The role of the EBNA3 proteins in EBV biology and disease pathogenesis. (360G-Wellcome-092644_Z_10_Z)

The focus of this programme of research is the family of EBV-encoded nuclear proteins (EBNAs 3A, 3B and 3C) expressed in the type of viral latency generally associated with EBV-driven B cell proliferation. Although the EBNA3s are vital to EBV biology, our knowledge of their functions was until recently quite limited, but they are gradually moving centre stage. Using a series of unique, engineered recombinant viruses carrying a variety of mutations in the EBNA3 locus and microarray technology, we have discovered a remarkably large number of cell genes regulated by one or more of the EBNA3 proteins. Regulation in some cases involves stable epigenetic changes to chromatin and in some involves transcriptional elongation. Furthermore it is now clear at least one of these proteins (EBNA3C) additionally targets multiple cellular proteins involved in the regulation of cell cycle checkpoints. Key aims of the study are: a) To fully characterise the molecular mechanisms underpinning EBNA3 actio n and cooperation in gene regulation. b) To clarify the roles of the EBNA3s in cell cycle deregulation. c) To explore their contribution in lymphomagenesis using a small animal model. d) To understand their contribution to human disease involving EBV.