Modulation of E3 ubiquitin ligase activity in cell cycle and cancer: classical oscillations and neomorphic mutations
Thursday 25 May 2023
Joint MRC PPU and CeTPD Seminar, Vincenzo D’Angiolella, Oxford Institute for Radiation Oncology
University of Dundee
Dundee DD1 5HL
Host: Professor Satpal Virdee & Professor Alessio Ciulli
Location: Small Lecture Theatre: Medical Sciences Institute, SLS
Vincenzo D’Angiolella is an Associate Professor at the Oxford Institute for Radiation Oncology. His research group focuses on understanding the role of the ubiquitin system in cancer pathogenesis and response to treatment with chemo- and radiotherapy.
He is currently holding two programme grants from the Cancer Research UK (CRUK) and Medical Research Council (MRC), focused on the role of Cullin Ring ubiquitin Ligases (CRLs) in brain cancers (medulloblastoma and glioblastoma) pathogenesis. Studies from his laboratory have uncovered the mechanism of action and function of Fbxl17 in medulloblastoma (Raducu et al., 2016) and highlighted a novel synthetic lethal interaction between cyclin F loss and Chk1 kinase inhibition (Burdova et al., 2019). More recently, the laboratory has identified that mutations occurring on the E3 ligase KBTBD4 in medulloblastoma change substrate specificity driving the recognition of the chromatin remodelling complex CoREST (Chen et al., 2022). This work describes the first neomorphic mutation in an E3 ubiquitin ligase and elucidates a novel mechanism of tumorigenesis in medulloblastoma.
Vincenzo has a Medical Degree (MD) from the University of Naples “Federico II” and completed his PhD at the same University in the field of General Pathology. During his PhD utilizing X. Laevis as a model system, he investigated the process of mitosis and spindle checkpoint (D'Angiolella et al., 2001; D'Angiolella et al., 2003; D'Angiolella et al., 2007)
Following the completion of his studies, he worked as a postdoctoral fellow at the New York University School of Medicine in the USA in the laboratory of Professor Michele Pagano. During the postdoctoral studies, he elucidated the mechanism-of-action and function of cyclin F, the founding member of the F-box proteins. He uncovered that cyclin F does not partner with Cyclin Dependent Kinases (CDKs) like other cyclins do, but acts as an E3 ubiquitin ligase, forming a canonical CRL1 (D'Angiolella et al., 2012; D'Angiolella et al., 2010).
Burdova, K., Yang, H., Faedda, R., Hume, S., Chauhan, J., Ebner, D., Kessler, B.M., Vendrell, I., Drewry, D.H., Wells, C.I., et al. (2019). E2F1 proteolysis via SCF-cyclin F underlies synthetic lethality between cyclin F loss and Chk1 inhibition. EMBO J 38, e101443.
Chen, Z., Ioris, R.M., Richardson, S., Van Ess, A.N., Vendrell, I., Kessler, B.M., Buffa, F.M., Busino, L., Clifford, S.C., Bullock, A.N., et al. (2022). Disease-associated KBTBD4 mutations in medulloblastoma elicit neomorphic ubiquitylation activity to promote CoREST degradation. Cell Death Differ.
D'Angiolella, V., Costanzo, V., Gottesman, M.E., Avvedimento, E.V., Gautier, J., and Grieco, D. (2001). Role for cyclin-dependent kinase 2 in mitosis exit. Curr Biol 11, 1221-1226.
D'Angiolella, V., Donato, V., Forrester, F.M., Jeong, Y.T., Pellacani, C., Kudo, Y., Saraf, A., Florens, L., Washburn, M.P., and Pagano, M. (2012). Cyclin F-mediated degradation of ribonucleotide reductase M2 controls genome integrity and DNA repair. Cell 149, 1023-1034.
D'Angiolella, V., Donato, V., Vijayakumar, S., Saraf, A., Florens, L., Washburn, M.P., Dynlacht, B., and Pagano, M. (2010). SCF(Cyclin F) controls centrosome homeostasis and mitotic fidelity through CP110 degradation. Nature 466, 138-142.
D'Angiolella, V., Mari, C., Nocera, D., Rametti, L., and Grieco, D. (2003). The spindle checkpoint requires cyclin-dependent kinase activity. Genes Dev 17, 2520-2525.
D'Angiolella, V., Palazzo, L., Santarpia, C., Costanzo, V., and Grieco, D. (2007). Role for non-proteolytic control of M-phase-promoting factor activity at M-phase exit. PLoS One 2, e247.
Raducu, M., Fung, E., Serres, S., Infante, P., Barberis, A., Fischer, R., Bristow, C., Thezenas, M.L., Finta, C., Christianson, J.C., et al. (2016). SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development. EMBO J 35, 1400-1416