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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：Spartan蛋白酶修复DNA-蛋白质交联（DPC）并防止 DPC诱导的肿瘤发生 Spartan基因双等位基因突变的患者称为Ruijs-Aalfs（RJALS）综合征，肝细胞癌（HCC）和节段性早老症。斯巴达最初的特点是它的作用，促进紫外线损伤后的细胞存活。最近，Spartan的SprT结构域的金属蛋白酶活性，已显示切割DNA-蛋白质交联（DPC）。DPC是一种毒性损伤，在DNA复制过程中。未修复的分叉导致DNA断裂和分叉崩溃，导致基因组不稳定，细胞死亡或衰老。DPC修复已被证明是由特定的酶介导的，如酪氨酰- DNA磷酸二酯酶、核酸酶和/或核苷酸切除修复的协调作用，在某些情况下，同源重组DNA修复途径。然而，背后的确切机制 DPC修复在很大程度上尚不清楚。这项拟议的研究旨在评估分子机制， Spartan在停止的复制分叉处协调DPC的删除。我们将研究RJALS的效果患者突变对Spartan在肝细胞癌中的肿瘤抑制功能的体外和体内研究并靶向Spartan和Spartan介导的DPC修复作为癌症治疗剂。调查的职能 Spartan在DPC修复中的作用不仅将促进我们对RJALF综合征机制的理解，还有助于评估通过靶向斯巴达蛋白酶使癌细胞对化疗敏感的潜力， Spartan介导的DPC修复途径。