Hepatitis B virus X protein affects S phase progression leading to chromosome segregation defects by binding to damaged DNA binding protein 1

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http://www3.interscience.wiley.com/journal/120846949/abstract

Viral Hepatitis

Hepatitis B virus X protein affects S phase progression leading to chromosome

segregation defects by binding to damaged DNA binding protein 1

Silvia -Lluesma 1, Céline Schaeffer 1, Eva Isabelle 1, Pieter

Cornelis van Breugel 1, Olivier Leupin 1, Olivier Hantz 2, Michel Strubin 1 *§

1Department of Microbiology and Molecular Medicine, University Medical Centre

(C.M.U.), Geneva, Switzerland

2Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 871,

Lyon, France

email: Michel Strubin (Michel.Strubin@...)

*Correspondence to Michel Strubin, Department of Microbiology and Molecular

Medicine, University Medical Centre (C.M.U.), Rue Michel-Servet 1, 1211 Geneva

4, Switzerland

Potential conflict of interest: Nothing to report.

These authors contributed equally to this work.

§fax: (41)-(22)-379-5702.

Funded by:

French Association for Cancer Research

Roche

Lombard Odier Darier Hentsch

Swiss National Science Foundation; Grant Number: 3100A0-100785, 3100A0-112496

Abstract

Chronic hepatitis B virus (HBV) infection is a leading cause of hepatocellular

carcinoma (HCC), but its role in the transformation process remains unclear. HBV

encodes a small protein, known as HBx, which is required for infection and has

been implicated in hepatocarcinogenesis. Here we show that HBx induces lagging

chromosomes during mitosis, which in turn leads to formation of aberrant mitotic

spindles and multinucleated cells. These effects require the binding of HBx to

UV-damaged DNA binding protein 1 (DDB1), a protein involved in DNA repair and

cell cycle regulation, and are unexpectedly attributable to HBx interfering with

S-phase progression and not directly with mitotic events. HBx also affects

S-phase and induces lagging chromosomes when expressed from its natural viral

context and, consequently, exhibits deleterious activities in dividing, but not

quiescent, hepatoma cells. Conclusion: In addition to its reported role in

promoting HBV replication, the binding of HBx to DDB1 may induce genetic

instability in regenerating hepatocytes and thereby contribute to HCC

development, thus making this HBV-host protein interaction an attractive target

for new therapeutic intervention. (HEPATOLOGY 2008.)

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Received: 14 March 2008; Accepted: 17 July 2008

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