DNA Repair Factor Poly(ADP-Ribose) Polymerase 1 Is a Proviral Factor in Hepatitis B Virus Covalently Closed Circular DNA Formation

被引:7
作者
Chen, Yingshan [1 ,2 ]
Yao, Yongxuan [1 ,3 ]
Zhao, Kaitao [4 ,5 ]
Liu, Canyu [1 ,2 ]
Yuan, Yifei [1 ,2 ]
Sun, Hao [1 ,2 ]
Huang, Dan [1 ,2 ]
Zheng, Yi [9 ]
Zhou, Yuan [1 ]
Chen, Jizheng [1 ]
Wang, Yun [1 ]
Wu, Chunchen [6 ]
Zhang, Bixiang [7 ]
Guan, Yujuan [8 ]
Li, Feng [8 ]
Pei, Rongjuan [1 ]
Chen, Xinwen [1 ,2 ,10 ]
机构
[1] Chinese Acad Sci, Wuhan Inst Virol, State Key Lab Virol, Wuhan, Peoples R China
[2] Univ Chinese Acad Sci, Beijing, Peoples R China
[3] Guangzhou Women & Childrens Med Ctr, Dept Gastroenterol, Guangzhou, Peoples R China
[4] Wuhan Univ, State Key Lab Virol, Inst Med Virol, Sch Basic Med Sci, Wuhan, Peoples R China
[5] Wuhan Univ, Hubei Prov Key Lab Allergy & Immunol, Inst Med Virol, Sch Basic Med Sci, Wuhan, Peoples R China
[6] Huazhong Univ Sci & Technol, Maternal & Child Hlth Hosp Hubei Prov, Tongji Med Coll, Dept Lab Med, Wuhan, Peoples R China
[7] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Hepat Surg Ctr, Wuhan, Peoples R China
[8] Guangzhou Med Univ, Guangzhou Peoples Hosp 8, Inst Infect Dis, Guangzhou, Peoples R China
[9] Northeast Forestry Univ, Sch Life Sci, Harbin, Peoples R China
[10] Guangzhou Lab, Guangzhou, Peoples R China
基金
中国国家自然科学基金;
关键词
HBV; cccDNA; PARP1; PARylation; DNA repair system; BINDING; PARP-1; DAMAGE; TRANSCRIPTION; EXPRESSION; INFECTION; GENOME; CCCDNA;
D O I
10.1128/jvi.00585-22
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
The biogenesis and eradication of HBV cccDNA have been a research priority in recent years. In this study, we identified the DNA repair factor PARP1 as a host factor required for the HBV de novo cccDNA formation. The biogenesis of covalently closed circular DNA (cccDNA) from relaxed circular DNA (rcDNA) is essential for chronic hepatitis B virus (HBV) infection. Different host DNA repair proteins are involved in the conversion of rcDNA to cccDNA. Here, we reported that the DNA repair factor poly(ADP-ribose) polymerase 1 (PARP1) is engaged in HBV cccDNA formation. PARP1 depletion remarkably impaired HBV replication and cccDNA synthesis. Inhibition of PARP1 poly (ADP-ribosylation) activity by olaparib suppressed cccDNA synthesis both in vitro and in vivo. Specifically, the early stage of cccDNA reservoir establishment was more sensitive to olaparib, suggesting that PARP1 participated in de novo cccDNA formation. Furthermore, PARP1 was activated by recognizing the rcDNA-like lesions directly and combined with other DNA repair proteins. The results presented proposed that the DNA damage-sensing protein PARP1 and poly(ADP-ribosylation) modification play a key role in cccDNA formation, which might be the target for developing the anti-HBV drug. IMPORTANCE The biogenesis and eradication of HBV cccDNA have been a research priority in recent years. In this study, we identified the DNA repair factor PARP1 as a host factor required for the HBV de novo cccDNA formation. HBV infection caused PARylation through PARP1 in Huh7-NTCP cells, primary human hepatocytes, and human-liver chimeric mice. We found that PARP1 could directly bind to the rcDNA lesions and was activated, PARylating other DNA repair proteins. We address the importance of PARP1-mediated PARylation in HBV cccDNA formation, which is a potential therapeutic target for chronic hepatitis B.
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页数:17
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