BARD1 phosphorylation in breast and ovarian cancer

乳腺癌和卵巢癌中的 BARD1 磷酸化

• 批准号: 7477173
• 负责人: RICHARD J BAER
• 金额: $ 21.87万
• 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/7477173
• 关键词: BARD1 gene; BRCA1 Associated RING Domain 1 Protein; BRCA1 gene; BRCA2 gene; Biological; Biological Process; Breast; Cell Cycle Checkpoint; Cell Cycle Progression; Cell Line; Cells; Complex; DNA Damage; DNA Double Strand Break; Data; Event; Face; Genome Stability; Genotoxic Stress; Germ-Line Mutation; Hereditary Breast Carcinoma; Hereditary Breast and Ovarian Cancer Syndrome; Individual; Ionizing radiation; Life; Malignant neoplasm of ovary; Measures; Mediating; Mitosis; Mitotic; Mutation; Null Lymphocytes; Pathway interactions; Pattern; Phosphorylation; Phosphorylation Site; Phosphotransferases; Play; Principal Investigator; Process; Property; Proteins; Role; Site; Site-Directed Mutagenesis; Testing; Tumor Suppression; Tumor Suppressor Genes; Tumor Suppressor Proteins; carcinogenesis; in vivo; interest; novel; polypeptide; programs; repaired; response

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）：BRCA1肿瘤抑制基因的种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。尽管BRCA1参与多种生物过程，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，BRCA1对于同源定向修复双链DNA断裂和电离辐射（IR）诱导的几个细胞周期检查点至关重要。此外，这些途径可能通过在面对基因毒性胁迫时保持基因组稳定性来促进BRCA1的肿瘤抑制活性。有趣的是，在DNA损伤反应过程中，BRCA1在多个位点被磷酸化，其中一些位点现在被认为与BRCA1的特定检查点或修复功能有关。在活细胞中，BRCA1作为与BARD1蛋白的化学计量异源二聚体存在，通过大多数测量，其生物学功能似乎是通过BRCA1/BARD1复合物介导的。尽管BRCA1是DNA损伤反应的关键调节因子，但BARD1在这一过程中的作用尚不清楚。我们的初步数据表明，BARD1在细胞周期进程和对DNA损伤的反应中都被磷酸化，并且BARD1磷酸化是一些（但不是全部）ir诱导的细胞周期检查点所必需的。因此，为了阐明BARD1在DNA损伤反应中的作用，我们将1)确定IR诱导的BARD1磷酸化位点，并定义内源性BARD1在细胞周期进程和IR诱导方面的磷酸化模式，2)确定BARD1磷酸化在IR诱导的细胞周期检查点中的作用，包括G2积累和有丝分裂退出检查点。3)评估BARD1磷酸化在同源定向修复双链DNA断裂中的作用。通过明确BARD1在这些通路中的具体作用，这些研究将为BRCA1/BARD1肿瘤抑制复合物及其在DNA损伤反应中的作用提供更全面的视角。