BARD1 phosphorylation in breast and ovarian cancer

乳腺癌和卵巢癌中的 BARD1 磷酸化

• 批准号: 7145275
• 负责人: RICHARD J BAER
• 金额: $ 22.52万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7145275
• 关键词: DNA damage; cell cycle; mammary gland; ovary neoplasms; phosphorylation; role

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.

描述（由申请人提供）：BRCA 1肿瘤抑制基因的生殖系突变是大多数家族性乳腺癌和卵巢癌综合征病例的原因。虽然BRCA 1参与了多种生物学过程，但它在细胞对DNA损伤的反应中起着特别重要的作用。特别是，BRCA 1是必不可少的同源性定向修复双链DNA断裂和电离辐射（IR）诱导的几个细胞周期检查点。此外，这些途径可能有助于BRCA 1的肿瘤抑制活性，在面对遗传毒性应激时保持基因组稳定性。有趣的是，BRCA 1在DNA损伤反应过程中在多个位点磷酸化，其中几个位点现在已经涉及BRCA 1的特定检查点或修复功能。在活细胞中，BRCA 1与BARD 1蛋白以化学计量异源二聚体的形式存在，并且通过大多数措施，其生物学功能似乎通过BRCA 1/BARD 1复合物介导。虽然BRCA 1是DNA损伤反应的关键调节因子，但BARD 1在这一过程中的作用知之甚少。我们的初步数据表明，BARD 1是磷酸化的细胞周期进程中，并在DNA损伤的反应，BARD 1磷酸化所需的一些，但不是全部，IR诱导的细胞周期检查点。因此，为了阐明BARD 1在DNA损伤反应中的作用，我们将1）鉴定IR诱导的BARD 1磷酸化位点，并确定内源性BARD 1在细胞周期进程和IR诱导方面的磷酸化模式，2）确定BARD 1磷酸化在IR诱导的细胞周期检查点（包括G2积累和有丝分裂出口检查点）中的作用，和3）评估BARD 1磷酸化在同源定向修复双链DNA断裂中的作用。通过定义BARD 1对这些通路的具体贡献，拟议的研究应该提供BRCA 1/BARD 1肿瘤抑制复合物及其在DNA损伤反应中的作用的更全面的观点。