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（由适用提供）：基因组稳定性的维持对于生物体的福祉至关重要。细胞的基因组受到外源和内源性DNA损伤因子的持续攻击，例如辐射，致癌物和反应性自由基。为了维持基因组稳定性，细胞已经开发出一种精细的DNA损伤响应（DDR）系统，该系统负责感测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性，这是肿瘤发生的驱动力之一。许多人遗传癌易感综合征与DDR有缺陷有关。例如，在大约50％的家庭乳腺癌病例中发现了BRCA1基因中的突变。由于单个肿瘤在DDR途径中通常具有独特的缺陷，因此洞悉细胞修复不同DNA病变的基本机制也可以指导个性化的治疗。一个承诺的例子是在患有BRCA1和BRCA2突变的癌症中使用PARP抑制剂。另一方面，许多研究表明，DNA修复因子的过表达有助于对化学疗法的抗性。因此，研究该途径对癌症的发病机理和癌症治疗具有重要意义。该提案中的初步数据首次表明去泛素酶USP13调节同源重组介导的DNA修复。从机械上讲，USP13与Rap80相互作用并去泛素化RAP80，这反过来促进了Rap80-BRCA1复合物的募集，以双层断裂并促进同源重组。耗尽或抑制USP13会感受到卵巢癌细胞，而不是正常的卵巢上皮细胞对顺铂和PARP抑制剂。该提案的中心假设是USP13是DNA修复的新因素。 USP13通过去泛素化RAP80来调节DNA损伤响应和HR修复。 USP13的过表达通过增强DNA修复有助于化学疗法。这些实验将揭示USP13在DNA修复中的新功能和对化学疗法的反应。此外，它将通过靶向USP13-RAP80-BRCA1途径来揭示一个新的治疗靶标，尤其是那些过表达USP13的卵巢癌细胞，尤其是那些过表达USP13的靶标。具体目的是：1。研究USP13对RAP80的调节。 2。通过DDR信号来研究USP13的调节。 3。研究USP13在化学上的作用。

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