ArticleProceedings of the National Academy of Sciences of the United States of America2014
Involvement of the host DNA-repair enzyme TDP2 in formation of the covalently closed circular DNA persistence reservoir of hepatitis B viruses.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 139 papers.
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139 citing papers in PubMed, 224 citations in OpenAlex.
- Orthogonal CRISPR screens and human liver chimeric mice identify hepatitis B virus host factors.bioRxiv : the preprint server for biology · 2026Article
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- Nucleotide excision repair and poly(ADP-ribose) polymerase 1 cooperate in HBV cccDNA synthesis: A potential viral therapeutic target.JHEP reports : innovation in hepatology · 2026Article
- Insight into the Biology of Hepatitis B Virus and Recent Therapeutic Approaches.Current microbiology · 2026Review
- Chromatin remodeler BAF maintains HBV cccDNA transcriptional competence and represents a therapeutic target.Nucleic acids research · 2026Article
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- Identification of glycogen synthase kinase 3alpha/beta as a host factor required for HBV transcription using high-throughput screening.Hepatology (Baltimore, Md.) · 2025Article
- The Antiviral Activity of Polyphenols.Molecular nutrition & food research · 2025Review
- The Evolution of Cell Culture Systems to Study Hepatitis B Virus Pathogenesis and Antiviral Susceptibility.Viruses · 2025Review
- TRIM52 maintains cellular fitness and is under tight proteolytic control by multiple giant E3 ligases.Nature communications · 2025Article
- NEDD4-binding protein 1 suppresses hepatitis B virus replication by regulating viral RNAs.The Journal of general virology · 2025Article
- Hepatitis B virus hijacks MRE11-RAD50-NBS1 complex to form its minichromosome.PLoS pathogens · 2025Article
- Epigenetic regulation and its therapeutic potential in hepatitis B virus covalently closed circular DNA.Genes & diseases · 2025Review
- Targeting HBV cccDNA Levels: Key to Achieving Complete Cure of Chronic Hepatitis B.Pathogens (Basel, Switzerland) · 2024Review
- Mechanisms underlying the compromised clinical efficacy of interferon in clearing HBV.Virology journal · 2024Review
- The impact of integrated hepatitis B virus DNA on oncogenesis and antiviral therapy.Biomarker research · 2024Review
- Mechanisms of Hepatitis B Virus cccDNA and Minichromosome Formation and HBV Gene Transcription.Viruses · 2024Review
- SRPK2 Mediates HBV Core Protein Phosphorylation and Capsid Assembly via Docking Interaction.PLoS pathogens · 2024Article
- Detection of Hepatitis B Virus Covalently Closed Circular DNA and Intermediates in Its Formation.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Hepatitis B Virus and microRNAs: A Bioinformatics Approach.International journal of molecular sciences · 2023Review
79 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hepatitis B virus (HBV), the causative agent of chronic hepatitis B and prototypic hepadnavirus, is a small DNA virus that replicates by protein-primed reverse transcription. The product is a 3-kb relaxed circular DNA (RC-DNA) in which one strand is linked to the viral polymerase (P protein) through a tyrosyl-DNA phosphodiester bond. Upon infection, the incoming RC-DNA is converted into covalently closed circular (ccc) DNA, which serves as a viral persistence reservoir that is refractory to current anti-HBV treatments. The mechanism of cccDNA formation is unknown, but the release of P protein is one mandatory step. Structural similarities between RC-DNA and cellular topoisomerase-DNA adducts and their known repair by tyrosyl-DNA-phosphodiesterase (TDP) 1 or TDP2 suggested that HBV may usurp these enzymes for its own purpose. Here we demonstrate that human and chicken TDP2, but only the yeast ortholog of TDP1, can specifically cleave the Tyr-DNA bond in virus-adapted model substrates and release P protein from authentic HBV and duck HBV (DHBV) RC-DNA in vitro, without prior proteolysis of the large P proteins. Consistent with TPD2's having a physiological role in cccDNA formation, RNAi-mediated TDP2 depletion in human cells significantly slowed the conversion of RC-DNA to cccDNA. Ectopic TDP2 expression in the same cells restored faster conversion kinetics. These data strongly suggest that TDP2 is a first, although likely not the only, host DNA-repair factor involved in HBV cccDNA biogenesis. In addition to establishing a functional link between hepadnaviruses and DNA repair, our results open new prospects for directly targeting HBV persistence.
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