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


CONCLUSIONS
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.
Martin-Lluesma
Silvia
S
Department of Microbiology and Molecular Medicine, University Medical Centre, CMU, Geneva, Switzerland. Michel.Strubin@medecine.unige.ch
Schaeffer
Céline
C
Robert
Eva Isabelle
EI
van Breugel
Pieter Cornelis
PC
Leupin
Olivier
O
Hantz
Olivier
O
Strubin
Michel
M
D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations / Q000187:drug effects; D002877:Chromosomes, Human / Q000187:drug effects; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000502:physiology*; D018450:Disease Progression; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics; D006367:HeLa Cells; D006511:Hepatitis B Antigens / Q000502:physiology; D019694:Hepatitis B, Chronic / Q000503:physiopathology*; D006801:Humans; D008113:Liver Neoplasms; D015534:Trans-Activators / Q000494:pharmacology* / Q000502:physiology; D054334:Viral Regulatory and Accessory Proteins
D004268:DNA-Binding Proteins; D006511:Hepatitis B Antigens; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D049452:Green Fluorescent Proteins