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Investigating the role of E3 ubiquitin ligases in cancer pathogenesis


   Department of Oncology

  ,  Friday, December 09, 2022  Competition Funded PhD Project (Students Worldwide)

About the Project

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, 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. 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.  


References

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.

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