Available PhD projects
Post-doc and PhD student enquiries will always be considered. Please attach your CV and email Kevin Hardwick.
» PhD studentship
Re-engineering the spindle checkpoint response in fission yeast
We study mitosis and chromosome segregation in yeast, with a particular focus on the spindle checkpoint. This cell cycle control monitors interactions between chromosomes and the mitotic spindle and delays mitotic progression until all pairs of sister chromatids are attached appropriately to spindle microtubules (1). We employ synthetic biology approaches to analyse this signalling pathway, and have now successfully generated a ‘wait anaphase’ signal entirely independently of kinetochores in fission yeast (2). This requires tethering of Mps1 kinase to one of its key substrates (3), thereby producing an active signalling scaffold that is sufficient to generate a prolonged metaphase arrest.
In this project you will employ a combination of synthetic biology, yeast genetics, biochemical purification, mass spectrometry and live-cell imaging to further characterise and gain control of this highly conserved checkpoint pathway. In particular you will dissect how yeast cells turn off their spindle checkpoint response. Our aim is to be able to rapidly turn the checkpoint on and off, at will, in fission yeast. Once we are able to do this, we will transfer this synthetic approach to the fungal pathogen Cryptococcus neoformans and study the consequences of prolonged mitotic arrest.
This project provides an excellent training opportunity, due to the breadth of approaches being employed in the model system, followed up with experiments in an important human pathogen.
(1) London, N. and Biggins, S. (2014). Signalling dynamics in the spindle checkpoint response. Nature Rev Mol Cell Biology, 15, 736-747.
(2) Yuan, I., Leontiou, I., Amin, P., May, K.M., Chafraidh, S.S., Zlamalova, E. and Hardwick, K.G. (2017). Generation of a spindle checkpoint arrest from synthetic signalling assemblies. Current Biology, 27, 137-143.
(3) Shepperd, L.A., et al. (2012). Phosphodependent recruitment of Bub1 and Bub3 to Spc7/KNL1 by Mph1 kinase maintains the spindle checkpoint. Current Biology, 22, 891-899.
All available positions in our lab and those at the University of Edinburgh are posted on the university's job site.