Mechanisms of DNA helicases and nucleases in genome maintenance

DNA 解旋酶和核酸酶在基因组维护中的机制

• 批准号: 9753755
• 负责人: HENGYAO NIU
• 金额: $ 38.72万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753755
• 关键词: Award; Biochemical; Biological Models; Cell Cycle; Cells; DNA; DNA Repair; DNA biosynthesis; DNA lesion; DNA-Directed DNA Polymerase; Deoxyribonucleases; Disease; Excision; Excision Repair; Gene Mutation; Genetic; Genome; Genomic Instability; Genomics; Goals; Health; Knowledge; Lesion; Maintenance; Metabolism; Play; Research; Ribonucleotides; Risk; Role; Saccharomycetales; Structure; Syndrome; Yeasts; cancer risk; genome integrity; helicase; nuclease; repaired

Project Summary Helicases and nucleases play important roles in maintaining genome integrity by resolving intermediates produced during DNA metabolic processes, such as DNA replication and repair. Recent studies suggest that genomic ribonucleotide represents one of the most abundant DNA lesions in cells. In addition to the ribonucleotides that prime DNA replication, significant amount of ribonucleotides are mis-incorporated into the genome per cell cycle by replicating DNA polymerases. In this proposal, using budding yeast as a model system, we outlined research to define the roles of Srs2 helicase and its related nucleases in the error-free removal of both priming and mis-incorporated genomic ribonucleotides. Specifically, we will combine genetic, biochemical, and structural approaches to define the mechanisms of Top1-catalyzed genomic ribonucloetide excision repair with a focus on the Srs2-initiated error-free branch. In addition, the potential role of Srs2 in lagging strand maturation will also be delineated. Knowing that mutation of genes involved in ribonucloetide excision repair is associated with Aicardi-Goutleres Syndrome and genome instability caused by genomic ribonucloetide incorporation may increase the risk of cancer, our research has direct disease relevance. In compliance with goal of MIRA award, we will continue to tackle other key questions related to genome maintenance as we have done in the past.

项目摘要 解旋酶和核酸酶在维持基因组完整性方面起着重要作用 解决在DNA代谢过程中产生的中间体，例如DNA 复制和维修。最近的研究表明基因组核糖核苷酸 代表细胞中最丰富的DNA病变之一。除了 核糖核苷酸素的核糖核苷酸，大量的核糖核苷酸 通过复制DNA，将每个细胞周期中的基因组纳入基因组 聚合酶。在此提案中，使用芽酵母作为模型系统，我们 概述了确定SRS2解旋酶及其相关核酸酶的作用的研究 启动和分配错误的基因组无错误的去除 核糖核苷酸。具体而言，我们将结合遗传，生化和结构 定义top1催化基因组核糖酸酯的机制的方法 切除修复，重点关注SRS2引发的无错误分支。此外， SRS2在滞后链成熟中的潜在作用也将被描述。 知道参与核糖核酯切除修复的基因突变是 与AICARDI-Goutleres综合征和基因组不稳定性相关 基因组核糖核掺杂可能会增加癌症的风险 研究具有直接的疾病相关性。根据MIRA奖的目标，我们 我们将继续解决与基因组维持有关的其他关键问题 过去完成。