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The EBNA-3 gene family proteins disrupt the G2/M checkpoint.

The Epstein-Barr nuclear antigens (EBNA), EBNA-3, -4 and -6, have previously been shown to act as transcriptional regulators, however, this study identifies another function for these proteins, disruption of the G2/M checkpoint. Lymphoblastoid cell lines (LCLs) treated with a G2/M initiating drug azelaic bishydroxamine (ABHA) did not show a G2/M checkpoint response, but rather they display an increase in cell death, a characteristic of sensitivity to the cytotoxic effects of the drug. Cell cycle analysis demonstrated that the individual expression of EBNA-3, -4 or -6 are capable of disrupting the G2/M checkpoint response induced by ABHA resulting in increased toxicity, whereas EBNA-2, and -5 were not. EBNA-3 gene family protein expression also disrupted the G2/M checkpoint initiated in response to the genotoxin etoposide and the S phase inhibitor hydroxyurea. The G2 arrest in response to these drugs were sensitive to caffeine, suggesting that ATM/ATR signalling in these checkpoint responses may be blocked by the EBNA-3 family proteins. The function of EBNA-3, -4 and -6 proteins appears to be more complex than anticipated and these data suggest a role for these proteins in disrupting the host cell cycle machinery.

Pubmed ID: 14716295

Authors

  • Krauer KG
  • Burgess A
  • Buck M
  • Flanagan J
  • Sculley TB
  • Gabrielli B

Journal

Oncogene

Publication Data

February 19, 2004

Associated Grants

None

Mesh Terms

  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins
  • Checkpoint Kinase 2
  • DNA Damage
  • DNA-Binding Proteins
  • Epstein-Barr Virus Nuclear Antigens
  • G2 Phase
  • Histone Deacetylase Inhibitors
  • Humans
  • Hydroxamic Acids
  • Mitosis
  • Precipitin Tests
  • Protein-Serine-Threonine Kinases
  • Signal Transduction
  • Tumor Suppressor Proteins