Novel mechanisms in DNA mismatch repair

DNA错配修复的新机制

• 批准号: 10474605
• 负责人: Farid Kadyrov
• 金额: $ 29.5万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY CARBONDALE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10474605
• 关键词: Apoptosis; Bacteria; Biochemical; Cells; Closure by clamp; DNA; DNA Damage; DNA Repair; DNA biosynthesis; DNA metabolism; DNA-Directed DNA Polymerase; Data; Defect; Development; Epidemiology; Eukaryota; Fluorescence Microscopy; Genetic; Genetic Recombination; Genome Stability; Genomics; Goals; Health; Human; Immune response; Inherited; Malignant Neoplasms; Mismatch Repair; Molecular; Mutation; Neurodegenerative Disorders; Organ; Play; Process; Proteins; Regulation; Replication Error; Research; Role; Saccharomyces cerevisiae; Site; Syndrome; System; Yeasts; cancer cell; cancer predisposition; cancer therapy; cell injury; cytotoxic; endonuclease; genomic locus; helicase; human disease; innovation; insight; live cell microscopy; next generation sequencing; novel; novel strategies; nuclease; prevent; response; spleen exonuclease

Project summary: The mismatch repair system is a major DNA repair system that has been conserved from bacteria to humans. It maintains genome stability by removing DNA replication errors, preventing homeologous recombination, and participating in the cytotoxic response to irreparable DNA damage. Genome stability provided by the mismatch repair system protects humans from both sporadic and inherited cancers. Although mismatch repair is error-free in the majority of genomic sites, it is error-prone at certain genomic loci. Mutations formed by error-prone mismatch repair have both beneficial and detrimental consequences for human health. All functions of the mismatch repair system depend on its ability to process DNA mismatches. The initial step in processing of mismatch-containing DNA by the eukaryotic mismatch repair system is recognition of the mismatch by MutSα or MutSβ. The steps that occur downstream from the mismatch recognition step are not well understood. Recent progress in the field has revealed a eukaryotic mismatch repair mechanism that relies on the 5′→3′ exonuclease activity of Exo1. However, significant genetic, epidemiological, and biochemical evidence has suggested that the Exo1-dependent mechanism is not the only mechanism in eukaryotic mismatch repair. During our preliminary studies we have discovered that there are novel mechanisms in eukaryotic mismatch repair. The goal of this project is to define these novel mechanisms in the yeast S. cerevisiae and human cells. The proposed studies will take advantage of our unique expertise in the mismatch repair field and will utilize a diverse array of genetic and biochemical approaches, fluorescence microscopy of live cells, and next generation sequencing. The results will provide novel insights into the mechanisms in mismatch repair and will help to develop innovative approaches to prevent and treat human diseases caused by defects in mismatch repair.

项目摘要：不匹配维修系统是一种主要的DNA维修系统 对人类的细菌。它通过消除DNA复制错误来保持基因组稳定性 重组，并参与对无法弥补的DNA损伤的细胞毒性反应。基因组稳定性 不匹配维修系统提供的人类可保护人类免受零星和遗传性癌症的侵害。虽然 在大多数基因组部位，不匹配修复是无错误的，在某些基因组局部，它容易出错。突变 由容易出错的不匹配修复形成，对人类健康既有益和有害后果。 不匹配修复系统的所有功能都取决于其处理DNA不匹配的能力。第一步 通过真核不匹配修复系统处理不匹配的DNA的处理是认识 mutsα或mutsβ的不匹配。不匹配识别步骤下游发生的步骤不是 理解。该领域的最新进展揭示了一种依赖的真核生物不匹配修复机制 在exo1的5'→3'外切酶活性上。但是，显着的遗传，流行病学和生化 有证据表明，依赖于exo1的机制不是真核的唯一机制 不匹配维修。在我们的初步研究中，我们发现中有新的机制 真核生物不匹配维修。该项目的目的是在酵母中定义这些新机制。 酿酒酵母和人类细胞。拟议的研究将利用我们在不匹配方面的独特专业知识 修复场，将利用遗传和生化方法的潜水员阵列，荧光显微镜 活细胞和下一代测序。结果将提供有关机制的新见解 不匹配维修，将有助于开发创新的方法来预防和治疗引起的人类疾病 由于不匹配维修的缺陷。