Regulation of ribosomal quality control by E3 ubiquitin ligases

• PhD

Ribosomes are cellular factories that read the messenger RNA (mRNA) to produce new proteins. Damaged mRNA or cellular stresses lead to ribosomal stalling and collisions that are cleared by ribosomal quality control processes. In an ongoing project, we are investigating how the E3 ubiquitin ligase RNF14 ubiquitinates the ribosomal components elongation factor eEF1A and release factor eRF1 to resolve ribosomal stalling (unpublished).

In this project, students will now focus on the upstream and downstream processes of RNF14 activity to investigate 1) how RNF14 is recruited to the stalled ribosomes and activated, and 2) how RNF14-mediated ubiquitination leads to clearance of ribosomal stalling. Students will learn core techniques of the two labs, including recombinant protein expression and purification, structural biology, molecular biology and cell biology.

The Feltham and Lechtenberg labs study E3 ubiquitin ligases, enzymes that catalyse a cellular process termed ubiquitination. E3 ligases are molecular label makers that attach the small protein ubiquitin to other proteins to induce protein degradation or regulate protein activity, subcellular localisation or interactions. Ubiquitination provides a complex signalling code, regulates almost all processes inside the human cell and is a central player in human physiology and disease.

Our complementary interests cover a broad set of E3 ubiquitin ligase biology from structural and mechanistic work on E3 ligase catalysis and regulation to cell biology to understand the role of E3 ligases in cancer and inflammatory diseases. We aim to utilise these insights for drug discovery by developing E3 ligase inhibitors or targeted protein degraders (PROTACs).