Functional analysis of F-box proteins that are frequently rearranged in breast cancer.
Many genes are mutated in breast cancer by genome rearrangements—chromosome translocations, deletions, etc — and among the most frequently mutated are the uncharacterised genes FBXL17 and FBXL20. These genes encode F-box proteins, which regulate cellular pathways by ubiquitination. The aims of this project are to use ‘capture sequencing’ to analyse the mutations in FBXL17 and FBXL20, to determine the effect of the mutations on proteins, to perform high-throughput proteomic screening to find their ‘ubiquinomes,’ and to study the functional effects of FBXL mutations on their regulatory networks. We will establish which of these cellular pathways regulated by the Fbxl proteins are importantly altered in breast cancer and to identify pathways that are amenable to therapeutic targeting.
This project is funded through a Breast Cancer Now PhD scholarship.
D. E. Nelson, S. J. Randle and H. Laman. 2013. Beyond ubiquitination: The atypical functions of Fbxo7 and other F-box proteins. Open Biol. 3:130131.
V. S. Burchell*, D. E. Nelson*, A. Sanchez-Martinez*, M. Delgado-Camprubi, R. M. Ivatt, J. H. Pogson, S. J. Randle, S. Wray, P. A. Lewis, H. Houlden, A. Y. Abramov, J. Hardy, N. W. Wood, A. J. Whitworth, H. Laman and H. Plun-Favreau. 2013. The Parkinson’s disease genes Fbxo7 and Parkin interact to mediate mitophagy. Nat Neurosci. 2013 Aug 11. doi: 10.1038/nn.3489.
Newman S , Howarth KD, Greenman CD, Bignell GR, Tavaré S, Edwards PAW. (2013) The relative timing of mutations in a breast cancer genome. PLoS ONE. 2013;8:e64991.
Howarth KD, Pole JCM, Beavis JC, Batty EM, Newman S, Bignell GR, Edwards PAW. Large duplications at reciprocal translocation breakpoints that might be the counterpart of large deletions and could arise from stalled replication bubbles. Genome Research 2011; 21 (4) pp. 525-534.
D. E. Nelson, and H. Laman. 2011. J Biol Chem. 286(22):19804-15. A competitive binding mechanism between Skp1 and Exportin (CRM1) controls the localisation of a subset of F-box proteins.
More information on the supervisor’s research can be found on their research group website here