Overview
Deubiquitylases (DUBs) are an emerging class of drug targets, with around 100 enzymes forming this diverse family. Their therapeutic potential is increasingly recognised—most notably with USP1 and USP30 inhibitors now progressing through clinical trials in ovarian cancer and Parkinson’s disease. This studentship aims to broaden the landscape of DUB-focused drug discovery by investigating a largely unexplored DUB which we have linked to glioblastoma and cellular DNA damage repair pathways.
About this opportunity
This project will uncover the physiological role of this enzyme using advanced cell-based models, while in parallel driving early-stage development of small-molecule inhibitors. The dual biological and translational focus offers the opportunity to contribute to both mechanistic understanding and the identification of future therapeutic leads.
The supervisory team members are internationally active in ubiquitin signalling, DNA repair, and DUB inhibitor discovery. The successful candidate will receive comprehensive training in molecular and cell biology, including CRISPR/Cas9 genome editing, protein purification and characterisation, and a range of imaging- and viability-based assays. Mechanistic studies will involve protein depletion and rescue experiments, while cellular responses to radiation, replication stress, and DNA-damaging agents will be assessed using automated colony-formation assays and immunofluorescence of repair complexes.
Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of-the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, training opportunities or internships in science policy, science communication and beyond.
Further information on the programme and instructions on how to apply, including a link to the application portal, can be found on our website https://www.dimen.org.uk/
Further reading
1. Rusilowicz-Jones,E.V, Barone,F., Martins Lopes, F., Stephen,E., Mortiboys,H., Urbé,S., and Clague,M.J. (2022) Benchmarking a highly selective USP30 inhibitor for enhancement of mitophagy and pexophagy. Life Science Alliance, e202101287 doi: 10.26508/lsa.202101287.
2. Clague,M.J., Urbé,S. and Komander,D. Breaking the chains: deubiquitylase specificity begets function. (2019) Nature Reviews in Molecular Cell Biology, 20, 338-352 doi: 10.1038/s41580-019-0099-1.
3. Turnbull,A.P., Ioannidis,S., ….. Clague,M.J., Kessler,B., Komander,D. (2017) Molecular basis of USP7 inhibition by selective small molecule inhibitors, Nature, 550, 481-486. doi: 10.1038/nature24451