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: 10092116
• 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 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092116
• 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; Individual; Knowledge; Length; Malignant Neoplasms; Methods; Molecular; Mutation; PALB2 gene; Pathologic; Pathway interactions; Predisposition; Proteins; Reporting; Resected; Role; Tumor Suppression; Tumor Suppressor Proteins; Visualization; 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旁系同源物功能的机制，以及 这些蛋白质之间相互作用的后果，以深入了解它们在重组中的作用 DNA修复我们计划重建人类重组DNA修复的初始步骤， 了解这些蛋白质的生化功能。此外，我们将使用单分子成像， 揭示了这些蛋白作用的分子机制。

项目成果

BRCA2 chaperones RAD51 to single molecules of RPA-coated ssDNA.

• DOI: 10.1073/pnas.2221971120
• 发表时间: 2023-04-04
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Bell, Jason C.;Dombrowski, Christopher C.;Plank, Jody L.;Jensen, Ryan B.;Kowalczykowski, Stephen C.
• 通讯作者: Kowalczykowski, Stephen C.

PHF11 promotes DSB resection, ATR signaling, and HR.

• DOI: 10.1101/gad.291807.116
• 发表时间: 2017-01-01
• 期刊: Genes & development
• 影响因子: 10.5
• 作者: Gong Y;Handa N;Kowalczykowski SC;de Lange T
• 通讯作者: de Lange T