Targeting proteasome assembly to uncover cancer vulnerabilities

• 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. 

Cancer cells must continually remove damaged and unwanted proteins to sustain rapid growth and survive cellular stress. This creates a strong dependence on the proteasome, the molecular machinery responsible for much of the cell’s controlled protein degradation. Although drugs that block proteasome activity have transformed   treatment for some blood cancers, resistance and limited efficacy in other cancers highlight the need to explore new approaches. Could preventing proteasomes from       assembling expose a vulnerability in cancer cells?

This PhD will investigate that possibility using our newly developed 26S-splitNanoLuc technology. This sensitive, light-producing reporter allows us to monitor the           assembly of the 26S proteasome in living cells, providing a powerful platform for discovering molecules that interfere with its formation or stability.

Based in the Rousseau laboratory at the University of Dundee, you will work with the Dundee Drug Discovery Unit to identify candidate proteasome assembly inhibitors through high-throughput small-molecule screening. You will validate promising compounds using complementary biochemical and cellular approaches. You will then       investigate how these compounds affect protein degradation, cellular stress and survival, testing whether cancer cells are particularly vulnerable to this intervention.

Beyond their potential therapeutic value, these molecules will serve as experimental tools to explore how cancer cells respond and adapt to impaired proteasome assembly. You will investigate the mechanisms that enable cells to survive reduced protein degradation capacity and ask whether disrupting these adaptations increases their sensitivity to proteasome assembly inhibitors. This work could reveal fundamental principles of cellular resilience and identify vulnerabilities to guide future combination strategies.

You will receive interdisciplinary training in quantitative luminescence assays, high-throughput screening, human cell culture, CRISPR/Cas9 genome engineering, protein biochemistry and advanced microscopy. You will learn to design rigorous experiments, analyse quantitative datasets and connect molecular changes with cellular           behaviour, gaining experience at the interface of fundamental biology and drug discovery.

Through supportive supervision and EASTBIO’s wider training programme and student network, you will also develop scientific communication, collaboration and           independent research skills relevant to careers in academia and biotechnology.

This project offers an opportunity to discover new chemical tools, explain how cancer cells withstand disruption of an essential process, and explore an emerging route  towards therapeutic intervention.

Our research community thrives on the diversity of students and staff which helps to make the University of Dundee a UK university of choice for postgraduate research. We welcome applications from all talented individuals and are committed to widening access to those who have the ability and potential to benefit from higher education.