Seminar

The ubiquitin-like molecule NEDD8 under stress

Dimitris Xirodimas, PhD

Cells constantly respond to cellular stress that causes protein or DNA/RNA damage. Defects in repair or elimination of the damage can lead to many diseases including neurodegeneration and cancer. To prevent this toxicity, cells have evolved many protein quality control processes that cooperate to maintain protein homeostasis. Main effectors and regulators of such processes are the Ubiquitin and the Ubiquitin-like molecules (Ubls). Dr. Dimitris Xirodimas lab is interested in the Ubiquitin-like molecule NEDD8 (neural-precursor-cell-expressed developmentally down-regulated 8) that shares the highest sequence homology to Ubiquitin (60%). NEDD8 uses the same three-step process to modify substrates but employs its own and specific NEDD8 E1 activating enzyme (NAE), E2 conjugating enzymes and E3-ligases. NEDDylation is essential for the viability of many organisms and deregulation of this pathway has been linked to developmental abnormalities, cancer progression and neurodegenerative disorders. However, compared to ubiquitination or SUMO conjugation much less is known about molecular targets and pathways controlled by NEDD8. Furthermore, their knowledge on the NEDD8 response to stress is very limited. Their team’s general research aims are to identify and characterise novel substrates for NEDD8 and understand how NEDDylation is controlled, especially under cellular stress conditions. This area of research becomes increasingly important as NEDD8 inhibitors (MLN4924) are in clinical trials for the treatment of cancer. They are using biochemical, biological, proteomic and currently developing genetic approaches (C.elegans) to address the above biological questions.