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The anti-resection activity of the X protein encoded by Hepatitis Virus B

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posted on 2023-06-09, 17:27 authored by Laifeng Ren, Ming Zeng, Zizhi Tang, Mingyuan Li, Ziaojun Wang, Yang Xu, Yuding Weng, Xiaobo Wang, Liandi Guo, Bing Zuo, Xin Wang, Si Wang, Jiangyan Lou, Antony CarrAntony Carr, Penny Jeggo, others
Chronic infection of hepatitis virus B (HBV) is associated with an increased incidence of hepatocellular carcinoma (HCC). HBV encodes an oncoprotein (HBx) that is crucial for viral replication and interferes with multiple cellular activities including gene expression, histone modifications and genomic stability. To date, it remains unclear how disruption of these activities contributes to hepatocarcinogenesis. Here, we report that HBV exhibits a novel anti-resection activity by disrupting DNA end resection, thus impairing the initial steps of homologous recombination (HR). This anti-resection activity occurs in primary human hepatocytes (PHHs) undergoing a natural viral infection-replication cycle, as well as in cells with integrated HBV genomes. Among the seven HBV-encoded proteins, we identified HBx as the sole viral factor that inhibits resection. By disrupting an evolutionarily conserved Cullin4A-DDB1-RING type of E3 ligase, CRL4WDR70, via its H-box, we show that HBx inhibits H2B monoubiquitylation at lysine 120 (uH2B) at double strand breaks, thus reducing the efficiency of long-range resection. We further show that directly impairing H2B monoubiquitylation elicited tumorigenesis upon engraftment of deficient cells in athymic mice, confirming that the impairment of CRL4WDR70 function by HBx is sufficient to promote carcinogenesis. Finally, we demonstrated that lack of H2B monoubiquitylation is manifest in human HBV-associated HCC (HBVHCC) when compared with HBV-free HCC, implying corresponding defects of epigenetic regulation and end resection. We conclude that the anti-resection activity of HBx induces an HR defect and genome instability and contributes to tumorigenesis of host hepatocytes.


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  • Sussex Centre for Genome Damage Stability Publications

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  • Genome Damage and Stability Centre Publications

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