Evidence map›Paper›PMID 42092281›Full record

ArticleJHEP reports : innovation in hepatology2026

Nucleotide excision repair and poly(ADP-ribose) polymerase 1 cooperate in HBV cccDNA synthesis: A potential viral therapeutic target.

Hsu-Chin Hung, Hung-Wen Tsai, Yung-Tsung Li, Wen-Chun Liu, Kuang-Hsiung Cheng, Chia-Jui Yen, Yun-Ping Lee, Yuan-Hsin Fang, Cheng-Hsiang Chuang, Hui-Lin Wu and 2 more

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In one paragraph

Article in JHEP reports : innovation in hepatology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

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0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

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2 · The registry

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3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors.

Hsu-Chin HungInstitute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Hung-Wen TsaiDepartment of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Yung-Tsung LiHepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
Wen-Chun LiuDepartment of Nursing, National Tainan Junior College of Nursing, Tainan, Taiwan.
Kuang-Hsiung ChengDepartment of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Chia-Jui YenDivision of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Yun-Ping LeeDepartment of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Yuan-Hsin FangDepartment of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Cheng-Hsiang ChuangDepartment of Life Science, College of Life Sciences and Medicine, National Tsing Hua University, Hsinchu, Taiwan.
Hui-Lin WuHepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
Ting-Tsung ChangDivision of Gastroenterology and Hepatology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Wenya HuangInstitute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan. Electronic address: whuang@mail.ncku.edu.tw.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

BACKGROUND &

aimsBlocking the synthesis of HBV covalently closed circular (ccc)DNA is crucial for achieving a viral cure. Previous work showed that inhibiting nucleotide excision repair (NER) reduced cccDNA levels in HBV-producing liver cells. Here, we aimed to clarify the role of NER endonucleases in addressing the flap structure on relaxed circular DNA (rcDNA) and to explore an antiviral strategy that disrupts viral replication reservoirs.

methodsWe investigated the need for NER endonucleases for cccDNA synthesis in liver cells by examining the interactions between the complex of excision repair cross complementation group 1 (ERCC1)-xeroderma pigmentosum group F (XPF) and that of poly(ADP-ribose) polymerase 1 (PARP1)-tyrosyl-DNA phosphodiesterase 1 (TDP1). We also assessed the impact of a PARP1 inhibitor on cccDNA synthesis and developed a digital PCR method for quantifying cccDNA in human liver tissues with high sensitivity. Finally, we evaluated the correlation between the levels of ERCC1, XPF, TDP1, and PARP1 and cccDNA.

resultsERCC1-XPF NER endonuclease and TDP1 increased cccDNA in liver cells and were shown to directly bind each other to cleave the rcDNA flap. This was demonstrated through various protein interaction and in vitro rcDNA cleavage analyses. PARP1 inhibition effectively blocked cccDNA formation and was dependent on ERCC1, XPF, and TDP1. The interactions among these complexes suggest that inhibiting PARP1 could reduce cccDNA production. Furthermore, these complexes were found to associate with the HBV genome in human liver tissues, showing correlations between their levels and cccDNA concentration (p 0.003-0.034; r 0.31-0.43).

conclusionsERCC1-XPF and TDP1-PARP1 complexes work in tandem to achieve cccDNA synthesis, indicating PARP1 inhibition as a promising therapeutic strategy for clearing cccDNA. IMPACT AND IMPLICATIONS: Blocking HBV cccDNA synthesis is imperative for reaching the goal of a cure for HBV. This study delineated the involvement of host NER endonucleases in resolving the flap structure on rcDNA and seeking an antiviral strategy by blocking the production of viral replication reservoirs. The NER ERCC1-XPF endonuclease and the topoisomerase 1-associated TDP1-PARP1 complex directly bind to the HBV genome in the human liver, where these factors correlate with the cccDNA levels. The ERCC1-XPF and TDP1-PARP1 complexes function in tandem to cleave the HBV rcDNA flap so that cccDNA synthesis can proceed. Thus, PARP1 inhibition could be a promising therapeutic strategy for cccDNA clearance.

Indexed as

DNA, CircularDNA, ViralExcision RepairHepatitis B virusPoly (ADP-Ribose) Polymerase-1Antiviral AgentsDNA-Binding ProteinsEndonucleasesHumansPhosphoric Diester HydrolasesPoly(ADP-ribose) Polymerase InhibitorsVirus ReplicationAntiviral AgentsDNA-Binding ProteinsDNA, CircularDNA, ViralEndonucleasesERCC1 protein, humanPARP1 protein, humanPhosphoric Diester HydrolasesPoly (ADP-Ribose) Polymerase-1Poly(ADP-ribose) Polymerase Inhibitorsxeroderma pigmentosum group F proteincccDNAHBVNucleotide excision repairOlaparibPARP1

Identifiers

PMID42092281
PMCPMC13158411

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