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Journal article
DNA Polymerase alpha is essential for intracellular amplification of hepatitis B virus covalently closed circular DNA
PLoS pathogens, v 15(4), pp e1007742-e1007742
Apr 2019
PMID: 31026293
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Persistent hepatitis B virus (HBV) infection relies on the establishment and maintenance of covalently closed circular (ccc) DNA, a 3.2 kb episome that serves as a viral transcription template, in the nucleus of an infected hepatocyte. Although evidence suggests that cccDNA is the repair product of nucleocapsid associated relaxed circular (rc) DNA, the cellular DNA polymerases involving in repairing the discontinuity in both strands of rcDNA as well as the underlying mechanism remain to be fully understood. Taking a chemical genetics approach, we found that DNA polymerase alpha (Pol α) is essential for cccDNA intracellular amplification, a genome recycling pathway that maintains a stable cccDNA pool in infected hepatocytes. Specifically, inhibition of Pol α by small molecule inhibitors aphidicolin or CD437 as well as silencing of Pol α expression by siRNA led to suppression of cccDNA amplification in human hepatoma cells. CRISPR-Cas9 knock-in of a CD437-resistant mutation into Pol α genes completely abolished the effect of CD437 on cccDNA formation, indicating that CD437 directly targets Pol α to disrupt cccDNA biosynthesis. Mechanistically, Pol α is recruited to HBV rcDNA and required for the generation of minus strand covalently closed circular rcDNA, suggesting that Pol α is involved in the repair of the minus strand DNA nick in cccDNA synthesis. Our study thus reveals that the distinct host DNA polymerases are hijacked by HBV to support the biosynthesis of cccDNA from intracellular amplification pathway compared to that from de novo viral infection, which requires Pol κ and Pol λ.
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Details
- Title
- DNA Polymerase alpha is essential for intracellular amplification of hepatitis B virus covalently closed circular DNA
- Creators
- Liudi Tang - Drexel UniversityMuhammad Sheraz - Drexel UniversityMichael McGrane - FlowMetric Diagnostics, Doylestown, PA, United States of America.Jinhong Chang - Baruch S. Blumberg InstituteJu-Tao Guo - Baruch S. Blumberg Institute
- Publication Details
- PLoS pathogens, v 15(4), pp e1007742-e1007742
- Publisher
- Public LIbrary of Science (PLOS)
- Grant note
- R01 AI113267 / NIAID NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000466742700055
- Scopus ID
- 2-s2.0-85065806018
- Other Identifier
- 991019168526104721
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InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Web of Science research areas
- Microbiology
- Parasitology
- Virology