Many cancers harbor homologous recombination defects (HRDs). A HRD is a therapeutic target that is being successfully utilized in treatment of breast/ovarian cancer via synthetic lethality. However, canonical HRD caused by BRCAness mutations do not prevail in liver cancer. Here we report a subtype of HRD caused by the perturbation of a proteasome variant (CDW19S) in hepatitis B virus–bearing (HBV-bearing) cells. This amalgamate protein complex contained the 19S proteasome decorated with CRL4^WDR70 ubiquitin ligase, and assembled at broken chromatin in a PSMD4^Rpn10- and ATM-MDC1-RNF8–dependent manner. CDW19S promoted DNA end processing via segregated modules that promote nuclease activities of MRE11 and EXO1. Contrarily, a proteasomal component, ADRM1^Rpn13, inhibited resection and was removed by CRL4^WDR70-catalyzed ubiquitination upon commitment of extensive resection. HBx interfered with ADRM1^Rpn13 degradation, leading to the imposition of ADRM1^Rpn13-dependent resection barrier and consequent viral HRD subtype distinguishable from that caused by BRCA1 defect. Finally, we demonstrated that viral HRD in HBV-associated hepatocellular carcinoma can be exploited to restrict tumor progression. Our work clarifies the underlying mechanism of a virus-induced HRD subtype.

中文翻译：

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乙型肝炎病毒感染通过稳定切除抑制剂 ADRM1 破坏肝细胞癌的同源重组

许多癌症都存在同源重组缺陷（HRD）。HRD 是一种治疗靶点，已成功用于通过合成致死治疗乳腺癌/卵巢癌。然而，由 BRCAness 突变引起的典型 HRD 在肝癌中并不普遍。在这里，我们报告了一种 HRD 亚型，是由携带乙型肝炎病毒 (HBV-bearing) 的细胞中蛋白酶体变体 (CDW19S) 的扰动引起的。^{这种混合蛋白复合物含有用 CRL4 WDR70}泛素连接酶修饰的 19S 蛋白酶体，并以 PSMD4 ^Rpn10和 ATM-MDC1-RNF8 依赖性方式在断裂的染色质处组装。CDW19S 通过促进 MRE11 和 EXO1 核酸酶活性的分离模块促进 DNA 末端加工。相反，蛋白酶体成分 ADRM1 ^Rpn13抑制切除，并在进行广泛切除后被CRL4 ^WDR70催化的泛素化去除。HBx 干扰 ADRM1 ^Rpn13降解，导致 ADRM1 ^Rpn13依赖性切除屏障的施加，以及随后与BRCA1缺陷引起的病毒 HRD 亚型区分开来。最后，我们证明了 HBV 相关肝细胞癌中的病毒 HRD 可用于限制肿瘤进展。我们的工作阐明了病毒诱导的 HRD 亚型的潜在机制。