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The Antiresection Activity of the X Protein Encoded by Hepatitis Virus B
Author(s) -
Ren Laifeng,
Zeng Ming,
Tang Zizhi,
Li Mingyuan,
Wang Xiaojun,
Xu Yang,
Weng Yuding,
Wang Xiaobo,
Wang Huan,
Guo Liandi,
Zuo Bing,
Wang Xin,
Wang Si,
Lou Jiangyan,
Tang Yaxiong,
Mu Dezhi,
Zheng Ning,
Wu Xianhui,
Han Junhong,
Carr Antony M.,
Jeggo Penelope,
Liu Cong
Publication year - 2019
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.30571
Subject(s) - hbx , carcinogenesis , hepatitis b virus , biology , genome instability , epigenetics , viral replication , virology , histone , cancer research , virus , gene , dna damage , dna , genetics
Chronic infection of hepatitis B virus (HBV) is associated with an increased incidence of hepatocellular carcinoma (HCC). HBV encodes an oncoprotein, hepatitis B x protein (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 antiresection activity by disrupting DNA end resection, thus impairing the initial steps of homologous recombination (HR). This antiresection activity occurs in primary human hepatocytes 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–damage‐specific DNA binding protein 1–RING type of E3 ligase, CRL4 WDR70 , through its H‐box, we show that HBx inhibits H2B monoubiquitylation at lysine 120 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 CRL4 WDR70 function by HBx is sufficient to promote carcinogenesis. Finally, we demonstrate that lack of H2B monoubiquitylation is manifest in human HBV‐associated HCC when compared with HBV‐free HCC, implying corresponding defects of epigenetic regulation and end resection. Conclusion: The antiresection activity of HBx induces an HR defect and genomic instability and contributes to tumorigenesis of host hepatocytes.