Regulation of SPRTN protease and SPRTN-mediated DNA-Protein Crosslink Repair

SPRTN 蛋白酶的调节和 SPRTN 介导的 DNA-蛋白质交联修复

• 批准号: 10641893
• 负责人: GARGI GHOSAL
• 金额: $ 31.47万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641893
• 关键词: Alleles; Attenuated; BRCA1 gene; Bypass; CHEK1 gene; Cell Aging; Cell Death; Cell physiology; Cells; Chromatin; Coupled; Cytoplasm; DNA; DNA Damage; DNA Repair Gene; DNA biosynthesis; DNA replication fork; DNA-Binding Proteins; DNA-protein crosslink; Data; Defect; Deubiquitination; Genetic Epistasis; Genome; Genomic Instability; Histones; IRS4 gene; Lead; Lesion; Maintenance; Mediating; Metabolic; Metabolism; Metalloproteases; Molecular; Monoubiquitination; Mutation; Pathway interactions; Patients; Peptide Hydrolases; Peptides; Play; Polymerase; Primary carcinoma of the liver cells; Process; Progeria; Protease Domain; Proteolysis; Publishing; Regulation; Role; S phase; Signal Transduction; Site; Sumoylation Pathway; Syndrome; TOP1 gene; TOP2A gene; Testing; Ubiquitination; cancer cell; chemotherapy; crosslink; design; early onset; enzyme pathway; gain of function; knock-down; mutant; novel; novel strategies; overexpression; premature; prevent; protein crosslink; recruit; repair enzyme; repaired; targeted treatment; ubiquitin isopeptidase; ubiquitin-protein ligase

PROJECT SUMMARY DNA-Protein crosslinks (DPCs) are irreversible covalent crosslinks of proteins to DNA that stall replication forks during DNA replication. Unrepaired stalled forks lead to DNA breaks and fork collapse, leading to genome instability, cell death or senescence. SPRTN is a DNA-dependent replication-coupled metalloprotease that catalyzes proteolysis of DPCs during DPC repair. SPRTN also regulates replication fork progression and translesion DNA synthesis. Ruijs-Aalfs (RJALS) syndrome patients with bi-allelic mutations in SPRTN protease domain are prone to genome instability, segmental progeria and early-onset hepatocellular carcinoma. Regulation of SPRTN protease function is critical for accurate DNA replication fork progression and DPC repair. This proposed study is designed to characterize novel regulators of SPRTN and investigate the molecular mechanism underlying SPRTN-mediated replication-coupled DPC repair. Investigating the regulation of SPRTN and SPRTN-mediated DPC repair pathway will further our understanding of the DPC repair pathway, delineate the mechanism of RJALS syndrome, and help develop novel strategies for sensitizing cancer cells to chemotherapy by targeting SPRTN-mediated DPC repair pathway.

项目总结