Ubiquitylation is one of the cell’s most powerful control switches, fine-tuning everything, from protein stability to gene expression. When this system malfunctions, it fuels diseases including cancer, neurodegeneration and immunity disorders. This PhD project will focus on exploring non-canonical ubiquitylation - a paradigm-shifting discovery where ubiquitin tags not just lysine residues on proteins but also serine, threonine, DNA, RNA, and sugars. Decoding this hidden molecular “language” of ubiquitin could transform our understanding of cell regulation and uncover untapped therapeutic possibilities.

Recent work in the De Cesare lab has identified the UBE2Q family of ubiquitin-conjugating enzymes (UBE2Q1, UBE2Q2, and UBE2QL1) as key mediators of non-canonical ubiquitylation[1]. These enzymes are linked to vital processes such as lysophagy and embryo implantation and are dysregulated in cancer and neuronal apoptosis - pointing to a widespread but hidden role in human health and disease.

As the PhD candidate, you will:

• Define the biological functions of the UBE2Q enzyme family, identifying and validating their substrates, and uncovering novel disease pathways and therapeutic targets.
• Map non-canonical ubiquitylation events at a proteome-wide scale using cutting-edge quantitative proteomics.
• Dissect molecular mechanisms using a multidisciplinary toolkit: structural biology, molecular and cell biology, protein biochemistry, and biophysics.

The De Cesare lab houses a world-leading high-throughput MALDI-TOF/MS platform [2, 3] - uniquely optimized to interrogate ubiquitin enzymes with precision and scale. The lab is embedded within the MRC Protein Phosphorylation and Ubiquitylation Unit, an internationally recognised centre with a strong culture of collaboration with both academia and industry.

By the end of this PhD, you will be proficient in high-throughput MALDI-TOF/MS, quantitative proteomics, protein biochemistry, molecular and cell biology and data analysis, equipped with a broad, transferable skill set that will open career opportunities across academia, biotechnology, and pharmaceutical research.

We welcome highly motivated and curious candidates who want to explore uncharted scientific territory and make discoveries with real biomedical impact.

References

1. Abdul Rehman, S.A., et al., Discovery and characterization of noncanonical E2-conjugating enzymes. Sci Adv, 2024. 10(13): p. eadh0123.

2. De Cesare, V., et al., High-throughput matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry-based deubiquitylating enzyme assay for drug discovery. Nat Protoc, 2020. 15(12): p. 4034-4057.

3. De Cesare, V., et al., Deubiquitinating enzyme amino acid profiling reveals a class of ubiquitin esterases. Proceedings of the National Academy of Sciences, 2021. 118(4): p. e2006947118.