Uncovering the non-canonical proteolytic activity of Deubiquitinating enzymes

• Funding – BBSRC funded 4 year studentship, providing tuition fees, training/research costs and an annual stipend at the UKRI rate, currently £21,805
• Start Date – September 2027
• Applicants are expected to have a degree (equivalent of Honours or Masters) in a relevant discipline

One of the key challenges in molecular biology is understanding how post-translational modifications regulate protein function. Pathogens and cancer cells are highly effective at hijacking these mechanisms to advance their own agendas: degrading host defence proteins, disrupting genome-protective pathways, and promoting invasion and metastasis. Understanding how these modifications work at the molecular level could transform our understanding of cell regulation and uncover untapped therapeutic opportunities.

Recent work in the Maniaci lab has identified members of the USP family of ubiquitin-deconjugating enzymes (DUBs) as key operators of non-canonical deubiquitylation events we call "cleave-to-modify" [1] — a previously unrecognised layer of proteome regulation distinct from DUBs' canonical activity. These enzymes are linked to vital processes such as immune response and inflammation, and are dysregulated in cancer and neurodegenerative disorders, pointing to a widespread but hidden role in human health and disease.

As part of this project, you will use peptide-based tools and cleavage assays to define how USPs select their substrates, mass spectrometry-based proteomics to identify novel cleavage events across the proteome, and CRISPR-engineered cell lines to determine how this mechanism affects genome integrity, splicing fidelity, and cellular behaviour.

This is a discovery-driven project situated at the interface of enzymology, structural biology, and cell biology, offering scope to define a genuinely new area of protein    regulation. You will receive hands-on training and close mentorship from your supervisor and senior lab members, with regular lab meetings and journal clubs, opportunities to present at national and international conferences, and access to the wider collaborative network of the MRC PPU. The Maniaci lab is a young, dynamic, and supportive group, committed to your development as an independent scientist.

This studentship is well suited to candidates with a background in biochemistry, molecular or cell biology, or a related discipline, and an interest in acquiring skills across biochemistry, mass spectrometry, structural biology, and cell-based approaches.

References

Hales, L.T., Tammiste, P.M., Walker, A.J. et al. A Proteolytic Switch: USP5 controls SDE2 function via UBL-directed cleavage. Nat. Commun. (2026). https://doi.org/10.1038/s41467-026-76751-6

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