Martin Singleton


Structural biology of chromosome segregation

Our lab is interested in understanding the molecular mechanisms of chromosome segregation in eukaryotic cells. This precisely controlled process requires the coordinated action of many multi-protein complexes associated with chromosomes. We are particularly interested in the kinetochore and the cohesin complex. Kinetochores are the large proteinaceous structures that comprise the connection between chromosomes and the mitotic spindle. In addition to providing a physical link between these huge cellular components, the kinetochore is responsible for generating the spindle assembly checkpoint (SAC), which ensures that all chromatids are correctly attached to the spindle before anaphase onset. The duplicated sister chromatids themselves are held together by the cohesin complex, which ensures that each sister is physically linked from the time of DNA replication to anaphase. This large, ring-shaped complex is loaded onto, and removed from chromosomes in a multi-stage process. Some of the factors required for this process have been identified, but their exact activities are still not yet fully understood.

We are studying protein and protein-nucleic acid complexes involved both of these systems, primarily by X-ray crystallography and electron microscopy. By determining their three-dimensional structures we can generate hypotheses about the underlying mechanisms that can then be tested both in vitro and in vivo, and inform further structural approaches. We are seeking a motivated Ph.D. student who wishes to answer fundamental questions about the mechanisms of chromosome segregation using multiple biophysical, biochemical, and genetic techniques.

These are examples of the sorts of project that might be available in this research group. Only one studentship is available with this group and the precise project will be decided on consultation with the supervisor.

1. Losada, A. (2014)
Cohesin in cancer: chromosome segregation and beyond.
Nature Reviews Cancer 14: 389-393. PubMed abstract

2. Santaguida, S. and Musacchio, A. (2009)
The life and miracles of kinetochores.
EMBO Journal 28: 2511-2531. PubMed abstract

3. Chao, W. C. H., Wade, B. O., Bouchoux, C., Jones, A. W., Purkiss, A. G., Federico, S., O'Reilly, N., Snijders, A. P., Uhlmann, F. and Singleton, M. R. (2017)
Structural basis of Eco1-mediated cohesin acetylation.
Scientific Reports 7: 44313. PubMed abstract

4. Chao, W. C. H., Murayama, Y., Muñoz, S., Jones, A. W., Wade, B. O., Purkiss, A. G., Hu, X.-W., Borg, A., Snijders, A. P., Uhlmann, F. and Singleton, M. R. (2017)
Structure of the cohesin loader Scc2.
Nature Communications 8: 13952. PubMed abstract