of DNA double-stranded breaks by interacting with RAD51. In addition, BRCA2 may have chromatin modifying activity through interaction with a histone acetyltransferase protein, p300/CBP-associated factor (P/CAF). To explore how the functions of BRCA2 may be regulated, the post-translational modifications of BRCA2 throughout the cell cycle were examined. We found that BRCA2 is hyperphosphorylated specifically in M phase and becomes dephosphorylated as cells exit M phase and enter interphase. This specific phosphorylation of BRCA2 was not observed in cells treated with DNA-damaging agents. Systematic mapping of the potential mitosis specific phosphorylation sites revealed the N-terminal 284 amino acids of BRCA2 (BR-N1) as the major region of phosphorylation and mass spectrometric analysis identified two phosphopeptides that contain "phosphorylation consensus motifs" for Polo-like kinase 1 (Plk1). Phosphorylation of BR-N1 with Plk1 recapitulated the electrophoretic mobility change as seen in BR-N1 isolated from M phase cells. Plk1 interacts with BRCA2 in vivo, and mutation of Ser¹⁹³, Ser^205/206, and Thr^203/207 to Ala in BR-N1 abolished Plk1 phosphorylation, suggesting that BRCA2 is the substrate of Plk1. Furthermore, both the hyperphosphorylated and hypophosphorylated forms of BRCA2 bind to RAD51, whereas the M phase hyperphosphorylated form of BRCA2 no longer associates with the P/CAF, suggesting that the dissociation of P/CAF-BRCA2 complex is regulated by phosphorylation. Taken together, these results implicate a potential role of BRCA2 in modulating M phase progression.

Received for publication, October 18, 2002 , and in revised form, April 1, 2003.

^* This research was supported by Grants CA 81020 and CA 94170 from the National Institutes of Health (to W.-H. L.). 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.

Supported by Pre-doctoral Training Grant DAMD 17-99-1-9402 from the United States Army Medical Research and Materiel Command.

^¶ Recipient of a post-doctoral fellowship from the Susan G. Komen Breast Cancer Foundation.

^** To whom correspondence should be addressed: Dept. of Biological Chemistry, University of California, Irvine, 124 Sprague Hall, Irvine, CA 92697-4037. Tel.: 949-824-4492; Fax: 949-824-9767; E-mail: whlee{at}uci.edu.

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