Deubiquitinases in regulation of BRCA1 pathway

去泛素酶对 BRCA1 通路的调节

• 批准号: 10006119
• 负责人: SCOTT H KAUFMANN
• 金额: $ 36.37万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10006119
• 关键词: Affect; BRCA1 Mutation; BRCA1 gene; BRCA2 Mutation; Biochemical; Cancer Etiology; Cancer Patient; Cell Cycle; Cell physiology; Cells; Cessation of life; Cisplatin; Clinical Trials; Combined Modality Therapy; Complex; DNA Damage; DNA Repair; DNA lesion; Data; Defect; Enzymes; Epithelial Cells; Failure; Female Genital Neoplasms; Genes; Genome; Genome Stability; Genomic Instability; Hereditary Breast Carcinoma; Human Genetics; Individual; Link; Maintenance; Malignant Neoplasms; Malignant neoplasm of ovary; Mechanics; Mediating; Modeling; Mutation; Organism; Ovarian; Pathogenesis; Pathway interactions; Patients; Personal Satisfaction; Platinum; Post-Translational Protein Processing; Predisposition; Proteins; Regulation; Resistance; Role; Signal Transduction; Syndrome; System; Testing; Time; United States; base; cancer cell; cancer genetics; cancer therapy; chemotherapy; clinical phenotype; clinically relevant; driving force; experimental study; homologous recombination; individualized medicine; inhibitor/antagonist; insight; knock-down; new therapeutic target; novel; overexpression; public health relevance; radiation carcinogen; recruit; repaired; response; therapeutic target; treatment strategy; tumor; tumorigenesis

 DESCRIPTION (provided by applicant): Maintenance of genomic stability is critical for the well-being of organisms. The genome of a cell is under constant attack from exogenous and endogenous DNA damaging factors such as radiation, carcinogens and reactive radicals. To maintain genomic stability, cells have developed an elaborate DNA damage response (DDR) system, which is responsible for sensing DNA damage, halting the ongoing cell cycle, and repairing the damaged DNA. Failure in the DDR pathway leads to genomic instability, which is one of the driving forces of tumorigenesis. Many human genetic cancer predisposition syndromes are linked to defective DDR. For example, mutations in the BRCA1 gene are found in about 50% of familial breast cancer cases. Since individual tumors often have unique defects in the DDR pathway, insight into the basic mechanisms by which cells repair different DNA lesions can also guide individualized therapy. A promising example is the use of PARP inhibitors in cancers with BRCA1 and BRCA2 mutations. On the other hand, many studies suggest that overexpression of DNA repair factors contributes to resistance to chemotherapy. Therefore, studying this pathway has important implications in cancer pathogenesis and cancer therapy. Preliminary data within this proposal showed for the first time that the deubiquitinase, USP13, regulates homologous recombination mediated DNA repair. Mechanically, USP13 interacts with RAP80 and deubiquitinates RAP80, which in turn facilitates the recruitment of RAP80-BRCA1 complex to double strand breaks and promotes homologous recombination. Depleting or inhibiting USP13 sensitizes ovarian cancer cells but not the normal ovarian epithelial cells to cisplatin and PARP inhibitor. The central hypothesis of the proposal is that USP13 is a new factor in DNA repair. USP13 regulates DNA damage response and HR repair by deubiquitinating RAP80. Overexpression of USP13 contributes to chemotherapeutic resistance by enhancing DNA repair. These experiments will reveal a novel function of USP13 in DNA repair and response to chemotherapy. In addition, it will reveal a new therapeutic target in sensitizing ovarian cancer cells, especially those overexpressing USP13, by targeting the USP13-RAP80-BRCA1 pathway. The Specific Aims are the following: 1. Investigate the regulation of RAP80 by USP13. 2. Study the regulation of USP13 by DDR signaling. 3. Investigate the role of USP13 in chemoresistance.

 描述（由申请方提供）：基因组稳定性的维持对于生物体的健康至关重要。细胞的基因组不断受到外源性和内源性DNA损伤因素的攻击，如辐射，致癌物质和活性自由基。为了维持基因组的稳定性，细胞已经开发出一种复杂的DNA损伤反应（DDR）系统，负责感知DNA损伤，停止正在进行的细胞周期，并修复受损的DNA。DDR途径的失败导致基因组不稳定，这是肿瘤发生的驱动力之一。许多人类遗传性癌症易感综合征与DDR缺陷有关。例如，BRCA 1基因的突变在大约50%的家族性乳腺癌病例中发现。由于个体肿瘤通常在DDR途径中具有独特的缺陷，因此了解细胞修复不同DNA损伤的基本机制也可以指导个体化治疗。一个有希望的例子是PARP抑制剂在BRCA 1和BRCA 2突变的癌症中的应用。另一方面，许多研究表明，DNA修复因子的过度表达有助于对化疗的抵抗。因此，研究该通路对肿瘤的发病机制和治疗具有重要意义。该提案中的初步数据首次表明，去遍在蛋白酶USP 13调节同源重组介导的DNA修复。在机械上，USP 13与RAP 80相互作用并使RAP 80去泛素化，这反过来又促进RAP 80-BRCA 1复合物募集到双链断裂并促进同源重组。消耗或抑制USP 13可使卵巢癌细胞而非正常卵巢上皮细胞对顺铂和PARP抑制剂敏感。该提案的核心假设是USP 13是DNA修复中的一个新因子。USP 13通过去泛素化RAP 80调节DNA损伤反应和HR修复。USP 13的过表达通过增强DNA修复而有助于化疗抗性。这些实验将揭示USP 13在DNA修复和对化疗反应中的新功能。此外，它还将揭示一种新的治疗靶点，通过靶向USP 13-RAP 80-BRCA 1通路，使卵巢癌细胞，特别是过表达USP 13的卵巢癌细胞敏感。 具体目标如下：1.研究USP 13对RAP 80的规定。2.研究DDR信号对USP 13的调控。3.研究USP 13在化疗耐药性中的作用。

项目成果

Kinetics model of DNA double-strand break repair in eukaryotes.

真核生物 DNA 双链断裂修复的动力学模型。

• DOI: 10.1016/j.dnarep.2020.103035
• 发表时间: 2021
• 期刊: DNA repair
• 影响因子: 3.8
• 作者: Shen,Wangtao;Ma,Yun;Qi,Huizhou;Wang,Wuzhou;He,Junyan;Xiao,Fangzhu;Zhu,Hui;He,Shuya
• 通讯作者: He,Shuya