Principal Supervisor: Dr Clare Davies, Institute of Cancer and Genomic Sciences
Co-supervisor: Dr Aga Gambus, Institute of Cancer and Genomic Sciences
PhD project title: Exploring how arginine methylation impacts on DNA repair
The genome is constantly being challenged with exogenous and endogenous stresses that induce DNA lesions that must be repaired to maintain genomic stability. An inability to do so leads to mutagenic events that predispose individuals to numerous pathological conditions, including cancer and neurological dysfunction.
Dynamic regulation of protein function via post-translational modifications is an incredibly importantly regulator of the DNA damage response. Whilst this has been increasingly appreciated for protein phosphorylation and ubiquitination, other less-well characterised modifications have recently been shown to be equally important.
One such modification is the methylation of arginine residues, and whilst this modification was recognised more than 40 years ago, it is only with the recent identification of the enzymes that catalyse these reactions, PRMTs, that we are starting to understand the significance of arginine methylation for the DNA damage response. One way in which to explore this is through the identification of novel substrates. Recently, my laboratory has described PRMT5 as an essential component of the DNA damage response and the repair of double strand breaks through the methylation of RUVBL1 (Clarke et al., Molecular Cell, 2017). However, because different types of DNA damage require distinct pathways for repair, it is highly likely that PRMT5 is methylating other substrates in a DNA damage-dependent manner, or that histones themselves are subjected to modification.
This PhD project will further explore how arginine methylation impacts on the DNA repair process. This is a very exciting time for the field of arginine methylation as small molecular compounds that target specific PRMTs are in development. Hence, a better understanding of PRMTs during the DNA damage response may discover novel strategies in which to treat cancer or neurological disease.
- Clarke, T.L., Sanchez-Bailon, M.P., Chiang, K., et al. (2017) PRMT5-Dependent Methylation of the TIP60 Coactivator RUVBL1 Is a Key Regulator of Homologous Recombination. Molecular cell.
- Auclair, Y. and Richard, S. (2013) The role of arginine methylation in the DNA damage response. DNA repair.
BBSRC Strategic Research Priority: Molecules, Cells and Systems
Techniques that will be undertaken during the project:
The student will work mainly with human cell lines but will have the opportunity to conduct in vivo analysis using mouse models and biochemical studies using cell-free Xenopus laevis egg extract system. Techniques will include molecular biology, RNA interference, CRISPR-Cas9, protein biochemistry, cell biology, microscopy and mass spectrometry approaches.
Contact: Dr Clare Davies, Institute of Cancer and Genomic Sciences