The Antiresection Activity of the X Protein Encoded by Hepatitis Virus B

doi:10.1002/hep.30571

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	The Antiresection Activity of the X Protein Encoded by Hepatitis Virus B
	Ren, Laifeng 7,8,9; Zeng, Ming 9; Tang, Zizhi 9; Li, Mingyuan 8; Wang, Xiaojun 6; Xu, Yang 9; Weng, Yuding 9; Wang, Xiaobo 9; Wang, Huan 8; Guo, Liandi 9
刊名	HEPATOLOGY
	2019
卷号	69 期号:6 页码:2546-2561
ISSN号	0270-9139
DOI	10.1002/hep.30571
产权排序	5
文献子类	Article
英文摘要	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.
学科主题	Gastroenterology & Hepatology
URL标识	查看原文
WOS关键词	HEPATOCELLULAR-CARCINOMA ; DNA-DAMAGE ; HOMOLOGOUS RECOMBINATION ; CELLULAR-DNA ; UBIQUITIN ; CELLS ; BRCA1 ; GENE ; ARCHITECTURE ; REPLICATION
WOS研究方向	Gastroenterology & Hepatology
语种	英语
出版者	WILEY
WOS记录号	WOS:000470926600019
内容类型	期刊论文
源URL	[http://210.75.237.14/handle/351003/31009]
专题	国家天然药物工程技术研究中心_天然产物研究
通讯作者	Liu, Cong
作者单位	1.Univ Sussex, Sch Life Sci, Genome Damage & Stabil Ctr, Brighton, E Sussex, England 2.Sichuan Univ, West China Hosp, State Key Lab Biotherapy & Ctr Canc, Chengdu, Sichuan, Peoples R China; 3.Hitgen Ltd, Tianfu Sci Pk, Peoples R China; 4.Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA; 5.Chinese Acad Sci, Chengdu Inst Biol, Chengdu, Sichuan, Peoples R China; 6.Genomark, Pidu District, Peoples R China; 7.Shanxi Med Univ, Dept Immunol, Affiliated Canc Hosp, Taiyuan, Shanxi, Peoples R China; 8.Sichuan Univ, West China Sch Basic Sci & Forsen Med, Dept Microbiol, Chengdu, Sichuan, Peoples R China; 9.West China Second Univ Hosp, Dept Paediat, Minist Educ, Key Lab Birth Defects & Related Dis Women & Child, Chengdu, Sichuan, Peoples R China;
推荐引用方式 GB/T 7714	Ren, Laifeng,Zeng, Ming,Tang, Zizhi,et al. The Antiresection Activity of the X Protein Encoded by Hepatitis Virus B[J]. HEPATOLOGY,2019,69(6):2546-2561.
APA	Ren, Laifeng.,Zeng, Ming.,Tang, Zizhi.,Li, Mingyuan.,Wang, Xiaojun.,...&Liu, Cong.(2019).The Antiresection Activity of the X Protein Encoded by Hepatitis Virus B.HEPATOLOGY,69(6),2546-2561.
MLA	Ren, Laifeng,et al."The Antiresection Activity of the X Protein Encoded by Hepatitis Virus B".HEPATOLOGY 69.6(2019):2546-2561.