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.

项目概述：错配修复系统是一个主要的DNA修复系统， 细菌对人类它通过消除DNA复制错误来维持基因组的稳定性， 重组，并参与对不可修复的DNA损伤的细胞毒性反应。基因组稳定性 由错配修复系统提供的基因保护人类免受散发性和遗传性癌症的侵害。虽然 错配修复在大多数基因组位点中是无错误的，但在某些基因组位点中是易错的。突变 由易错配修复形成的缺陷对人类健康既有利又有害。 错配修复系统的所有功能都依赖于其处理DNA错配的能力。中的初始步骤 真核细胞错配修复系统对含有错配的DNA的加工是识别错配的DNA。 MutSα或MutSβ的错配。在不匹配识别步骤的下游发生的步骤不 很好理解。该领域的最新进展揭示了真核生物的错配修复机制， 对Exo 1的5′→3′核酸外切酶活性的影响。然而，重要的遗传学、流行病学和生物化学， 有证据表明，依赖于Exo1的机制不是真核生物中唯一的机制。 错配修复在我们的初步研究中，我们发现了一些新的机制， 真核错配修复本项目的目标是在酵母S. 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长， 修复领域，并将利用各种各样的遗传和生化方法，荧光显微镜， 活细胞和下一代测序这一结果将为深入了解 错配修复，并将有助于开发创新的方法，以预防和治疗人类疾病引起的 由失配修复中的缺陷引起的。