ND8-NOS · The role of the ubiquitin-like molecule NEDD8 in nucleolar signalling

Ubiquitin and ubiquitin-like molecules (Ubls) such as SUMO and NEDD8 regulate myriad of biological processes. NEDD8 was discovered as one of 10 genes that are down regulated in mice brains during development. Amongst the family of Ubls, NEDD8 has the highest homology and identity to ubiquitin, but a distinct conjugation pathway exists that leads to the covalent conjugation of NEDD8 to substrate proteins. Genetic experiments in plants, S. pombe, Drosophila, C. elegans, and mice, have demonstrated a vital role for NEDD8 in cell growth, viability and development. However, compared to ubiquitination or SUMO conjugation much less is known about molecular targets and pathways controlled by NEDD8.We established proteomic methods to identify NEDDylated proteins, which showed that the NEDD8 proteome is more diverse than previously thought. Following on the proteomic studies we discovered a new role for NEDD8 in controlling the function of the nucleolus as a sensor of perturbations in cell growth. Additional proteomic studies defined the molecular changes in the nucleolar proteome caused by inhibition of NEDDylation, establishing the nucleolus as key target for the NEDD8 pathway. Recently, we developed a genetic model system (C. elegans) for components of the NEDD8 machinery. Our goal is to capitalize on these discoveries and further develop an internationally competitive research program in: The role of NEDD8 in controlling the nucleolus and to establish genetic model systems for nucleolar signalling.As inhibitors of NEDDylation are in clinical trials for the treatment of cancer, we believe our studies will also identify targets and mechanisms for the action of these potential chemotherapeutics.