Functional interplay between Epstein-Barr virus and the 53BP1/ATM DNA damage response pathway during viral replication. (360G-Wellcome-086373_Z_08_Z)

Epstein-Barr virus (EBV, HHV4) is a human gamma herpes virus that poses major clinical problems worldwide. Activating viral replication in EBV positive tumour cells enhances the host immune response to the virally infected cell; this can be of therapeutic value. A multifunctional viral protein, Zta, is critical for initiating viral replication. Delineating the molecular mechanisms of action of Zta and its interactions with host proteins will greatly increase our understanding of the basic mechan isms used by EBV to replicate and may suggest future avenues to modulate Zta function in therapeutic settings. EBV interacts with the DNA damage response (DDR) pathway through Zta: it interacts with the DDR protein 53BP1 directly and a Zta-associated viral protein kinase directs the phosphorylation of H2AX. Furthermore, ATM is activated during EBV replication and contributes to viral replication. Here we will identify the steps of EBV genome replication that are influenced by DDR activation, focusing on the chromatin environment around the origin of lytic replication and the generation of linear DNA genomes from the concatameric replication product. Furthermore, we will fully characterise the Zta/53BP1 complex during replication and identify the contribution of viral protein kinase to functional modulation of components of the complex.