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

项目摘要 DNA-蛋白质交联（DPC）是蛋白质与DNA之间不可逆的共价交联，它阻碍了DNA的复制 DNA复制过程中的分叉未修复的停滞分叉导致DNA断裂和分叉崩溃，导致基因组 不稳定、细胞死亡或衰老。SPRTN是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， 跨损伤DNA合成。SPRTN蛋白酶双等位基因突变的Ruijs-Aalfs（RJALS）综合征患者 结构域的基因容易发生基因组不稳定性、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。 这项研究旨在表征SPRTN的新型调节剂，并研究SPRTN的分子机制。 SPRTN介导的复制偶联DPC修复的潜在机制。 研究SPRTN和SPRTN介导的DPC修复途径的调节将进一步我们的研究。 了解DPC修复途径，描述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。

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.