Chromatin Regulation of Double-Strand Break Repair

双链断裂修复的染色质调控

• 批准号: 7554133
• 负责人: MARY ANN OSLEY
• 金额: $ 25.85万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7554133
• 关键词: Biological Assay; Candidate Disease Gene; Chemicals; Chromatin; Chromatin Remodeling Factor; Complex; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Sequence Rearrangement; DNA biosynthesis; DNA damage checkpoint; Distal; Double Strand Break Repair; Elements; Enhancers; Gene Conversion; Genetic; Genetic Recombination; Genetic Transcription; Genome; Genome Stability; Histone H2A; Histone H3; Ionizing radiation; Kinetics; Lesion; Lysine; Mating Types; Mediating; Methylation; Modification; Monitor; Mutation; NURF; Nonhomologous DNA End Joining; Nucleosomes; Outcome; Pathway interactions; Phosphorylation; Play; Process; Proteins; Radiation; Recruitment Activity; Regulation; Research Design; Research Personnel; Resistance; Risk; Role; Saccharomyces cerevisiae; Series; Site; Staging; System; Tertiary Protein Structure; Testing; Tumor Suppression; Yeasts; cancer radiation therapy; chemotherapy; chromatin immunoprecipitation; chromatin modification; chromatin protein; chromatin remodeling; histone modification; homologous recombination; man; mutant; novel; programs; promoter; repaired; response; tumor

DMA repair and DNA damage checkpoints are important for tumor suppression, and are critical determinants of tumor resistance to radiation and chemotherapeutics. DNA double-strand breaks (DSBs) are produced by genotoxic chemicals and ionizing radiation, and arise spontaneously during DNA replication. DSBs are repaired by non-homologous end-joining (NHEJ) and homologous recombination (HR). DSBs occur in the context of chromatin, and chromatin alterations play important roles in the recruitment of DNA repair and checkpoint proteins to damage sites. The proposed studies are designed to determine the roles of chromatin modification and remodeling in protein recruitment to DSBs, and in the regulation of DSB repair outcome in the yeast Saccharomyces cerevisiae. Our central hypothesis is that DSB repair efficiency and outcome are regulated through the integrated actions of repair proteins, checkpoint proteins, and chromatin dynamics. We will test this hypothesis by pursuing three Specific Aims focused on (1) the roles of chromatin changes in recruitment of repair and checkpoint proteins to DSBs; (2) defining chromatin changes at a DSB site and a donor locus during HR; and (3) determining how chromatin regulates DSB repair. As with phosphorylation of histone H2A, we found that nucleosome displacement plays a role in the timely recruitment of repair proteins to DSBs. The roles of these and other chromatin alterations in protein recruitment to DSBs, regulation of DSB repair, and checkpoint activation will be investigated. These studies will clarify how chromatin alterations regulate cellular responses to DSBs and thereby determine the genetic consequences of DSB damage. The proposed studies are relevant because chromatin modifications, DSB repair, and checkpoint responses are conserved from yeast to man. The studies are significant because they will reveal new regulatory mechanisms in DSB repair, and thus identify new targets to exploit in cancer radio- and chemotherapy.

DMA 修复和 DNA 损伤检查点对于肿瘤抑制很重要，而且至关重要 肿瘤对放射和化疗耐药的决定因素。 DNA 双链断裂 (DSB) 由基因毒性化学物质和电离辐射产生，在 DNA 过程中自发产生 复制。 DSB 通过非同源末端连接 (NHEJ) 和同源重组进行修复 （人力资源）。 DSB 发生在染色质背景下，染色质改变在 招募 DNA 修复和检查点蛋白到损伤位点。拟议的研究旨在 确定染色质修饰和重塑在蛋白质招募到 DSB 中的作用，以及 酿酒酵母 DSB 修复结果的调节。我们的中心假设是 DSB 修复效率和结果是通过修复蛋白的综合作用来调节的， 检查点蛋白和染色质动力学。我们将通过追求三个具体目标来检验这一假设 重点关注 (1) 染色质变化在修复和检查点蛋白招募到 DSB 中的作用； (2) 定义 HR 期间 DSB 位点和供体位点的染色质变化； (3) 确定染色质如何 调节 DSB 修复。与组蛋白 H2A 的磷酸化一样，我们发现核小体位移 在 DSB 及时招募修复蛋白方面发挥作用。这些和其他染色质的作用 DSB 的蛋白质募集、DSB 修复的调节和检查点激活的改变将 调查了。这些研究将阐明染色质改变如何调节细胞对 DSB 的反应和 从而确定 DSB 损伤的遗传后果。拟议的研究是相关的，因为 染色质修饰、DSB 修复和检查点反应从酵母到人类都是保守的。这 研究意义重大，因为它们将揭示 DSB 修复的新调控机制，从而确定 癌症放疗和化疗中探索的新靶点。