BARD1 phosphorylation in breast and ovarian cancer

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DESCRIPTION (provided by applicant): Germline mutations of the BRCA1 tumor suppressor gene are responsible for most cases of the familial breast and ovarian cancer syndrome. Although BRCA1 is involved in various biological processes, it plays an especially important role in the cellular response to DNA damage. In particular, BRCA1 is essential for homology-directed repair of double-strand DNA breaks and for several of the cell cycle checkpoints induced by ionizing radiation (IR). Moreover, these pathways are likely to contribute to the tumor suppression activity of BRCA1 by preserving genomic stability in the face of genotoxic stress. Interesting, BRCA1 is phosphorylated at multiple sites during the DNA damage response, and several of these sites have now been implicated in specific checkpoint or repair functions of BRCA1. In living cells, BRCA1 exists as a stoichiometric heterodimer with the BARD1 protein, and by most measures its biological functions appear to be mediated through the BRCA1/BARD1 complex. Although BRCA1 is key regulator of the DNA damage response, the role of BARD1 in this process is poorly understood. Our preliminary data indicate that BARD1 is phosphorylated during both cell cycle progression and in response to DNA damage, and that BARD1 phosphorylation is required for some, but not all, of the IR-induced cell cycle checkpoints. Thus, to elucidate the role of BARD1 in the DNA damage response, we will 1) identify the IR-induced phosphorylation sites of BARD1 and define the phosphorylation pattern of endogenous BARD1 with respect to both cell cycle progression and IR inducibility, 2) determine the role of BARD1 phosphorylation in the IR-induced cell cycle checkpoints, including the G2 accumulation and mitotic exit checkpoints, and 3) evaluate the role of BARD1 phosphorylation in homology-directed repair of double-strand DNA breaks. By defining the specific contributions of BARD1 to these pathways, the proposed studies should provide a more comprehensive view of the BRCA1/BARD1 tumor suppressor complex and its role in the DNA damage response.