DSB REPAIR RECOMBINATION, AND GENOME STABILITY

DSB 修复重组和基因组稳定性

• 批准号: 7198028
• 负责人: Jac A Nickoloff
• 金额: $ 24.3万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-18 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7198028
• 关键词: Biochemical; Cells; Chemicals; Chromatin Structure; Complement; Complementary DNA; Complex; DNA; DNA Damage; DNA Double Strand Break; DNA biosynthesis; DNA lesion; DNA repair protein; DNA-PKcs; Data; Defect; Dimerization; Dominant-Negative Mutation; Double Strand Break Repair; Frequencies; G22P1 gene; Genetic; Genetic Recombination; Genome Stability; Genomic Instability; Goals; Intervention; Lead; Link; Loss of Heterozygosity; Malignant Neoplasms; Mediating; Molecular Conformation; NBS1 gene; Nature; Outcome; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Predisposition; Proteins; Radiation; Radiation therapy; Regulation; Relative (related person); Research; Role; Syndrome; Testing; Thinking; XRCC5 gene; cancer therapy; improved; insertion/deletion mutation; insight; leukemia/lymphoma; link protein; neoplastic cell; recombinational repair; repaired

DESCRIPTION (provided by applicant): The goal of the proposed research is to determine how proteins at the interface of homologous recombinational repair (HR) and nonhomologous end-joining (NHEJ) modulate DNA double-strand break (DSB) repair fidelity. Defects in HR and NHEJ proteins are linked to cancer predisposition. DSBs are key DNA lesions produced by genotoxic chemicals and radiation, and DSBs may arise spontaneously during DNA replication. HR and NHEJ compete for the repair of DSBs, and the genetic consequences of the two repair pathways are significantly different. Many factors are likely to influence the choice between HR and NHEJ, some of which are substrate-dependent. Perhaps more important from the standpoint of potential targets for chemo- or radiotherapeutic intervention in cancer treatment are trans factors, i.e., DNA repair proteins, including their concentrations, physical interactions, and biochemical activities. HR and NHEJ may compete passively for DSBs, with each operating independently of the other. Alternatively, competition may be active, with HR proteins interacting with, and modulating the activities of NHEJ proteins, and vice versa. Although most DSB repair proteins have been assigned to the HR or the NHEJ pathway, some influence both pathways, such as the MRE11/RAD50/NBS1 (MRN) complex. Recent evidence indicates that DNAPKcs and Ku are also at the NHEJ/HR interface. These proteins therefore play important roles in determining the genetic consequences of DSB damage. Other data indicate that DNA-PKcs, Ku, and MRN also regulate spontaneous HR, suggesting another mechanism by which these proteins regulate genome stability. Our central hypothesis is that proteins at the HR/NHEJ interface regulate genome stability by controlling the relative levels and outcomes of NHEJ and HR during DSB repair, and by controlling spontaneous FIR levels. We will determine how DSB repair is regulated by DNA-PKcs (Aim 1), Ku (Aim 2), MRN (Aim 3), and we will determine if spontaneous HR is regulated by these proteins (Aim 4). These projects will provide insight into the regulation of mammalian DSB repair and spontaneous HR that can be exploited to develop more effective agents to sensitize tumor cells to DNA damaging agents, and thereby improve cancer therapy.

描述（由申请人提供）：拟议研究的目标是确定同源重组修复（HR）和非同源末端连接（NHEJ）界面处的蛋白质如何调节DNA双链断裂（DSB）修复保真度。HR和NHEJ蛋白的缺陷与癌症易感性有关。DSB是由遗传毒性化学品和辐射产生的关键DNA损伤，并且DSB可以在DNA复制期间自发产生。HR和NHEJ竞争DSB的修复，并且两种修复途径的遗传后果显著不同。许多因素可能会影响HR和NHEJ之间的选择，其中一些是底物依赖性的。从癌症治疗中化疗或放疗干预的潜在靶点的角度来看，可能更重要的是反式因子，即，DNA修复蛋白，包括它们的浓度，物理相互作用和生化活性。HR和NHEJ可能会被动地竞争DSB，彼此独立运作。或者，竞争可以是活跃的，HR蛋白与NHEJ蛋白相互作用并调节NHEJ蛋白的活性，反之亦然。虽然大多数DSB修复蛋白已被分配到HR或NHEJ途径，但一些影响两种途径，如MRE 11/RAD 50/NBS 1（MRN）复合物。最近的证据表明，DNAPKcs和Ku也在NHEJ/HR界面。因此，这些蛋白质在决定DSB损伤的遗传后果方面发挥重要作用。其他数据表明，DNA-PKcs，Ku和MRN也调节自发HR，这表明这些蛋白质调节基因组稳定性的另一种机制。我们的中心假设是，在HR/NHEJ接口的蛋白质调节基因组的稳定性，通过控制DSB修复过程中的NHEJ和HR的相对水平和结果，并通过控制自发FIR水平。我们将确定DSB修复如何受DNA-PKcs（Aim 1），Ku（Aim 2），MRN（Aim 3）调节，我们将确定自发HR是否受这些蛋白质调节（Aim 4）。这些项目将提供对哺乳动物DSB修复和自发HR的调节的深入了解，这些调节可以用于开发更有效的药物，以使肿瘤细胞对DNA损伤剂敏感，从而改善癌症治疗。