Core components of DNA lagging strand synthesis machinery are essential for hepatitis B virus cccDNA formation.

Nature Microbiology
Lei Wei, Alexander Ploss

Abstract

Chronic hepatitis B virus (HBV) infections result in 887,000 deaths annually. The central challenge in curing HBV is eradication of the stable covalently closed circular DNA (cccDNA) form of the viral genome, which is formed by the repair of lesion-bearing HBV relaxed circular DNA delivered by the virions to hepatocytes. The complete and minimal set of host factors involved in cccDNA formation is unknown, largely due to the lack of a biochemical system that fully reconstitutes cccDNA formation. Here, we have developed experimental systems where various HBV relaxed-circular-DNA substrates are repaired to form cccDNA by both cell extracts and purified human proteins. Using yeast- and human-extract screenings, we identified five core components of lagging-strand synthesis as essential for cccDNA formation: proliferating cell nuclear antigen, the replication factor C complex, DNA polymerase δ, flap endonuclease 1 and DNA ligase 1. We reconstituted cccDNA formation with purified human homologues, establishing these as a minimal set of factors for cccDNA formation. We further demonstrated that treatment with the DNA-polymerase inhibitor aphidicolin diminishes cccDNA formation both in biochemical assays and in HBV-infected human cells...Continue Reading

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Citations

Aug 18, 2020·Cellular Microbiology·Anindita ChakrabortyJane A McKeating
Jun 6, 2020·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Qiong Zhao, Ju-Tao Guo
Nov 26, 2020·Viruses·Zhenfeng Zhang, Stephan Urban
Mar 4, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Cristian PrietoRodrigo A Villanueva
Dec 23, 2020·Gastroenterology·Alexander PlossWenhui Li
Mar 13, 2021·Nature Communications·Lei Wei, Alexander Ploss
Mar 14, 2021·Nature Communications·Xiaodong ZhuangJane A McKeating
Apr 13, 2021·Expert Opinion on Therapeutic Targets·Mohube Betty MaepaPatrick Arbuthnot
May 25, 2021·Current Opinion in Virology·Gaëtan LigatThomas F Baumert
May 30, 2021·Journal of Hepatology·Maria Guadalupe MartinezFabien Zoulim
Jun 25, 2021·World Journal of Gastroenterology : WJG·Prashika SinghKristie Bloom
Aug 11, 2021·Viruses·Bingqian Qu, Richard J P Brown
Aug 29, 2021·Viruses·Lei Wei, Alexander Ploss
Sep 30, 2021·Annual Review of Virology·Timothy M BlockJu-Tao Guo

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Methods Mentioned

BETA
transfection
immunodepletion
gene knockout
electrophoresis
PCR
electrophoreses

Software Mentioned

ImageJ
Adobe Illustrator

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