Ubiquitin signaling in the pathogenesis and treatment of glioblastoma
Glioblastoma is the most common primary brain tumor in adults with a dismal prognosis of only 12 -15 months survival. Treatment consists of maximal surgical resection, followed by radiotherapy and chemotherapy. The treatment paradigm has not changed since the 70’s and doctors are in dire need of novel targets and compounds to increase patient survival. The D’Angiolella laboratory uses mass spectrometry, CRISPR, biochemistry and cell biology techniques to investigate the role of the Ubiquitin-Proteaome System (UPS) in brain tumor development with the goal of identifying new therapeutic approaches1-4.
The UPS is crucial for cell survival as it directs the fate of proteins in the cells by tagging them with ubiquitin. The UPS is amenable to specific chemical activation and inhibition however; the role of the UPS in glioblastoma development and response to radiotherapy is unknown. The laboratory has performed high-resolution CRISPR screens to identify key therapeutic vulnerabilities of glioblastoma in combination with radiotherapy. Students will study novel enzymes as therapeutic targets for glioblastoma, and interact with medicinal chemists to generate novel compounds. Training will be provided in techniques such as CRISPR and super-resolution microscopy. The laboratory offers the possibility to attend specialty courses (EMBO and others) and international conferences. Secondary supervision will be provided by Francesca Buffa. Funding for this project will be provided through a CRUK/MRC Oxford Institute for Radiation Oncology Studentship.
- D'Angiolella, V. et al. Cyclin F-mediated degradation of ribonucleotide reductase M2 controls genome integrity and DNA repair. Cell 149, 1023-1034, doi:10.1016/j.cell.2012.03.043 (2012).
- D'Angiolella, V. et al. SCF(Cyclin F) controls centrosome homeostasis and mitotic fidelity through CP110 degradation. Nature 466, 138-142, doi:10.1038/nature09140 (2010).
- Raducu, M. et al. SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development. The EMBO journal 35, 1400-1416, doi:10.15252/embj.201593374 (2016).
- Li, J. et al. USP33 regulates centrosome biogenesis via deubiquitination of the centriolar protein CP110. Nature 495, 255-259, doi:10.1038/nature11941 (2013).
Students are strongly advised to contact their prospective supervisor before applying to discuss their interest in the group’s research.