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

Spartan 蛋白酶修复 DNA-蛋白质交联 (DPC) 并防止 DPC 诱导的肿瘤发生

基本信息

批准号：
10117100
负责人：
GARGI GHOSAL
金额：
$ 33.35万
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：
2018
资助国家：
美国
起止时间：
2018-03-16 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10117100
关键词：
Adult Alleles C-terminal Cancer cell line Cell Aging Cell Death Cell Proliferation Cell Survival Cells Chemotherapy and/or radiation Cleaved cell DNA DNA Damage DNA Repair Gene DNA Repair Pathway DNA biosynthesis DNA lesion DNA replication fork DNA-protein crosslink Development Embryo Enzymes Epithelial Etoposide Excision Exposure to Formaldehyde Genomic Instability In Vitro Knockout Mice Lead Lesion Liver LoxP-flanked allele Malignant Neoplasms Malignant neoplasm of liver Mediating Metalloproteases Molecular Molecular Target Monoubiquitination Mosaicism Mus Mutation N-terminal Nebraska Nucleotide Excision Repair Pathway interactions Patients Peptide Hydrolases Pharmaceutical Preparations Phenotype Physiological Post-Translational Protein Processing Primary carcinoma of the liver cells Progeria Proteins Proteolysis Radiation therapy Regulation Role Site Sumoylation Pathway Susceptibility Gene Syndrome Therapeutic Topoisomerase Topoisomerase Inhibitors Tumor Suppressor Proteins UV induced DNA damage Ubiquitination Ultraviolet Rays Xenograft procedure cancer cell cancer therapy chemotherapy combinatorial crosslink design early onset high throughput screening homologous recombination in vivo migration mouse model mutant nuclease prevent protein function repaired response small molecule inhibitor tumor growth tumorigenesis tyrosyl-DNA phosphodiesterase ubiquitin-protein ligase ultraviolet damage virtual

项目摘要

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.

项目摘要/摘要：斯巴达蛋白酶维修DNA-蛋白交联（DPC），并防止 DPC诱导的Oncogensis 斯巴达坦中双性突变的患者称为Ruijs-AALFS（RJALS）综合征，容易出现早发作肝细胞癌（HCC）和节段后期。斯巴达最初因其在在紫外线破坏时促进细胞存活。最近，斯巴达人的SPRT域的金属蛋白酶活性已显示出裂解DNA-蛋白交联（DPC）。 DPC是停滞叉子的有毒病变在DNA复制过程中。未修复的叉会导致DNA断裂和叉子崩溃，导致基因组不稳定性，细胞死亡或衰老。 DPC修复已被证明是由特定酶（例如酪酶）介导的 DNA磷酸二酯酶，核酸酶和/或核苷酸切除修复的协调作用和/或在某些情况下，同源重组DNA修复途径。但是，基础的确切机制 DPC维修在很大程度上不清楚。这项拟议的研究旨在评估分子机制斯巴达人介导了在停滞的复制叉处的去除DPC。我们将研究RJALS的效果斯巴达坦在体外和体内的肝细胞癌中肿瘤抑制功能的患者突变靶标斯巴达人和斯巴达介导的DPC修复为癌症治疗剂。调查功能 DPC维修中的斯巴达人不仅会提高我们对RJALF综合征机制的理解，而且还将还有助于评估通过靶向斯巴达蛋白酶和斯巴达人介导的DPC修复途径。