Reversible ubiquitylation and phosphorylation are fundamental processes that control cellular signalling through regulation of protein stability and function. Ubiquitylation is controlled by reversible actions of E3 ubiquitin ligases and deubiquitylases, while phosphorylation is controlled by protein kinases and phosphatases. Abnormal protein function caused by dysregulated phosphorylation and ubiquitylation can lead to many human diseases, such as neurodegeneration and cancer. By targeting intracellular proteins of interest with desired post-translational modifications, we can fundamentally alter their abundance and/or function and rewire cell signalling. Through the Affinity-directed PROtein Missile (AdPROM) system developed in the Sapkota lab, we have been able to target the degradation of endogenous proteins (Fulcher et al, 2017; Roth et al, 2020; Simpson et al, 2020), uncover novel degradation-capable E3 ubiquitin ligases (Roth et al, 2023), and redirect protein kinases (Fulcher et al, 2018) and phosphatases (Simpson et al, 2023) to new protein substrates to alter their cellular functions. This project will build on these developments and enable the prospective PhD candidate to develop innovative small molecule approaches (such as PROTACs and Phosphatase-targeting chimeras) that serve to redirect endogenous E3 ubiquitin ligase and protein phosphatase activities to challenging disease-causing protein targets that are otherwise deemed undruggable by conventional approaches. The successful PhD candidate will employ cutting-edge CRISPR/Cas9 genome editing, microscopy and mass-spectrometry technologies as well as state-of-the-art blend of molecular, biochemical, chemical and cell biology methodologies.

At the MRC PPU, as well as the possibility of a PhD in one particular lab, we offer the possibility of two 4.5-month rotations in labs of their choice. A range of other projects from MRC PPU scientists are advertised on this website. Rotations provide valuable experience and help with deciding on the choice of PhD project and research group.