PhD Research Project: Investigating the dynamic regulation of PRMT5 activity during the DNA damage

Fully funded 4-year BBSRC iCASE PhD Studentship starting October 2018.

The DNA damage response is essential for maintaining genome stability and the prevention of diseases such as cancer and neurodegeneration. Post-translational modification of proteins is critically required for all types of DNA repair, and whilst this is well appreciated for ubiquitylation and phosphorylation, little is known about the importance of arginine methylation. We have recently shown that PRMT5, an enzyme that catalyses arginine methylation, is critical for double strand break repair via the methylation of RUVBL1 (Clarke et al Molecular Cell, 2017)). Interestingly, we have shown that the methylation of RUVBL1 is rapidly induced after DNA damage suggesting that PRMT5 activity is dynamically regulated in a context specific manner. Surprisingly, very little is known about how PRMT5 directs specific substrate methylation after a particular stimulus. Moreover, unlike lysine methylation, the identity of the in vivo arginine demethylase still remains elusive.

Using unique tools that the Davies lab has generated, this PhD project will further investigate the modulation of PRMT5 activity by post-translational modification downstream of DNA damage signalling, and utilise a CRISPR screen in conjunction with a custom epigenetic arrayed gRNA library to identify novel arginine demethylases. Methodologies used to address these questions will include protein biochemistry, enzyme assays, immunoblotting, appropriate cell biology assays, microscopy, CRISPR gene knockout and RNA interference in human cancer cell lines and mass spectrometry. This studentship is joint with AstraZeneca. He/she will be principally based in the Davies laboratory (University of Birmingham), but conduct a 3-6 month internship at AstraZeneca, Cambridge and attend regular meetings.

Person Specification

The Davies laboratory is part of the Institute of Cancer and Genomic Sciences and Birmingham Centre for Genome Biology (https://www.birmingham.ac.uk/research/activity/mds/centres/genome-biology/index.aspx), a grouping of laboratories specialising in DNA repair, epigenetics and gene expression, offering the student excellent training opportunities and mentoring. Applicants should have a strong background in cancer biology, DNA repair and protein biochemistry, and be excited to work in a highly dynamic and fast-paced research group. They should be ambitious, hard working and committed to their PhD programme, and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in a relevant subject.

How to apply

Informal enquiries should be directed to Dr. Clare Davies (c.c.davies@bham.ac.uk)

Applications should be directed to David Piela (d.piela@bham.ac.uk). To apply, please send:

• A detailed CV, including your nationality and country of birth;
• Names and addresses of two referees;
• A covering letter highlighting your research experience/capabilities;
• Copies of your degree certificates with transcripts;
• Evidence of your proficiency in the English language, if applicable.

Funding Notes

British and EU nationality applicants are eligible for both the cost of tuition fees and a yearly stipend over the course of the PhD programme.

References

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.