DNA REPAIR AND TUMOR SUPPRESSOR GENES

基因组不稳定性是癌细胞的一个特征。多种细胞过程中的缺陷，包括DNA修复和细胞周期检查点控制，可以引起这种表型。最近的研究提供了异常DNA双链断裂（DSB）修复与遗传性癌症之间联系的证据。本项目的总体目标是阐明DSB修复的分子机制，并研究肿瘤抑制基因BRCA1、BRCA2和ATM的产物对这一过程的调控。我们假设DSB修复中的异常，可能是DNA损伤感知机制，信号转导反应或修复过程本身，是许多人类癌症的重要致病因素。该研究项目结合了生化、细胞和遗传方法来描述DSB修复机制的组装和作用机制，肿瘤抑制基因产物如何调节细胞对DNA损伤的反应，以及肿瘤抑制基因的失活如何导致基因组不稳定，从而导致癌症的形成。单个项目将研究：(1)DSB修复的启动，包括Mre11/Rad50/p95核酸酶的断裂加工和Rad51及相关蛋白的异双工形成；(2)完成DSB修复所需的DNA合成和连接步骤；(3) atm介导的激酶级联对DSB修复机制的调节；(4) BRCA1、BRCA2和两种新型蛋白因子MLB1和RLB1对DNA修复机制的调节。这些研究项目将得到动物研究、核酸和蛋白质分析、成像等核心设施以及行政核心的支持。这些高度整合的项目将协同作用，以增强我们对复杂的多组分DNA修复系统的认识，该系统在维持基因组稳定性中起着关键作用。这些研究的结果将构成癌症检测、预防和治疗新策略的基础。

DESCRIPTION (Applicant's Description) Genomic instability is a hallmark of cancer cells. Defects in multiple cellular processes, including DNA repair and cell cycle checkpoint control, can give rise to this phenotype. Recent studies have provided evidence for a link between aberrant DNA double-strand break (DSB) repair and inherited forms of cancer. The overall goal of this program project is to elucidate the molecular mechanisms of DSB repair and to examine the regulation of this process by the products of the tumor suppressor genes BRCA1, BRCA2 and ATM. We hypothesize that abnormalities in DSB repair, which may be in the DNA damage sensing mechanisms, signal transduction responses, or in the repair process itself, are an important causative factor in many human cancers. This research program combines biochemical, cellular, and genetic approaches to delineate the assembly and mechanism of action of DSB repair machinery, how tumor suppressor gene products modulate cellular responses to DNA damage, and how inactivation of tumor suppressor genes results in genomic instability, leading to cancer formation. The individual projects will study: (1) the initiation of DSB repair including break processing by the Mre11/Rad50/p95 nuclease and heteroduplex formation by Rad51 and associated proteins; (2) the DNA synthesis and ligation steps that are required for the completion of DSB repair; (3) the modulation of the DSB repair machinery by an ATM-mediated kinase cascade; (4) the modulation of the DNA repair machinery by BRCA1, BRCA2, and two novel protein factors MLB1 and RLB1. The research projects will be supported by core facilities for animal studies, nucleic acid and protein analyses, and imaging, along with an administrative core. These highly integrated projects will interact synergistically to enhance our knowledge of a complex multi-component DNA repair system that plays a critical role in the maintenance of genomic stability. Results from these studies will form the basis for new strategies in cancer detection, prevention, and treatment.