Investigating the role of E3 ubiquitin ligases in cancer pathogenesis
Primary Supervisor: Professor Vincenzo D’Angiolella
Project Overview:
The Ubiquitin Proteasome System (UPS) is a crucial regulator of cell survival in normal conditions and after DNA damage. The function of UPS is dysregulated in cancer, thus providing a large repertoire of targets to exploit for better cancer treatment. While there are more than 1000 genes composing the UPS, the function and mechanisms of action of the majority of them are unknown.
The mission of the D’Angiolella laboratory is to decipher the role of the E3 ubiquitin ligases Fig.1A, components of the UPS, in cancer pathogenesis and response to treatment with Ionising Radiation . The laboratory collaborates closely with structural biologists to decipher the role of Cul3 ubiquitin ligases (Fig.1B). The laboratory has conducted UPS focused CRISPR screens to have a system-wide view of the role of individual components of the UPS in the cellular responses to IR and cancer pathogenesis.
Investigation into the role of E3s will provide insights in the pathogenetic mechanisms of cancers and pose the basis for drug development through PROteolysis TArgeting Chimeras (PROTACs) and immunomodulatory IMiDs, such as lenalidomide (Fig.1C).
Figure 1. The modular architectures of Cullin-RING E3 Ligases (CRLs). (A) CRL1 ubiquitin ligase complexes are perhaps the best known examples and bind their substrates via an F-box containing subunit. D'Angiolella discovered the function of cyclin F (FBXO1), the founding member of the F-box family of Cullin-RING ubiquitin ligases3,4. (B) BTB-Kelch proteins, such as KBTBD4, assemble into CRL3 ubiquitin ligase complexes in which the BTB domain binds to Cullin3 and the Kelch domain forms the substrate recognition domain. (C) Some Cullin-RING ubiquitin ligase subunits, such as VHL, have been targeted by small molecule PROTACs. These bivalent molecules are designed to recruit neo-substrates (e.g. oncoproteins) to an E3 complex (e.g. CRL2VHL) for ubiquitylation and degradation2.
Training Opportunities:
Students will be trained in techniques such as high resolution CRISPR screens, biochemical assays and super resolution microscopy. There will be comprehensive training on methods to investigate the ubiquitin system including novel techniques and approaches for PROTACs generation. The laboratory offers the possibility to attend international courses (EMBO and others). Attendance to at least one international conference is guaranteed.
Relevant Publications:
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. and D’Angiolella, V., 2022. Disease-associated KBTBD4 mutations in medulloblastoma elicit neomorphic ubiquitylation activity to promote CoREST degradation. Cell Death & Differentiation, pp.1-15.
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(5), pp.1023-1034.
Burdova, K., Yang, H., Faedda, R., Hume, S., Chauhan, J., Ebner, D., Kessler, B.M., Vendrell, I., Drewry, D.H., Wells, C.I. and Hatch, S.B., 2019. E2F1 proteolysis via SCF‐cyclin F underlies synthetic lethality between cyclin F loss and Chk1 inhibition. The EMBO journal, 38(20), p.e101443.