去泛素酶USP19调控DNA损伤应答及卵巢癌耐药性分子机制研究

BRCA1 is an important tumor suppressor, and play an important role in homologous recombination (HR) repair. The mutations of BRCA1 would result in defect in DNA repair, which would lead to genomic instability and tumor. On the other hand, the chemotherapy drug, PARP inhibitor kill the cancer cells through induction of DNA damage. The cancers with mutations in BRCA1 are more sensitive to PARP inhibitors because of the defect in DNA repair. However, the deubiquitination of BRCA1 remains unclear. Our preliminary data indicated that USP19 could bind to and deubiquitinate BRCA1. We will study the mechanism that how USP19 regulates HR repair through BRCA1. On the other hand, we will confirm the phosphorylation on USP19 by ATM and investigate the role of the ATM-USP19-BRCA1 signaling pathway in HR repair. Our preliminary data showed that USP19 is up regulated in ovarian cancer while knockdown of USP19 in ovarian cancer cells would sensitize the cells to chemotherapy drugs. We will further study if USP19 regulates the initiation and development of ovarian cancer with cells and PDS mice model. Furthermore, we will screen the drug candidates to find specific inhibitors of USP19 and design the mimic peptides according to the binding region between USp19 and BRCA1.Then we will test if the combination of PARP inhibitor with USP19 specific inhibitor or mimic peptide will improve the killing effect on ovarian cancer. The study will shed lights on the solution to drug tolerance in ovarian cancer therapy.

BRCA1是重要抑癌因子，调控DNA同源重组修复是其主要功能。BRCA1突变导致DNA修复异常，引起基因组不稳定，诱发肿瘤；另一方面，肿瘤药物PARP抑制剂通过诱导DNA损伤杀伤肿瘤，BRCA1突变肿瘤因其DNA修复缺陷，对PARP抑制剂异常敏感。由此可见其在肿瘤发生及干预中的重要性。目前BRCA1去泛素化修饰尚无报导。本项目前期发现USP19去泛素化BRCA1。拟进一步阐明USP19通过BRCA1调控同源重组修复分子机制，并揭示DNA损伤通过ATM激活USP19分子机制，最终阐明ATM-USP19-BRCA1信号轴在同源重组修复中作用机理。前期发现USP19在卵巢癌中高表达，下调USP19提高卵巢癌细胞对化疗药物敏感性。拟通过细胞及PDX小鼠模型研究USP19是否调控卵巢癌发生发展；筛选USP19特异抑制剂，将其与PARP抑制剂联用，测试卵巢癌杀伤效果，为克服卵巢癌耐药提供可能的策略。

卵巢癌的耐药性是卵巢癌治疗面临的重要问题。在初始治疗中，铂类药物对大约80%的病人具有良好的疗效，但随后会出现严重的耐药性。经研究发现，耐药性产生的重要原因之一是部分肿瘤经药物治疗后，通过压力筛选进化，提高了自身DNA修复的效率，从而修复肿瘤药物诱导的DNA损伤，抵抗凋亡，产生耐药。因此，靶向抑制DNA修复通路与化疗药物结合可能成为解决卵巢癌耐药的重要策略。本研究阐明去泛素化酶USP19通过去泛素化BRCA1调控同源重组修复并介导卵巢癌耐药。并进一步提示USP19作为卵巢癌治疗的潜在靶标，提出通过抑制USP19联合化疗药物治疗解决卵巢癌的耐药性的新策略。