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

基本信息

批准号：
10446610
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
项目类别：
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/10446610
关键词：
Address 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 Salvelinus Signal Transduction Site Sumoylation Pathway Syndrome TOP1 gene TOP2A gene Testing Ubiquitination base cancer cell chemotherapy crosslink design early onset gain of function knock-down mutant novel novel strategies overexpression premature prevent protein crosslink recruit repair enzyme repaired ubiquitin-protein ligase

项目摘要

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.

项目摘要 DNA-蛋白交联（DPC）是蛋白质与DNA的不可逆共价交联，该复制 DNA复制过程中的叉子。未修复的停滞叉会导致DNA断裂和叉子崩溃，导致基因组不稳定性，细胞死亡或衰老。 SPRTN是DNA依赖性复制偶联的金属蛋白酶， DPC修复过程中DPC催化蛋白水解。 SPRT还调节复制叉进度和透疗DNA合成。 ruijs-aalfs（RJALS）综合征患有SPRTN蛋白酶双行突变的患者结构域容易发生基因组不稳定性，节段后代和早期发作的肝细胞癌。 SPRTN蛋白酶功能的调节对于准确的DNA复制叉进程和DPC修复至关重要。这项拟议的研究旨在表征SPRTN的新调节剂并研究分子 SPRTN介导的复制耦合DPC修复的机制。调查SPRTN和SPRTN介导的DPC修复途径的调节将进一步了解DPC修复途径，描述RJALS综合征的机制，并帮助发展新颖通过靶向SPRN介导的DPC修复途径来使癌细胞对化疗的策略。