Molecular Functions of Recombination in Genome Stability and Tumor Suppression

重组在基因组稳定性和肿瘤抑制中的分子功能

• 批准号: 9311800
• 负责人: Stephen Charles Kowalczykowski
• 金额: $ 35.91万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-15 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9311800
• 关键词: Affect; BRCA1 gene; BRCA2 gene; Biochemical; Chromosomal Instability; DNA; DNA Repair; Defect; EXO1 gene; Excision; Genetic; Genetic Recombination; Genome Stability; Health; Human; Imagery; Individual; Knowledge; Length; Malignant Neoplasms; Methods; Molecular; Mutation; Pathologic; Pathway interactions; Predisposition; Proteins; Reporting; Resected; Role; Tumor Suppression; Tumor Suppressor Proteins; 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 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, and thereby understand the biochemical functions of these proteins. In addition, we will use single-molecule imaging to reveal the molecular mechanisms by which these proteins act.

项目摘要/摘要 这一提议的广泛目标是了解同源基因的分子机制。 人类中的重组，并了解重组DNA修复中缺陷的后果 导致染色体不稳定和易患癌症。了解细胞内关键蛋白的功能 同源重组，其中许多是肿瘤抑制基因，将提供洞察突变如何在 这些蛋白质会使人患上癌症。我们计划阐明生物化学的作用并检查 BRCA1、BLM、EXO1、PALB2、WRN和RAD51 Paralog功能的机制，以及 这些蛋白质之间相互作用的结果，以提供对它们在重组中的作用的洞察 DNA修复。我们计划重建人类重组DNA修复的初始步骤，从而 了解这些蛋白质的生化功能。此外，我们将使用单分子成像来 揭示这些蛋白质发挥作用的分子机制。