About the Project
Human adenoviruses are small non-enveloped viruses with a linear, double-stranded DNA genome. Since the observation that adenovirus 12 could induce tumours in newborn rodents, adenovirus has served as a faithful model for dissecting the molecular basis of key cellular signalling pathways that regulate fundamental biological processes such as cell growth, cell differentiation and cell survival. Studies investigating the roles of the adenovirus early region proteins in both adenovirus-transformed, and adenovirus-infected cells have led to key advances in the understanding of basic cellular processes and how adenovirus usurps control of these pathways in order to promote viral replication and/or 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, depending on the extent of DNA damage incurred. It is becoming increasingly 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 (DDR) pathways such as those regulated by ATM and ATR. Adenovirus has thus evolved to bypass, or inactivate, host cell cycle checkpoints that would otherwise initiate cell cycle arrest or apoptotic programmes in the infected cell. Indeed, many DDR proteins are recruited to Viral Replication Centres (VRCs) and PML-containing nuclear tracks, during infection.
The aim of this studentship is to further our understanding of cellular DDR pathways and determine how viruses exploit host cell DDR pathways in order to promote viral replication. We will use a combination of cell biological and proteomic techniques to identify novel cellular proteins targeted to VRCs and nuclear tracks, during infection, and use methods well-established in our laboratory to determine whether these cellular proteins function in DDR pathways. We will also determine whether cellular proteins targeted by adenovirus during infection possess inherent anti-viral activity. It is anticipated that results from this project will enhance further our understanding of DDR pathways and give further insight into how viruses regulate DDR pathways to promote viral replication.
Funding Notes
The University of Birmingham also offers Research Council UK (BBSRC, MRC) PhD studentships each year. Fully funded research council studentships are normally only available to UK nationals (or EU nationals resident in the UK). The deadline for applications for research council studentships is in January each year.
References
Turnell AS, Grand RJ (2012). Viral regulation of DNA damage response pathways. J. Gen. Virol. 93:2076-2097.
Forrester NA, Patel RN, Speiseder T, Groitl P, Sedgwick GG, Shimwell NJ, Seed RI, Ó Catnaigh P, McCabe CJ, Stewart GS, Dobner T, Grand RJ, Martin A, Turnell AS. (2012) Adenovirus E4orf3 targets Transcriptional Intermediary Factor 1 for proteasome-dependent degradation during infection. J. Virol. 86:3167-3179.
Forrester NA, Sedgwick GG, Thomas A, Blackford AN, Speiseder T, Dobner T, Byrd PJ, Stewart GS, Turnell AS, Grand RJ. (2011) Serotype-specific inactivation of the cellular DNA damage response during adenovirus infection. J Virol. 85:2201-2211.
Blackford AN, Patel RN, Forrester NA, Theil K, Groitl P, Stewart GS, Taylor AMR, Morgan IM, Dobner T, Grand RJA, Turnell AS. (2010) Adenovirus 12 E4orf6 inhibits ATR activation by promoting TOPBP1 degradation. Proc. Natl. Acad. Sci. USA. 107:12251-12256.