Novel mechanisms in DNA mismatch repair

DNA错配修复的新机制

• 批准号: 10244954
• 负责人: Farid Kadyrov
• 金额: $ 29.25万
• 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/10244954
• 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：错配修复系统是一种主要的DNA修复系统