About the Project
This project seeks to address the generic problem of how to identify and match individual phosphorylation events to functional interactions that may be rather transient in nature, initially in the specific context the DDR. This will require a highly multi-disciplinary approach combining structural, chemical and synthetic biology methods, high-throughput expression/purification and mass spectrometry to interrogate the phospho-interactome of a key DDR signalling component, Nbs1. The focus will be to generate engineered Nbs1 variants that are able to trap interacting phospho-proteins allowing more robust identification than has previously been possible, thus expanding our systems-level understanding of the intricacies of DDR signalling pathways and networks.
Applicants should have a strong background in biochemistry, and ideally a background in molecular biology and/or chemistry. They should have a commitment to research in biomedicine and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in biochemistry.
2. Larsen, D.H., Hari, F., Clapperton, J.A., Gwerder, M., Gutsche, K., Altmeier, M., Jungmichel, S., Fink, D., Lukas, C., Nielsen, M.L., Smerdon, S.J., Lukas, J., Stucki, M. (2014) ‘The NBS1-TCOF1/Treacle complex controls ribosomal RNA transcription in response to DNA damage’ Nature Cell Biol. 16, 792-803.
3. Yata, K., Lloyd, J., Maslen, S., Skehel, M., Smerdon, S.J., Esashi, F. (2012) ‘Plk1 and casein kinase 2 act in concert to regulate Rad51 during recombinational repair’ Mol. Cell 45, 371-383.
4. Lloyd, J., Chapman, J.R., Clapperton, J.A., Haire, L.F., Hartsuiker, E., Li, J., Carr, A.M., Jackson, S.P., Smerdon, S.J. (2009) 'A supra-modular FHA/BRCT-repeat architecture mediates Nbs1 adaptor function in response to DNA-damage' Cell 139, 100-111.
5. Stucki, M., Clapperton, J.A., Mohammad, D., Yaffe, M.B., Smerdon, S.J.*, Jackson, S.P. (2005) 'Mdc1 directly associates with phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks' Cell 123, 1213-1226.
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