| Summary: | Epstein Barr Virus (EBV) is a γ-herpesvirus infecting around 95% of the human population. EBV infection is life-long and asymptomatic in the majority of individuals, however EBV is associated with Nasopharyngeal Carcinoma, Burkitt's lymphoma and Hodgkin's lymphoma. The transcription factor Zta is an immediate early gene of EBV able to reactivate the virus from latency, cause cell cycle arrest and bind to sequence specific DNA elements. Cercopithecine herpesvirus-15 is a closely related virus, infecting rhesus monkeys, with a homologue to Zta; ZtaRh. A comparison of features of these proteins may be informative about critical residues in each protein. Binding to almost all response elements is conserved between the two proteins. A Zta response element (ZRE3Rh) in the CeHV-15 Rta gene promoter that is not functional for either protein was identified. ZRE3 from EBV is methylation dependent for Zta binding. Analysis of ZRE3 using competition EMSA assays has shown the importance of methylation of individual CpG motifs. ZtaRh is compromised in reactivating EBV from latency and this appears to be mediated by changes at the extreme C-terminus. ZtaRh is unable to cause G1 cell cycle arrest, however this function maps to the transactivation domain. Known binding partners of Zta were cloned to enable investigation of binding by ZtaRh or other mutants. Co-transfection of p53 and Zta resulted in rapid degradation of both proteins. Co-transfection of C/EBPα and Zta produced a larger additional Zta species. Neither effect was seen with a Zta CT mutant. RNA from HEK293-ZKO cells transfected with Zta or a C-terminal Zta mutant was analysed using a QPCR array probing 595 human genes associated with cancer, revealing possible host cell proteins influenced by Zta. Further information on the precise mechanisms of Zta could contribute to the development of future therapies for the prevention or treatment of EBV related diseases.
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