Viral regulation of host cell DNA damage response pathways

Human adenoviruses are small non-enveloped viruses and possess a linear, double-stranded DNA genome. Adenovirus has long been used as a tool to dissect the molecular basis of key biological processes such as growth, differentiation and death. Indeed, studies investigating the roles of the adenovirus early region proteins has led to key advances in the understanding of these basic cellular processes and provided insight into how adenovirus usurps control of molecular signalling pathways in order to promote viral replication and cellular transformation.

The phosphoinositide 3-kinase like kinase protein products of the Ataxia Telangiectasia (A-T) Mutated gene, ATM, and ATM-Rad3-related gene, ATR, function as key transducers of signals initiated in response to DNA damage and serve to activate cell cycle checkpoints to allow for DNA repair, or apoptosis. It is apparent that, in order to replicate their genomes efficiently in host cells, viruses employ numerous strategies to selectively activate and/or evade host cell DNA damage response pathways. As such, adenovirus has evolved largely to bypass, or inactivate, host cell DNA damage response pathways that would otherwise initiate cell cycle arrest or apoptosis in the infected cell. Indeed, many DNA damage response proteins are inactivated during infection by either proteasomal-mediated degradation and/or recruitment to viral replication centres or PML-containing nuclear tracks.

The aim of this studentship is to further our understanding of cellular DNA damage response pathways at the molecular level and determine how adenoviruses targets these pathways in order to promote viral replication.