Role of the Shu Complex in Homology-directed Chromosome Repair

Shu 复合物在同源定向染色体修复中的作用

• 批准号: 8447187
• 负责人: WILLIAM GAINES
• 金额: $ 5.22万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8447187
• 关键词: Affect; Alkylating Agents; Binding; Biochemical; Biochemical Genetics; Biological Models; Bloom Syndrome; Cancer Biology; Cells; Chemicals; Chromosomes; Complex; DNA; DNA Binding; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Pathway; DNA Sequence Rearrangement; Defect; Disease; Dissection; Eukaryota; Exhibits; Fanconi' s Anemia; Fellowship; Filament; Generations; Genes; Genetic; Genetic Epistasis; Genome; Genomic Instability; Genomics; Goals; Hereditary Breast Carcinoma; Human; Hydrolysis; In Vitro; Investigation; Ionizing radiation; Knowledge; Life; Light; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Meiosis; Modeling; Organism; Orthologous Gene; Pathway interactions; Phenotype; Play; Positioning Attribute; Predisposition; Process; Property; Proteins; Rad51 recombinase; Radiation; Reaction; Role; Saccharomyces cerevisiae; Sister Chromatid; Werner Syndrome; Work; assault; crosslink; homologous recombination; in vivo; injured; member; mutant; novel; presynaptic; protein complex; recombinase; reconstitution; repaired; research study; telomere; tool

DESCRIPTION (provided by applicant): Studies in the model eukaryote Saccharomyces cerevisiae have revealed that homologous recombination (HR) is an important tool for the repair of chromosomes injured by various mutagenic chemicals including alkylating agents and DNA cross-linking agents, and by ionizing radiations that cause DNA double strand breaks. HR also participates in the repair of stalled replication forks and incomplete telomeres. Proteins encoded by evolutionarily conserved genes of the RAD52 epistasis group catalyze the HR reaction. The goal of this project is to elucidate the functional role of the Shu1-Shu2-Csm2-Psy3 (Shu) complex of S. cerevisiae. Several genetic investigations of the Shu complex have revealed that it is an integral component of the RAD52 group, but to date, no mechanistic information is available on the Shu complex. In light of this knowledge gap, we have purified the Shu complex and found that it interacts physically with key components of the HR pathway. Building off of our preliminary findings, the specific aims of this proposal are to: 1) define the biochemical properties of the Shu complex and determine their functional relevance in vivo, and 2) delineate how the Shu complex functions in HR by examining its effects upon the well- understood activities of its interaction partners. These studies seek to shed light on the evolutionarily conserved mechanisms by which the HR pathway maintains genomic integrity. Defects in HR leads to diseases predisposing to cancer in humans, including familial breast and ovarian cancers, Fanconi anemia, Werner's syndrome, and Bloom's syndrome. As such, the results of this work will contribute to a broader understanding of cancer biology.

描述（由申请人提供）：酿酒酵母的模型真核生糖酵母中的研究表明，同源重组（HR）是修复由各种诱变化学物质受伤的染色体的重要工具，包括烷基化剂和包括DNA交叉链接剂，以及导致DNA双重链球的离子化辐射剂。人力资源还参加了停滞的复制叉和不完整的端粒的修复。由RAD52上毒组的进化保守基因编码的蛋白质催化HR反应。该项目的目的是阐明S. cerevisiae的Shu1-Shu2-CSM2-PSY3（SHU）复合物的功能作用。 SHU络合物的一些遗传研究表明，它是RAD52组的整体组成部分，但迄今为止，SHU复合物上尚无机械信息。鉴于这种知识差距，我们已经纯化了SHU复合物，并发现它与HR途径的关键组成部分进行了物理相互作用。在我们的初步发现的基础上，该提案的具体目的是：1）定义SHU综合体的生化特性，并确定其在体内的功能相关性，以及2）描述SHU复合物如何通过检查其对其相互作用伙伴的良好理解活动的效果来在HR中发挥作用。这些研究试图阐明HR途径保持基因组完整性的进化保守机制。人力资源缺陷导致疾病易于人类的癌症，包括家族性乳腺癌和卵巢癌，Fanconi贫血，Werner's综合征和Bloom综合征。因此，这项工作的结果将有助于更广泛地了解癌症生物学。