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J Biol Chem, Vol. 273, Issue 50, 33327-33332, December 11, 1998
From the Department of Pathology, University Medical School, Teviot
Place, Edinburgh EH8 9AG, Scotland, and the § Department of
Medicine and Genetics, Stanford University School of Medicine,
Stanford, California 94305-5115
The mechanisms by which the hepatitis B x protein
(HBx) contributes to hepatocarcinogenesis remain unclear. However,
interaction with the tumor suppressor gene p53 and
inhibition of p53-dependent cellular functions, including
nucleotide excision repair, could be central to this process. We
studied the levels of global repair (removal of cyclobutane pyrimidine
dimers (CPDs) and 6-4 photoproducts) and transcription-coupled repair
(removal of CPDs in both strands of the dihydrofolate reductase gene)
in primary wild-type and p53-null mouse hepatocytes. We
show that global repair of CPDs appears to be more efficient in mouse
hepatocytes than in other commonly studied rodent cells and approaches
the levels of human cells and that p53 is required for global genomic
DNA repair of CPDs but not for transcription-coupled repair. We then
investigated the effect of HBx expression on hepatocyte nucleotide
excision repair. We demonstrate that HBx expression affects DNA repair in a p53-dependent manner. Transient HBx expression reduces
global DNA repair in wild-type cells to the level of
p53-null hepatocytes and has no effect on the repair of a
transfected damaged plasmid. Therefore, in viral hepatitis, the
hepatitis B virus could inhibit the
p53-dependent component of global repair
leading, over time, to accumulation of genetic defects and fostering carcinogenesis.
Hepatitis B x Protein Inhibits p53-dependent DNA
Repair in Primary Mouse Hepatocytes
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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