The hepatitis B virus x protein inhibits thymine DNA glycosylase initiated base excision repair

PLoS One. 2012;7(11):e48940. doi: 10.1371/journal.pone.0048940. Epub 2012 Nov 8.

Abstract

The hepatitis B virus (HBV) genome encodes the X protein (HBx), a ubiquitous transactivator that is required for HBV replication. Expression of the HBx protein has been associated with the development of HBV infection-related hepatocellular carcinoma (HCC). Previously, we generated a 3D structure of HBx by combined homology and ab initio in silico modelling. This structure showed a striking similarity to the human thymine DNA glycosylase (TDG), a key enzyme in the base excision repair (BER) pathway. To further explore this finding, we investigated whether both proteins interfere with or complement each other's functions. Here we show that TDG does not affect HBV replication, but that HBx strongly inhibits TDG-initiated base excision repair (BER), a major DNA repair pathway. Inhibition of the BER pathway may contribute substantially to the oncogenic effect of HBV infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / virology
  • DNA Repair*
  • DNA Replication
  • HEK293 Cells
  • Hep G2 Cells
  • Hepatitis B / genetics
  • Hepatitis B / metabolism
  • Hepatitis B / virology
  • Humans
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / virology
  • Thymine DNA Glycosylase / antagonists & inhibitors*
  • Thymine DNA Glycosylase / genetics
  • Thymine DNA Glycosylase / metabolism
  • Trans-Activators / genetics*
  • Viral Regulatory and Accessory Proteins

Substances

  • Trans-Activators
  • Viral Regulatory and Accessory Proteins
  • hepatitis B virus X protein
  • Thymine DNA Glycosylase

Grant support

This work was funded by Sanquin Blood Supply Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.