Connections and redundancy in the BRCA1-BRCA2 pathway of homologous recombination

BRCA1-BRCA2 同源重组途径中的连接和冗余

• 批准号: 8600661
• 负责人: Simon N. Powell
• 金额: $ 35.59万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8600661
• 关键词: Address; BRCA1 Protein; BRCA1 gene; BRCA2 Protein; BRCA2 gene; Back; Biological; Breast Cancer Cell; Cancer cell line; Cancer-Predisposing Gene; Cell Cycle Checkpoint; Cell Line; Cell Survival; Cells; Classification; DNA Damage; DNA Repair; DNA biosynthesis; DNA lesion; Defect; Dependence; Ensure; Excision; Failure; Gene Mutation; Genetic; Genome; Germ-Line Mutation; Goals; Human; Knock-out; Knowledge; Link; Maintenance; Malignant Neoplasms; Mammalian Cell; Mediating; Mediator of activation protein; Mutation; Nature; Oncogenes; Pathway interactions; Phosphorylation; Phosphotransferases; Post-Translational Protein Processing; Process; Proteins; Rad52 protein; Recruitment Activity; Reporting; Role; Serine; Signal Transduction; Site; Testing; Work; base; cancer therapy; gene function; homologous recombination; improved; insight; malignant breast neoplasm; member; neoplastic cell; protein function; public health relevance; research study; response; tool; tumor

DESCRIPTION (provided by applicant): The DNA damage response and DNA repair defects found in cells with a deficiency of the BRCA1 or BRCA2 protein have been extensively characterized in the last decade. However, the connections between the two proteins remain relatively poorly understood, as they function at different steps in the pathway of homologous recombination. The major role of the BRCA1-BRCA2 pathway of homologous recombination (HR) is to protect the genome from errors arising out of endogenously created double-strand breaks, which are created during DNA replication. BRCA1 is activated to promote homologous recombination by a critical post-translational modification by Chk2 on serine 988, which then results in controlling the extent of 5'-end resection at double- strand breaks. The first aim will focus on how BRCA1 controls both end resection and the subsequent recruitment of downstream factors in homologous recombination including BRCA2. The second aim is specifically focused on what happens to double-strand breaks, created during replication or exogenously, in the absence of BRCA1 or BRCA2. The Rad52 protein is redundant for homologous recombination in mammalian cells, but in the absence of a functioning BRCA1-BRCA2 pathway, it becomes critical for cell viability. The goals of this second aim are to understand the Rad52-Rad51 pathway in mammalian cells as it may give insight on how tumor cells defective in BRCA1-BRCA2 pathway survive normal DNA replication. Rad52 is therefore a key tumor-specific target for therapy in BRCA-deficient tumors. The third aim plans to look at new connections in the BRCA1-BRCA2 pathway that are defective in sporadic breast cancers, where there is no genetic defect in BRCA1 or BRCA2, but the pathway is not connected. A failure to recruit BRCA1 to sites of DNA damage is observed and the "road-block" appears to occur in the upstream DNA damage pathway to BRCA1 between RAP80 and Abraxas. All three aims are focused on the connections in the BRCA1-BRCA2 pathway of homologous recombination, and the knowledge from these proposed experiments should allow new insight for treating human cancers with defects in this pathway.

描述（由申请人提供）：在过去十年中，在 BRCA1 或 BRCA2 蛋白缺陷的细胞中发现的 DNA 损伤反应和 DNA 修复缺陷已得到广泛表征。然而，这两种蛋白质之间的联系仍然知之甚少，因为它们在同源重组途径的不同步骤中发挥作用。 BRCA1-BRCA2 同源重组 (HR) 途径的主要作用是保护基因组免受因 DNA 复制过程中产生的内源性双链断裂而产生的错误。 BRCA1 通过 Chk2 对丝氨酸 988 进行关键的翻译后修饰而被激活以促进同源重组，从而控制双链断裂处 5' 端切除的程度。第一个目标将集中于 BRCA1 如何控制末端切除以及随后在同源重组中招募下游因子（包括 BRCA2）。第二个目标特别关注在缺乏 BRCA1 或 BRCA2 的情况下，复制过程中或外源产生的双链断裂会发生什么。 Rad52 蛋白对于哺乳动物细胞中的同源重组来说是多余的，但在缺乏功能性 BRCA1-BRCA2 通路的情况下，它对细胞活力变得至关重要。第二个目标是了解哺乳动物细胞中的 Rad52-Rad51 通路，因为它可以深入了解 BRCA1-BRCA2 通路缺陷的肿瘤细胞如何在正常 DNA 复制中存活。因此，Rad52 是治疗 BRCA 缺陷肿瘤的关键肿瘤特异性靶点。第三个目标计划研究散发性乳腺癌中存在缺陷的 BRCA1-BRCA2 通路中的新连接，即 BRCA1 或 BRCA2 没有遗传缺陷，但该通路并未连接。观察到未能将 BRCA1 招募到 DNA 损伤位点，并且“路障”似乎发生在 RAP80 和 Abraxas 之间通往 BRCA1 的上游 DNA 损伤途径中。所有三个目标都集中在 BRCA1-BRCA2 同源重组途径中的联系，这些拟议实验中的知识应该为治疗具有该途径缺陷的人类癌症提供新的见解。