PhD student profiles

     
     

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Chris Earl
Wellcome Trust 4-year Interdisciplinary PhD Programme, beginning in Autumn 2012

Project title
The role of uracil-DNA glycosylases in viral replication

Principle investigator: Dr Renos Savva, ISMB, Birkbeck
Co-investigators: Dr Tracey Barrett and Dr Mark Williams, ISMB, Birkbeck

 
Background

I studied chemical engineering and biotechnology at the University of Manchester graduating in 2012 (MEng (Hons)). My interest in structural biology led me to take on a thesis project concerned with benchmarking DyamO, a course-grain molecular dynamics program, for the purposes of ab initio protein folding simulations. I subsequently joined the ISMB as a PhD student on the Wellcome Trust 4-year interdisciplinary program in structural, chemical, and computational biology.

 
Rotation projects

In order to smooth the transition to a new field, I spent my first rotation in Prof. Peter Coveney’s group, the Centre for Computational Science. During this rotation, I produced a homology model of the HIV-1 intasome which I then used in molecular dynamics simulations using Gromacs. My second rotation was in Dr. Renos Savva’s lab where I chose to do my PhD (see below). I joined Prof. Alethea Tabor’s group for my chemical biology rotation where I solved the NMR structure of ring D of Nisin, a lanthionine-containing antibacterial peptide, in collaboration with Prof. Paul Driscoll.

 
PhD Project

Uracil-DNA glycosylases (UDGs) are highly conserved enzymes which catalyse the excision of uracil bases from DNA in vital cellular processes including DNA maintenance, innate immunity, and the development of acquired immunity. Some viruses encode proteins to disrupt host UDG activity whilst others hijack host UDGs for viral DNA maintenance. Kaposi’s sarcoma associated herpesvirus (KSHV or HHV8) utilises both a host UDG and its own UDG for different functions.

The KSHV life-cycle consists of a latent phase and a lytic phase. During the latent phase, the virus persists as an extrachromosomal episome and gene expression is highly restricted. For the purposes of viral DNA maintenance, KSHV has evolved a mechanism to recruit a human uracil-DNA glycosylase (UNG2) using its latency associated nuclear antigen protein (LANA). During the lytic phase, UNG2 is unavailable in sufficient quantities to maintain the viral genome and so KSHV encodes its own UDG (KSHV UNG). Although KSHV UNG is a functional UDG, it also has a non-canonical (and not well-studied) role as a structural element in the viral DNA replication machinery and a factor influencing the structure and organisation of the viral genome. This role of KSHV UNG involves a direct protein-protein interaction with the KSHV DNA polymerase processivity factor (PF-8).

Since there are no published structures and little biophysical data concerning UDGs in complex with herpesviral proteins, we aim to further our understanding of the way in which KSHV utilises UDGs by structural and biophysical characterisation of KSHV UNG in complex with PF-8, and UNG2 in complex with LANA.

 

 

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