1. Hepatitis B virus infection disrupts homologous recombination in hepatocellular carcinoma by stabilizing resection inhibitor ADRM1
- Author
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Zeng, Ming, Tang, Zizhi, Ren, Laifeng, Wang, Haibin, Wang, Xiaojun, Zhu, Wenyuan, Mao, Xiaobing, Li, Zeyang, Mo, Xianming, Chen, Jun, Han, Junhong, Kong, Daochun, Ji, Jianguo, Carr, Antony M., and Liu, Cong
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R and D Systems -- International economic relations ,Computer software industry -- International economic relations ,Chromatin -- Health aspects -- Genetic aspects ,Biotechnology -- Genetic aspects -- Health aspects ,Ubiquitin -- Genetic aspects -- Health aspects ,Ligases -- Health aspects -- Genetic aspects ,Hepatitis B -- Development and progression -- Genetic aspects ,Hepatitis B virus -- Genetic aspects -- Development and progression ,Hepatoma -- Development and progression -- Genetic aspects ,Surgery -- Health aspects ,Health care industry - Abstract
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.sup.WDR70] ubiquitin ligase, and assembled at broken chromatin in a [PSMD4.sup.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.sup.Rpn13], inhibited resection and was removed by [CRL4WDR.sup.70]-catalyzed ubiquitination upon commitment of extensive resection. HBx interfered with [ADRM1.sup.Rpn13] degradation, leading to the imposition of [ADRM1.sup.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., Introduction Long-term liver infection with hepatitis B virus (HBV) predisposes carriers to hepatocellular carcinoma (1). Therapy for late-stage HBV-associated hepatocellular carcinoma remains a major challenge, with poor therapy responses and [...]
- Published
- 2023
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