DNA Repair Genes and Proteins of the RAD52 Group

RAD52 组的 DNA 修复基因和蛋白质

• 批准号: 9879032
• 负责人: Patrick Sung
• 金额: $ 15万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9879032
• 关键词: DNA; Repair; Genes; Proteins; RAD52

 DESCRIPTION (provided by applicant): Studies in the model eukaryote Saccharomyces cerevisiae have revealed that homologous recombination (HR) provides a major mechanism for eliminating DNA double-stranded breaks (DSBs) induced by ionizing radiation or are associated with injured DNA replication forks. During the repair process, the ends of the DNA breaks are resected nucleolytically to yield 3' ssDNA tails, which are bound by HR factors. The nucleoprotein complex thus formed then conducts a search to locate an undamaged DNA homolog, and catalyzes the formation of a DNA joint, called D-loop, with the homolog. Resolution of the D-loop can proceed via at least three mechanistically distinct pathways, two of which generate only non-crossover recombinants and are therefore more adept at genome preservation, with the remaining pathway being able to produce crossovers frequently. Proteins encoded by evolutionarily conserved genes of the RAD52 epistasis group catalyze the HR reaction. Our studies have provided insights into the mechanistic underpinnings of the HR machinery that harbors proteins of this gene group. In this renewal project, a combination of biochemical, genetic, and other cell-based approaches will be employed to (i) define the mechanism of action of the DNA motor-driven path of DSB end resection and its functional crosstalk with Exo1-mediated resection in both yeast and human cells, and (ii) delineate the roles that the conserved Rad51 paralogs fulfill in the assembly of Rad51-ssDNA nucleoprotein filaments. The results from our endeavors will allow us to formulate detailed models to elucidate HR mechanisms in eukaryotes. Given the importance of HR-mediated chromosome damage repair in tumor suppression, our work also has direct, strong relevance to cancer biology.

 描述（由申请人提供）：对模型真核生物酿酒酵母的研究表明，同源重组（HR）提供了消除电离辐射引起的或与受损的DNA复制叉相关的DNA双链断裂（DSB）的主要机制。在修复过程中，DNA 断裂的末端被溶核切除，产生 3' ssDNA 尾部，并与 HR 因子结合。由此形成的核蛋白复合物然后进行搜索以定位未受损的DNA同源物，并催化与同源物形成DNA接头，称为D环。 D环的解析可以通过至少三个机械上不同的途径进行，其中两个仅产生非交叉重组体，因此更擅长基因组保存，其余途径能够频繁产生交叉。由 RAD52 上位基团的进化保守基因编码的蛋白质催化 HR 反应。我们的研究提供了对包含该基因组蛋白质的 HR 机制的机制基础的见解。在这个更新项目中，将采用生物化学、遗传和其他基于细胞的方法相结合，以（i）定义DSB末端切除的DNA马达驱动路径的作用机制及其与酵母和人类细胞中Exo1介导的切除的功能串扰，以及（ii）描述保守的Rad51旁系同源物在组装中所发挥的作用。 Rad51-ssDNA 核蛋白丝。我们努力的结果将使我们能够制定详细的模型来阐明真核生物的 HR 机制。鉴于 HR 介导的染色体损伤修复在肿瘤抑制中的重要性，我们的工作也与癌症生物学具有直接、强烈的相关性。