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Global cellular controls in eukaryotic cells


PhD Programme

Dr P Nurse Wednesday, November 11, 2020 Funded PhD Project (Students Worldwide)

About the Project

This 4-year PhD studentship is offered in Dr Paul Nurse’s Group based at the Francis Crick Institute (the Crick).

The Cell Cycle Laboratory works on how the cyclin dependent kinases (CDKs) ensure orderly progression through the events of the eukaryotic cell cycle, particularly the onset of S-phase and of mitosis. The lab has proposed a model whereby cell cycle temporal order is brought about by rising CDK activity, with low activity phosphorylating substrates required for S-phase and high activity phosphorylating substrates for mitosis. The level of CDK activity in the cell is correlated with the increasing cell mass that occurs during the cell cycle.

The potential PhD project will investigate this model of cell cycle control, working on the fission yeast Schizosaccharomyces pombe. This organism has been used for many years for study of eukaryotic cell cycle control, and has an extensive range of resources available for its study including genetic, genomic, chemical, cell biological and molecular biological tools. It has the most complete genome wide gene deletion collection available for any eukaryote. This collection has allowed the identification of the majority of genes required for the cell cycle and a sub-set of these genes which control cell cycle progression and CDK regulation.

The project has a number of different aspects that can be pursued as a PhD student. One is how the cell determines its size and feeds this information into CDK activity. Candidate molecules have been identified which regulate CDK activity and which change in level as cell size increases. These molecules need to be investigated to determine if and how they function in a cell size monitoring mechanism. A second aspect is how CDK activity is regulated by ploidy, because cells of higher ploidy divide at an increased cell size. Candidate molecular components are not known for this mechanism, but possible molecules might be titrated out by fixed numbers of sites on structures which increase when ploidy increases, for example chromatin and the centrosome. A third aspect is how the different CDK substrates have differential sensitivities to rising CDK activity. This underpins the temporal order of S-phase and mitosis during the cell cycle. Possible mechanisms are a role for cellular localisation of either the CDK or its substrates, the presence of accessory proteins binding CDK, inherent differences in substrate proteins which determine their ability to act as substrates, and the role of phosphatases dephosphorylating CDK substrates. All of these mechanisms can be investigated. Related to this problem are potential positive feedback controls which turn the analogue cell cycle increase in CDK activity into digital outputs, such as the onset of S-phase and mitosis.

All the tools and methodologies necessary are available to investigate these problems. The precise project will be developed with me and will be 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 myself and other lab members.

Candidate background

An enthusiast who is highly curious about how cells work, and is passionate about finding out how they work. It would be good if they are interactive, open to new ideas, and like broadly scoped questions.


Talented and motivated students passionate about doing research are invited to apply for this PhD position. The successful applicant will join the Crick PhD Programme in September 2021 and will register for their PhD at one of the Crick partner universities (Imperial College London, King’s College London or UCL).

Applicants should hold or expect to gain a first/upper second-class honours degree or equivalent in a relevant subject and have appropriate research experience as part of, or outside of, a university degree course and/or a Masters degree in a relevant subject.

APPLICATIONS MUST BE MADE ONLINE VIA OUR WEBSITE https://www.crick.ac.uk/careers-and-study/students/phd-students BY 12:00 (NOON) 12 November 2020. APPLICATIONS WILL NOT BE ACCEPTED IN ANY OTHER FORMAT.

Funding Notes

Successful applicants will be awarded a non-taxable annual stipend of £22,000 plus payment of university tuition fees. Students of all nationalities are eligible to apply.

References

1. Coudreuse, D. and Nurse, P. (2010)

Driving the cell cycle with a minimal CDK control network.

Nature 468: 1074-1079. PubMed abstract

2. 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

3. Swaffer, M.P., Jones, A.W., Flynn, H.R., Snijders, A.P. and Nurse, P. (2018)

Quantitative phosphoproteomics reveals the signaling dynamics of cell-cycle kinases in the fission yeast Schizosaccharomyces pombe.

Cell Reports 24: 503-514. PubMed abstract

4. Patterson, J.O., Rees, P. and Nurse, P. (2019)

Noisy cell-size-correlated expression of Cyclin B drives probabilistic cell-size homeostasis in fission yeast.

Current Biology 29: 1379-1386.e1374. PubMed abstract

5. Basu, S., Roberts, E.L., Jones, A.W., Swaffer, M.P., Snijders, A.P. and Nurse, P. (2020)

The hydrophobic patch directs cyclin B to centrosomes to promote global CDK phosphorylation at mitosis.

Current Biology 30: 883-892.e884. PubMed abstract


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