乙肝病毒抑制同源重组修复的分子机制

原发性肝癌是最常见的恶性肿瘤之一，严重威胁人类健康。在我国，乙肝病毒（HBV）的慢性感染是原发性肝癌发生的重要因素，但其发病机制尚不清楚。申请人最近的研究表明，HBV编码的X蛋白阻断CRL4-WDR70泛素酶的组装，干扰RAP80的去泛素化并抑制BRCA1的功能，造成同源重组修复关键步骤DNA末端回切的缺陷，最终推动肝癌的发生。因此, HBV相关肝癌是一种新型同源重组缺陷型肿瘤，并提出利用现有的同源重组缺陷型肿瘤靶向药物（PARP抑制剂）治疗此类肿瘤。以此为基础，本项目以阐明新的RAP80泛素化修饰调控BRCA1活性的分子机制为核心，深入研究HBV干扰DNA末端回切的信号网络，并利用DSB-Capture技术解析HBV抗回切活性所导致的肿瘤基因组突变特征，为肝癌的靶向治疗提供理论依据。

Hepatocellular Carcinoma (HCC) is one of the most common malignant tumors, which pose serious threat to human health. In China, chronic infection of hepatitis B virus (HBV) is a high-risk factor for HCC, but its pathogenesis is not clear. Our recent work showed that HBx disrupts complex assembly of CRL4-WDR70 ubiquitin ligase, thus interferes the function of BRCA1, causing deficiencies of DNA end resection and homologous recombination(HR). We conclude that HBV related HCC is a novel type of HRD (HR deficient) tumor, and propose a new therapeutic strategy for HBVHCC by HRD-targeting drug (PARP inhibitor). On this basis, we will investigate the interference of DNA end resection by HBV, focusing on the RAP80-regulated BRCA1, and analyze the genomic characteristics of anti-resection of HBV by DSB-Capture technology. Our study will provide theoretical basis for targeted treatment of liver cancer.