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Student project- Investigating the role of E3 Ubiquitin ligases in the cancer responses to Ionising Radiation (IR)

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).  

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.

Vincenzo D'Angiolella

Associate Professor

Research Summary

Our group objective is to understand the role of the ubiquitin system in cancer cell survival and response to radiation treatment. Further investigation in this process will prove to be a powerful tool for the design and implementation of novel cancer treatments

GROUP MEMBERS

Luke Humphreys, Postdoctoral Researcher
Rafael Maciel Ioris, Postdoctoral Researcher
Hongbing Yang, Postdoctoral Researcher
Paul Smith, Postdoctoral Researcher
Shahd Maneh Fouad, DPhil Student
Katherine Ferris, DPhil Student

Vincenzo D'Angiolella's Group

(l to r):   Rafael Maciel Ioris, Luke Humphreys, Shahd Maneh Fouad, Hongbing Yang
(l to r): Rafael Maciel Ioris, Luke Humphreys, Shahd Maneh Fouad, Hongbing Yang

COLLABORATORS

Professor Benedikt Kessler, Nuffield Department of Medicine, Oxford
Professor Alex Bullock, Nuffield Department of Medicine, Structural Genomic Consortium, Oxford
Professor Andrei Chabes, Department of Medical Biochemistry and Biophysics, Umeå University, Sweden
Professor Skirmantas Kriaucionis, Nuffield Department of Medicine, Ludwig Cancer Institute, Oxford

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 and his laboratory discovered functions of cyclin F (FBXO1), the founding member of the F-box family of Cullin-RING ubiquitin ligases. (B) BTB-Kelch proteins 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 Cereblon are bound by “molecular glue” drugs (e.g. lenalidomide) that enable the recruitment of neo-substrates (e.g. Ikaros) for ubiquitylation. Similarly, bifunctional small molecule PROTAC drugs can bind to the E3 ligase VHL to recruit neo-substrates (e.g. oncoproteins) for ubiquitylation and degradation .

Biography

Vincenzo D’Angiolella is a junior Group Leader at the Oxford Institute for Radiation Oncology. He 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. 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.

He has been awarded fellowships from AIRC (Associazione Italiana per la Ricerca sul Cancro) and AICF (American Italian Cancer Foundation) and was a Scholar of the Leukemia & Lymphoma Society from 2008 to 2011.