Functions of BRCA1 and RAD51 Paralogs in Genome Stability and Tumor Suppression via Homologous Recombination

BRCA1 和 RAD51 旁系同源物在基因组稳定性和同源重组肿瘤抑制中的功能

• 批准号: 10565421
• 负责人: Stephen Charles Kowalczykowski
• 金额: $ 36.56万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10565421
• 关键词: Affect; BARD1 gene; BRCA1 gene; BRCA2 gene; Biochemical; Chromosomal Instability; Complex; DNA; DNA Repair; Defect; Enzymes; Event; Excision; Exodeoxyribonuclease I; Genetic; Genome Stability; Health; Human; Individual; Knowledge; Malignant Neoplasms; Methods; Molecular; Mutation; PALB2 gene; Pathologic; Pathway interactions; Predisposition; Process; Proteins; RAD51C gene; Rationalization; Resected; Role; Single-Stranded DNA; Technology; Translating; Tumor Suppression; Tumor Suppressor Proteins; Visualization; XRCC2 gene; XRCC3 gene; cancer predisposition; helicase; homologous recombination; insight; macromolecular assembly; molecular imaging; mutant; novel; novel therapeutic intervention; paralogous gene; protein function; reconstitution; single molecule

Project Summary/Abstract The broad objective of this proposal is to understand the molecular mechanism of homologous recombination in humans, and to understand how the consequences of defects in recombinational DNA repair result in chromosomal instability and predisposition to cancers. Understanding the functions of key proteins in homologous recombination, many of which are tumor suppressors, will provide insight into how mutations in these proteins can predispose individuals to cancer. We plan to elucidate the biochemical roles and examine the mechanism of BRCA1, BLM, EXO1, PALB2, WRN, and the RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3) functions, as well as the consequences of the interactions between these proteins, to provide insight into their role in recombinational DNA repair. We plan to reconstitute the initial steps of human recombinational DNA repair, focusing on the DNA resection step, and thereby understand the biochemical functions of these proteins. In addition, we will use single-molecule technologies to reveal the molecular mechanisms by which these proteins act.

项目总结/摘要 这项建议的主要目的是了解同源的分子机制， 在人类重组，并了解如何在重组DNA修复缺陷的后果 导致染色体不稳定和易患癌症。了解关键蛋白质的功能 同源重组，其中许多是肿瘤抑制因子，将提供深入了解突变如何在肿瘤细胞中， 这些蛋白质可使个体易患癌症。我们计划阐明其生物化学作用， BRCA 1、BLM、EXO 1、PALB 2、WRN和RAD 51旁系同源物（RAD 51 B，RAD 51 C， RAD 51 D、XRCC 2和XRCC 3）功能，以及这些功能之间相互作用的结果。 蛋白质，以提供深入了解其在重组DNA修复中的作用。我们计划重建最初的步骤 人重组DNA修复，重点是DNA切除步骤，从而了解 这些蛋白质的生化功能。此外，我们将使用单分子技术来揭示 这些蛋白质的分子机制。