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Molecular and Cellular Biology, January 2004, p. 708-718, Vol. 24, No. 2
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.2.708-718.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Chk2 Phosphorylation of BRCA1 Regulates DNA Double-Strand Break Repair

Junran Zhang,1 Henning Willers,1 Zhihui Feng,1 Jagadish C. Ghosh,1 Sang Kim,2 David T. Weaver,3 Jay H. Chung,4 Simon N. Powell,1* and Fen Xia1*

Department of Radiation Oncology,1 MGH Cancer Center, Massachusetts General HospitalHarvard Medical School, Charlestown, Massachusetts 02129,2 Center for Blood Research, Boston, Massachusetts 02115,3 Laboratory of Biochemical Genetics, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 208924

Received 25 July 2003/ Returned for modification 4 September 2003/ Accepted 23 October 2003

The pathway determining malignant cellular transformation, which depends upon mutation of the BRCA1 tumor suppressor gene, is poorly defined. A growing body of evidence suggests that promotion of DNA double-strand break repair by homologous recombination (HR) may be the means by which BRCA1 maintains genomic stability, while a role of BRCA1 in error-prone nonhomologous recombination (NHR) processes has just begun to be elucidated. The BRCA1 protein becomes phosphorylated in response to DNA damage, but the effects of phosphorylation on recombinational repair are unknown. In this study, we tested the hypothesis that the BRCA1-mediated regulation of recombination requires the Chk2- and ATM-dependent phosphorylation sites. We studied Rad51-dependent HR and random chromosomal integration of linearized plasmid DNA, a subtype of NHR, which we demonstrate to be dependent on the Mre11-Rad50-Nbs1 complex. Prevention of Chk2-mediated phosphorylation via mutation of the serine 988 residue of BRCA1 disrupted both the BRCA1-dependent promotion of HR and the suppression of NHR. Similar results were obtained when endogenous Chk2 kinase activity was inhibited by expression of a dominant-negative Chk2 mutant. Surprisingly, the opposing regulation of HR and NHR did not require the ATM phosphorylation sites on serines 1423 and 1524. Together, these data suggest a functional link between recombination control and breast cancer predisposition in carriers of Chk2 and BRCA1 germ line mutations. We propose a dual regulatory role for BRCA1 in maintaining genome integrity, whereby BRCA1 phosphorylation status controls the selectivity of repair events dictated by HR and error-prone NHR.

* Corresponding author. Mailing address for Simon N. Powell: Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, 149 13th St., Charlestown, MA 02129. Phone: (617) 726-8162. Fax: (617) 724-8320. E-mail: snpowell{at}partners.org. Present address for Fen Xia: Department of Radiation Oncology, Vanderbilt University Medical Center, 1301 22nd Ave. South, Nashville, TN 37232. Phone: (615) 322-2555. Fax: (615) 343-6589. E-mail: fen.xia{at}vanderbilt.edu.

Molecular and Cellular Biology, January 2004, p. 708-718, Vol. 24, No. 2
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.2.708-718.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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