About the Project
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 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 inactivated during infection by either proteasomal-mediated degradation and/or recruitment to viral replication centres or PML-containing nuclear tracks. Our laboratory has a strong track-record in this area and have published many papers in this area (please see references below for further details).
The aim of this studentship is to further our understanding of cellular DDR pathways and determine how adenoviruses target host cell DDR pathways in order to promote viral replication. We will use a combination of proteomics, live cell imaging and confocal microscopy to identify novel cellular proteins that are either targeted to viral replication centres and nuclear tracks during infection, and/or targeted for proteasomal-mediated degradation. Furthermore, we will use methods well-established in our laboratory to determine whether these cellular proteins function in DDR pathways. It is anticipated that results from this project will enhance our understanding of DDR pathways at the molecular level and give further insight into how adenovirus early region proteins regulate DDR pathways in order to promote viral replication.
Interested students should send a detailed CV and covering letter highlighting research experience and capabilities to Dr Andy Turnell at [Email Address Removed]
Forrester NA, Patel RN, Speiseder T, Groitl P, Sedgwick GG, Shimwell NJ, Seed R I, Ó Catnaigh P, McCabe CJ, Stewart GS, Dobner T, Grand RJ, Martin A, Turnell A S. (2012). Adenovirus E4orf3 targets Transcriptional Intermediary Factor 1gamma for proteasome-dependent degradation during infection. J. Virol. 86:3167-3179.
Turnell AS, Grand RJ (2012). Viral regulation of DNA damage response pathways. J. Gen. Virol. 93:2076-2097.
Blackford AN, Patel RN, Forrester NA., Theil K, Groitl P, Stewart GS, Taylor AMR, Morgan IM, Dobner T, Grand RJ, Turnell AS (2010). Adenovirus 12 E4orf6 inhibits ATR activation by promoting TOPBP1 degradation Proc. Natl. Acad. Sci. USA. 107:12251-12256.
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