Regulation and Localization of Mismatch Repair Proteins

错配修复蛋白的调控和定位

• 批准号: 10671757
• 负责人: Joanna E Haye
• 金额: $ 18.75万
• 依托单位: XAVIER UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10671757
• 关键词: Acetylation; Affect; Binding; Biological Assay; Chromatin; Colon; Complex; DNA; DNA biosynthesis; DNA-Directed DNA Polymerase; Defect; Dependence; Dimerization; Endometrial Carcinoma; Eukaryota; Frequencies; Genetic Transcription; Genomic Instability; Hepatobiliary; Hereditary Neoplastic Syndromes; Hereditary Nonpolyposis Colorectal Neoplasms; Histones; Human; Immunoblot Analysis; Investigation; Lysine; Maintenance; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Methylation; Methyltransferase; Microsatellite Instability; Mismatch Repair; Mismatch Repair Deficiency; Modeling; Modification; Mutagenesis; Mutagens; Mutation; Pathway interactions; Polymerase Chain Reaction; Post-Translational Protein Processing; Principal Investigator; Process; Prokaryotic Cells; Proteins; Proteomics; Publications; Publishing; Regulation; Repair Complex; Research; Role; Saccharomyces cerevisiae; Site; Small Intestines; Syndrome; Testing; Tissues; Two-Hybrid System Techniques; Urinary tract; Work; Yeasts; cancer type; chromatin immunoprecipitation; demethylation; early onset colon cancer; experimental study; gene repair; genetic manipulation; genetic predictors; genome integrity; histone methylation; histone modification; mutant; overexpression; programs; recruit; repair function

Principal Investigator/Program Director (Last, first, middle): Haye, Joanna, Elizabeth Abstract: DNA mismatch repair (MMR) is a highly conserved process. A functional MMR pathway is essential for maintaining genome integrity; loss of MMR results in genome instability and cancer in higher eukaryotes. For example, defects in MMR genes result in Lynch Syndrome, a common hereditary cancer syndrome resulting in early onset cancers of the colon, endometrium, ovaries, small intestine, hepatobiliary tract, upper urinary tract as well as other tissues. In our most recent publication, we showed that in yeast, deletion of Modulator of Transcription (also known as Not4) or General Control Nonderepressible 5 (Gcn5) modulate the levels of Msh2, a major MMR component. Loss of Gcn5 significantly decreases Msh2, whereas deleting Not4 stabilizes functional Msh2. Not4 and Gcn5 are proteins that ubiquitylate and acetylate various proteins respectively. We hypothesize that Not4 and Gcn5 modify yeast MutSα (comprised of Ms2 and Msh6) and that the modifications affect the stability of the complex. Using the yeast Saccharomyces cerevisiae (S. cerevisiae), the first aim of the proposed research is to establish the role of Gcn5 and Not4 in the regulation of the major mismatch recognition complex MutSα. Our previous experiments have also shown that yeast MutS tracks with the replication machinery during DNA replication. Human MutSα is recruited to chromatin through specific histone modifications and interacts with the replication machinery by binding PCNA, the DNA polymerase processivity factor. However, the modifications that recruit human MutSα are not utilized in yeast. How yeast MutSα is recruited to chromatin remains elusive. The second aim of this research is to determine the role of post- translational modifications in MutSα recruitment to chromatin. PHS398 (Rev. 5/01) Page Continuation Format Page

首席研究员/项目主管（倒数第一中）：海耶、乔安娜、伊丽莎白