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.

项目概要/摘要 该提案的广泛目标是了解同源的分子机制 人类重组，并了解重组 DNA 修复缺陷的后果 导致染色体不稳定并易患癌症。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）将提供关于突变如何发生的见解。 这些蛋白质会使人容易患癌症。我们计划阐明生化作用并检查 BRCA1、BLM、EXO1、PALB2、WRN 和 RAD51 旁系同源物（RAD51B、RAD51C、 RAD51D、XRCC2 和 XRCC3) 功能，以及这些功能之间相互作用的后果 蛋白质，以深入了解它们在重组 DNA 修复中的作用。我们计划重建最初的步骤 人类重组 DNA 修复的研究，重点关注 DNA 切除步骤，从而了解 这些蛋白质的生化功能。此外，我们将利用单分子技术来揭示 这些蛋白质发挥作用的分子机制。