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Project title: Synthetic/chemical biology approaches to identify novel interactions in the DNA-damage response


Institute of Cancer and Genomic Sciences

About the Project

The DNA-damage response (DDR) is underpinned by a complex set of signalling pathways involving interactions that are often regulated by post-translation modifications (PTMs). In most cases the physiological effects of these modifications are unknown but it has become clear that many act as molecular ‘switches’, signalling the spatially and temporally appropriate formation of protein assemblies. Of the many known PTMs, phosphorylation is arguably the most important and abundant and we now know of several proteins and domains that are able to specifically ‘read’ phosphorylated motif signatures in target proteins. Nonetheless, the range of interactions regulated in this way remains frustratingly unclear.

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.

References

1. Hořejší, Z., Stach, L., Flower, T.G., Joshi, D., Flynn, H., Skehel, J.M., O’Reilly, N.J., Ogrodowicz, R.W., Smerdon, S.J.*, Boulton, S.J. (2014) ‘CK2-dependent PIH1D1 interactions define substrate specificity of the R2TP co-chaperone complex’ Cell Reports, 7, 19-26.

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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