Spartan Protease Repairs DNA-Protein Cross-Links (DPCs) and Prevents DPC-Induced Oncogenesis

项目摘要/摘要：斯巴达蛋白酶修复DNA-蛋白质交联(DPC)并防止 DPC诱导的肿瘤形成 在斯巴达人中有双等位基因突变的患者被称为Ruijs-Aalfs(RJALS)综合征，容易早发 肝细胞癌和节段性早衰。斯巴达最初的特点是在 促进细胞在紫外线损伤下存活。最近，斯巴达的SPRT结构域的金属蛋白酶活性 已被证明可以裂解DNA-蛋白质交联物(DPC)。DPC是阻碍复制分叉的有毒损害 在DNA复制过程中。未经修复的分叉会导致DNA断裂和分叉崩溃，导致基因组不稳定， 细胞死亡或衰老。DPC修复已被证明是由特定的酶介导的，如酪氨酸- DNA磷酸二酯酶、核酸酶和/或核苷酸切除修复和/或 在某些情况下，同源重组DNA修复途径。然而，潜在的确切机制 DPC修复在很大程度上还不清楚。这项拟议的研究旨在评估通过 斯巴达人在停滞不前的复制叉子上调解DPC的移除。我们将调查RJALS的影响 肝细胞癌患者体内和体外斯巴达抑癌基因突变的研究 并将斯巴达和斯巴达介导的DPC修复作为癌症治疗的靶点。调查研究的功能 斯巴达在DPC修复中不仅将促进我们对RJALF综合征机制的理解，而且将 也有助于评估通过靶向斯巴达蛋白水解酶和蛋白水解酶使癌细胞对化疗敏感的可能性 斯巴达介导的DPC修复途径。

Project Summary/Abstract: Spartan Protease Repairs DNA-Protein Cross-Links (DPCs) and Prevents DPC-Induced Oncogensis Patients with bi-allelic mutations in Spartan, termed Ruijs-Aalfs (RJALS) syndrome, are prone to early-onset hepatocellular carcinoma (HCC) and segmental progeria. Spartan was initially characterized for its role in promoting cell survival upon UV-damage. Recently, the metalloprotease activity of the SprT domain of Spartan has been shown to cleave DNA-protein crosslinks (DPCs). DPCs are toxic lesions that stall replication forks during DNA replication. Unrepaired forks lead to DNA breaks and fork collapse, leading to genome instability, cell death or senescence. DPC repair has been shown to be mediated by specific enzymes such as tyrosyl- DNA phosphodiesterase, nucleases and/or the coordinated action of nucleotide excision repair and homologous recombination DNA repair pathways in some cases. However, the precise mechanism underlying DPC repair is largely unclear. This proposed study is designed to evaluate the molecular mechanism by which Spartan mediates the removal of DPCs at stalled replication forks. We will investigate the effect of RJALS patient mutations on the tumor suppressor functions of Spartan in hepatocellular carcinoma in vitro and in vivo and target Spartan and Spartan-mediated DPC repair as cancer therapeutics. Investigating the functions of Spartan in DPC repair will not only advance our understanding of the mechanism of RJALF syndrome, but will also help evaluate the potential of sensitizing cancer cells to chemotherapy by targeting Spartan protease and Spartan mediated DPC repair pathway.