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J. Biol. Chem., Vol. 280, Issue 39, 33525-33535, September 30, 2005

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The Hepatitis B Virus X Protein Sensitizes HepG2 Cells to UV Light-induced DNA Damage^*

Alvin T. C. Lee, Jianwei Ren, Ee-Tsin Wong, Kenneth H. K. Ban, Linda A. Lee¶, and Caroline G. L. Lee1

From the Division of Medical Sciences, National Cancer Centre, Singapore 169610, Singapore, the Department of Biochemistry, National University of Singapore, Singapore 119077, Singapore, and the ^¶Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287

Various reports have implicated the virally encoded HBx protein as a cofactor in hepatocarcinogenesis. However, direct evidence of the role of HBx as a promoter of oncogenesis in response to an initiating factor such as DNA damage remains inadequate. Here, we report the effects of HBx in HepG2 cells exposed to UV light-induced DNA damage. HBx expression was found not to affect the morphology, viability, and cell cycle/apoptotic profiles or DNA repair machinery of untreated cells. Nonetheless, upon UV treatment, HBx protein levels increased concomitantly with p53 levels. Both HBx and p53 proteins were found to interact and colocalize primarily in the nucleus. The binding of HBx to p53 modulated (but did not inhibit) the transcriptional activation function of p53. Notably, HBx-expressing cells exhibited increased sensitivity to UV damage, resulting in greater G₂/M arrest and apoptosis of these cells. Additionally, these cells displayed a reduced DNA repair capacity in response to UV damage. In conclusion, this work suggests that DNA damage may be an initiating factor in hepatocarcinogenesis and that HBx may act as the promoting factor by inhibiting DNA repair. In hepatitis B virus-infected hepatocytes, a chronic infection may present the opportunity for such a DNA-damaging event to occur, and accumulated errors caused by the inhibition of DNA repair by HBx may result in oncogenesis.

Received for publication, June 17, 2005 , and in revised form, July 29, 2005.

^* This work was supported by block grants from the National Medical Research Council of Singapore through the National Cancer Centre (to C. G. L. Lee) and from the National Science and Technology Board of Singapore through John Hopkins Singapore (to C. G. L. Lee and L. A. Lee). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Div. of Medical Sciences, National Cancer Centre, Level 6, Lab 5, 11 Hospital Dr., Singapore 169610, Singapore. Tel.: 65-6436-8353; Fax: 65-6372-0161; E-mail: bchleec{at}nus.edu.sg.

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