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

项目总结 DNA-蛋白质交联物(DPC)是蛋白质与DNA的不可逆共价交联物，可阻止复制 DNA复制过程中的分叉。未经修复的叉子会导致DNA断裂和叉子坍塌，从而导致基因组 不稳定，细胞死亡或衰老。SPRTN是一种依赖DNA的复制偶联金属蛋白酶 在DPC修复过程中催化DPC的蛋白质分解。SPRTN还调节复制分叉进程和 跨损伤的DNA合成。伴有SPRTN蛋白水解酶双等位基因突变的RJALS综合征患者 属性域容易发生基因组不稳定、节段性早衰和早发性肝细胞癌。 SPRTN蛋白水解酶功能的调节对于准确的DNA复制、分叉进展和DPC修复至关重要。 这项拟议的研究旨在表征SPRTN的新调节子并研究其分子 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修复途径的调控将进一步促进我们的 了解DPC修复途径，阐明RJALS综合征的发病机制，有助于开发新的 通过靶向SPRTN介导的DPC修复途径使癌细胞对化疗增敏的策略。

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.