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Hepatitis B viral DNA integration occurs within three days of infection and is enhanced by ATR inhibition.
Tumour Virus Res. 20:200332 (2025)
Chronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma, with viral DNA integration into the host genome playing a pivotal role in oncogenesis. While HBV integration has been historically considered an event occurring late in a chronic infection, sensitive assays have detected integrations early infection. This study investigates the specific timing and molecular mechanisms of HBV DNA integration using a replication deficient HBV reporter system (HBV-Zeo) in HepG2-NTCP cells. Infection of this virus followed by positive selection led to cellular colony formation, showing that the input virus is the substrate that undergoes integration. By inducing DNA double-strand breaks via X-ray irradiation at specific timepoints after HBV infection, we observed a 2-3-fold increase in integration frequency when cells are irradiated between 16 and 76 hours post-infection. Pharmacological inhibition of DNA repair pathways in this specific time window revealed that suppression of homologous recombination (HR) via ATR inhibitors significantly enhances integration rates (2.4-2.8-fold), while microhomology-mediated end joining (MMEJ) inhibition reduced integration to 17% of untreated controls. These findings suggest that MMEJ plays a key role in HBV DNA integration occurring within hours of HBV infection. Together, our results advance understanding of HBV-associated hepatocarcinogenesis and may inform therapeutic strategies to disrupt viral integration and mitigate HBV-associated liver cancer risk.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Dna Repair Pathways ; Double-stranded Linear Dna ; Hepatitis B Virus ; Hepatocellular Carcinoma ; Homologous Recombination ; Insertional Mutagenesis ; Microhomology-mediated End Joining ; Non-homologous End Joining; Double-strand Breaks; Clonal Expansion; Virus Infection; Hepatocytes; Repair; Sequences; Genome; Entry; Gene
ISSN (print) / ISBN
2666-6790
e-ISSN
2666-6790
Journal
Tumour Virus Research
Quellenangaben
Volume: 20,
Article Number: 200332
Publisher
Elsevier
Publishing Place
Radarweg 29, 1043 Nx Amsterdam, Netherlands
Reviewing status
Peer reviewed
Institute(s)
Institute of Virology (VIRO)
Grants
Ian Potter Foundation
GESA 2025 Lawrie Powell AC Mid-Career Grant
Australian National Health and Medical Research Council
Australian Centre for HIV and Hepatitis Virology Research
Cancer Institute, NSW
Robert W. Storr Bequest
Westmead Research Hub
Cancer Institute New South Wales
National Health and Medical Research Council
Paul and Valeria Ainsworth Precision Medicine Fellowship
GESA 2025 Lawrie Powell AC Mid-Career Grant
Australian National Health and Medical Research Council
Australian Centre for HIV and Hepatitis Virology Research
Cancer Institute, NSW
Robert W. Storr Bequest
Westmead Research Hub
Cancer Institute New South Wales
National Health and Medical Research Council
Paul and Valeria Ainsworth Precision Medicine Fellowship