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抑制基因的种系突变是家族性乳腺癌和卵巢癌综合征的大多数病例。尽管BRCA1参与了各种生物学过程，但它在对DNA损伤的细胞反应中起着特别重要的作用。特别是，BRCA1对于双链DNA断裂的同源性修复以及因电离辐射（IR）引起的几个细胞周期检查点所必需的。此外，这些途径可能通过在遗传毒性应激下保留基因组稳定性来导致BRCA1的肿瘤抑制活性。有趣的是，在DNA损伤响应期间，BRCA1在多个位点被磷酸化，现在其中几个与BRCA1的特定检查点或修复功能有关。在活细胞中，BRCA1作为具有Bard1蛋白的化学计量异二聚体存在，并且通过大多数衡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损伤响应的关键调节剂，但Bard1在此过程中的作用知之甚少。我们的初步数据表明，Bard1在细胞周期进程和对DNA损伤的响应过程中都是磷酸化的，并且某些但不是全部IR诱导的细胞周期检查点需要Bard1磷酸化。因此，为了阐明BARD1在DNA损伤响应中的作用，我们将1）确定Bard1的IR诱导的磷酸化位点，并定义内源性Bard1的磷酸化模式相对于细胞周期的进展和IR诱导性，2）确定IR诱导的g2累积的BARD1磷酸化作用，包括g2累积的C2累积累积， Bard1磷酸化在双链DNA断裂的同源指导修复中的作用。通过定义BARD1对这些途径的特定贡献，提出的研究应更全面地了解BRCA1/BARD1肿瘤抑制剂复合物及其在DNA损伤反应中的作用。