Regulation of the ubiquitin system in cancer

Virtually all signalling pathways are regulated by ubiquitin/Ub-like molecules (Ub/Ubls). The role of Neural precursor cell Expressed, Developmentally Down-regulated 8 (NEDD8) Ubl protein in viability, growth and development is well established. NEDD8 best-characterised role is the regulation of the Cullin RING E3 Ub ligases (CRLs). Covalent modification of CRLs by NEDD8 (NEDDylation) increases protien ubiquitylation. The COP9 signalosome (CSN) by deNEDDylating CRLs controls their function. Therapeutic targeting of the NEDD8 pathway is being explored in clinical trials for cancer, with the MLN4924 inhibitor. The rational for targeting the NEDD8 pathway emerged from the following points; (i) the clinical use of proteasome inhibitors (e.g. Bortezomib) in the treatment of myelomas and lymphomas; (ii) NEDD8 conjugation is essential for cell viability, through the CRL-dependent link to the ubiquitin-proteasome system; (iii) the observation that increased NEDDylation levels have been detected in cancer. Although NEDD8 is essential in higher eukaryotes, relatively little is known regarding its regulation. We propose in this project to study NEDD8 regulation using biochemistry and molecular, cellular and structural biology, particularly in the context of diffuse large B-cell lymphomas (DLBCL). This project would require a highly motivated candidate, is willing to learn different techniques, including gene editing using CRISPR-Cas9, mammalian cell culture, X-ray crystallography, NMR. The student will join a well-established and vibrant lab and work in collaboration with colleagues at the University of Nottingham (Prof Mark Searle) and in Montpellier (Dr Dimitris Xirodimas).