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http://dx.doi.org/10.14348/molcells.2018.0255

Hepatitis B Virus X Protein Stimulates Virus Replication Via DNA Methylation of the C-1619 in Covalently Closed Circular DNA  

Lee, Hyehyeon (Department of Microbiology, College of Natural Science, Pusan National University)
Jeong, Hyerin (Department of Microbiology, College of Natural Science, Pusan National University)
Lee, Sun Young (Department of Microbiology, College of Natural Science, Pusan National University)
Kim, Soo Shin (Department of Microbiology, College of Natural Science, Pusan National University)
Jang, Kyung Lib (Department of Microbiology, College of Natural Science, Pusan National University)
Publication Information
Molecules and Cells / v.42, no.1, 2019 , pp. 67-78 More about this Journal
Abstract
Methylation of HBV cccDNA has been detected in vivo and in vitro; however, the mechanism and its effects on HBV replication remain unclear. HBx derived from a 1.2-mer HBV replicon upregulated protein levels and enzyme activities of DNA methyltransferase 1 (DNMT1), 3a, and 3b, resulting in methylation of the negative regulatory region (NRE) in cccDNA, while none of these effects were observed with an HBx-null mutant. The HBx-positive HBV cccDNA expressed higher levels of HBc and produced about 4-fold higher levels of HBV particles than those from the HBx-null counterpart. For these effects, HBx interrupted the action of NRE binding protein via methylation of the C-1619 within NRE, resulting in activation of the core promoter. Treatment with 5-Aza-2′dC or DNMT1 knock-down drastically impaired the ability of HBx to activate the core promoter and stimulate HBV replication in 1.2-mer HBV replicon and in vitro infection systems, indicating the positive role of HBx-mediated cccDNA methylation in HBV replication.
Keywords
covalently closed circular DNA; DNA methylation; HBx; hepatitis B virus; negative regulatory region binding protein;
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