title: The EBNA-3 gene family proteins disrupt the G2/M checkpoint.
abstract: 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.
authors.affiliation: Queensland Institute of Medical Research and Joint Oncology Program, University of Queensland, Brisbane, Australia. keniaK@qimr.edu.au
authors.forename: Kenia G
authors.initials: KG
authors.lastname: Krauer
authors.forename: Andrew
authors.initials: A
authors.lastname: Burgess
authors.forename: Marion
authors.initials: M
authors.lastname: Buck
authors.forename: James
authors.initials: J
authors.lastname: Flanagan
authors.forename: Tom B
authors.initials: TB
authors.lastname: Sculley
authors.forename: Brian
authors.initials: B
authors.lastname: Gabrielli
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D064447:Checkpoint Kinase 2; D004249:DNA Damage / Q000502:physiology; D004268:DNA-Binding Proteins; D019309:Epstein-Barr Virus Nuclear Antigens / Q000276:immunology / Q000378:metabolism*; D016195:G2 Phase / Q000187:drug effects / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008938:Mitosis / Q000187:drug effects / Q000502:physiology*; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D025521:Tumor Suppressor Proteins
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D019309:Epstein-Barr Virus Nuclear Antigens; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D025521:Tumor Suppressor Proteins; C107648:azelaic bishydroxamic acid; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases