Mol. Cells 2018; 41(): 953  https://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
Hyehyeon Lee, Hyerin Jeong, Sun Young Lee, Soo Shin Kim, and Kyung Lib Jang*
Department of Microbiology, College of Natural Science, Pusan National University, Busan 46241, Korea
*Correspondence: kljang@pusan.ac.kr
Received June 11, 2018; Revised November 22, 2018; Accepted November 26, 2018.; Published online December 5, 2018.
© Korean Society for Molecular and Cellular Biology. All rights reserved.

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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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30 November 2018 Volume 41,
Number 11, pp. 933~992

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