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.

项目概要 DNA-蛋白质交联 (DPC) 是蛋白质与 DNA 之间不可逆的共价交联，可阻止复制 DNA复制过程中出现分叉。未修复的停滞叉会导致 DNA 断裂和叉崩溃，从而导致基因组不稳定、细胞死亡或衰老。 SPRTN 是一种 DNA 依赖性复制偶联金属蛋白酶，在 DPC 修复过程中催化 DPC 的蛋白水解。 SPRTN 还调节复制叉的进展和跨损伤DNA合成。具有 SPRTN 蛋白酶双等位基因突变的 Ruijs-Aalfs (RJALS) 综合征患者域容易出现基因组不稳定、节段性早衰和早发性肝细胞癌。 SPRTN 蛋白酶功能的调节对于准确的 DNA 复制叉进展和 DPC 修复至关重要。本研究旨在表征 SPRTN 的新型调节剂并研究其分子机制 SPRTN 介导的复制耦合 DPC 修复的潜在机制。研究 SPRTN 的调节和 SPRTN 介导的 DPC 修复途径将进一步促进我们的研究了解 DPC 修复途径，描绘 RJALS 综合征的机制，并帮助开发新的通过靶向 SPRTN 介导的 DPC 修复途径使癌细胞对化疗敏感的策略。