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J. Biol. Chem., Vol. 279, Issue 30, 31251-31258, July 23, 2004

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BRCA1-BARD1 Complexes Are Required for p53^Ser-15 Phosphorylation and a G₁/S Arrest following Ionizing Radiation-induced DNA Damage^*

Megan Fabbro, Kienan Savage¶, Karen Hobson, Andrew J. Deans||, Simon N. Powell**, Grant A. McArthur||, and Kum Kum Khanna

From the Queensland Institute of Medical Research, Post Office Royal Brisbane Hospital, Brisbane, Queensland 4029, Australia, ^¶Central Clinical Division, School of Medicine, University of Queensland, Brisbane, Queensland 4072, Australia, ^||Molecular Oncology Laboratory, Peter MacCallum Cancer Institute, East Melbourne 3002, Australia, and ^**Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts 02114

BRCA1 is a major player in the DNA damage response. This is evident from its loss, which causes cells to become sensitive to a wide variety of DNA damaging agents. The major BRCA1 binding partner, BARD1, is also implicated in the DNA damage response, and recent reports indicate that BRCA1 and BARD1 co-operate in this pathway. In this report, we utilized small interfering RNA to deplete BRCA1 and BARD1 to demonstrate that the BRCA1-BARD1 complex is required for ATM/ATR (ataxia-telangiectasia-mutated/ATM and Rad3-related)-mediated phosphorylation of p53^Ser-15 following IR- and UV radiation-induced DNA damage. In contrast, phosphorylation of a number of other ATM/ATR targets including H2AX, Chk2, Chk1, and c-jun does not depend on the presence of BRCA1-BARD1 complexes. Moreover, prior ATM/ATR-dependent phosphorylation of BRCA1 at Ser-1423 or Ser-1524 regulates the ability of ATM/ATR to phosphorylate p53^Ser-15 efficiently. Phosphorylation of p53^Ser-15 is necessary for an IR-induced G₁/S arrest via transcriptional induction of the cyclin-dependent kinase inhibitor p21. Consistent with these data, repressing p53^Ser-15 phosphorylation by BRCA1-BARD1 depletion compromises p21 induction and the G₁/S checkpoint arrest in response to IR but not UV radia-tion. These findings suggest that BRCA1-BARD1 complexes act as an adaptor to mediate ATM/ATR-directed phosphorylation of p53, influencing G₁/S cell cycle progression after DNA damage.

Received for publication, May 14, 2004

^* This work was supported by grants from the Sylvia and Charles Viertel Foundation and the National Health and Medical Research Council of Australia (to K. K. K.). 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.

These authors contributed equally to this work.

To whom correspondence should be addressed. Tel.: 61-7-3845-3770; Fax: 61-7-3362-0105; E-mail: kumkumK{at}qimr.edu.au.

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