Paul Nurse

 

Global cellular controls in eukaryotic cells

The laboratory is interested in the global networks that regulate the eukaryotic cell cycle, cell form and cell growth. These processes are central to the development of living organisms and can become deregulated in disease states. We take a multidisciplinary approach to the study of these problems, and explore a variety of methodologies when trying to tackle them.

A potential PhD project would investigate the regulation of the cell cycle control and the influence of cell size over this control.  The regular cylindrical shape and well characterised cell cycle control network of fission yeast (Schizosaccharomyces pombe) makes it ideal for this project:  extensive genetic, genomic, chemical and cell biological tools and resources offer unique opportunities to gain insights into this problem.

The advent of new single cell methodologies provides new approaches.  In the lab, we use microfluidics devices, advanced fluorescence microscopy and automated image analysis to extract phenotypic information from populations of growing cells. We are developing synthetic and chemical biology approaches to combine with imaging to provide direct readouts of cellular physiology in real time at the single cell level.  Because much cell regulation involves protein kinases the laboratory also makes extensive use of phosphoproteomic analyses.

Analysis of the large-scale data sets generated from these approaches benefits from a computational approach. Experimentally driven mathematical modelling can enhance our understanding of potential cell size control mechanisms.

Investigation of the molecular mechanisms of cell size control will benefit from the wide range of genetic tools available in S. pombe, for example genome-wide gene deletion collections and a fluorescently tagged cDNA library. An extensive array of phenotypic information provided by screens in the lab (Kim et al, 2010), (Navarro & Nurse, 2012), (Moris N et al, 2016) provides a rich resource of candidate regulators. A previously developed minimal cell cycle control network (Coudreuse & Nurse, 2010) provides a simplified system in which to study cell cycle control.  This engineered strain is driven by a single cyclin dependent kinase (CDK), and has led to a new model that major temporal order in the cell cycle is brought about by increasing CDK activity combined with different substrate sensitivity (Swaffer et al 2016).

Other projects studied in the laboratory relevant to global cellular controls are what determines the size of the membrane bound nucleus, and how the TOR pathway regulates overall cellular growth.  The precise project a student will follow will be developed with the supervisor and driven by the individual student's interests and curiosities.  The range of methodologies used will depend on the nature of the research question. This provides a unique PhD experience, allowing independence and the creative freedom to investigate your interests with support, training and guidance from other lab members.

1. Kim, D.-U., Hayles, J., Kim, D., Wood, V., Park, H.-O., Won, M., Yoo, H.-S., Duhig, T., Nam, M., Palmer, G., Han, S., Jeffery, L., Baek, S.-T., Lee, H., Shim, Y. S., Lee, M., Kim, L., Heo, K.-S., Noh, E. J., Lee, A.-R., Jang, Y.-J., Chung, K.-S., Choi, S.-J., Park, J.-Y., Park, Y., Kim, H. M., Park, S.-K., Park, H.-J., Kang, E.-J., Kim, H. B., Kang, H.-S., Park, H.-M., Kim, K., Song, K., Song, K. B., Nurse, P. and Hoe, K.-L. (2010)
Analysis of a genome-wide set of gene deletions in the fission yeast Schizosaccharomyces pombe.
Nature Biotechnology 28: 617-623. PubMed abstract

2. Navarro, F. J. and Nurse, P. (2012)
A systematic screen reveals new elements acting at the G2/M cell cycle control.
Genome Biology 13: R36. PubMed abstract

3. Moris, N., Shrivastava, J., Jeffery, L., Li, J.-J., Hayles, J. and Nurse, P. (2016)
A genome-wide screen to identify genes controlling the rate of entry into mitosis in fission yeast.
Cell Cycle 15: 3121-3130. PubMed abstract

4. Coudreuse, D. and Nurse, P. (2010)
Driving the cell cycle with a minimal CDK control network.
Nature 468: 1074-1079. PubMed abstract

5. Swaffer, M. P., Jones, A. W., Flynn, H. R., Snijders, A. P. and Nurse, P. (2016)
CDK substrate phosphorylation and ordering the cell cycle.
Cell 167: 1750-1761.e1716. PubMed abstract