Paul Nurse: Projects

Listed below are examples of specific projects that are currently of interest to the laboratory.

Monitoring cell size

A global cellular cell size control regulates cell cycle progression. Potential gene candidates for a network monitoring cell size can be identified as genes rate limiting for the G2 to M transition, as revealed by cell cycle haploinsufficient and small size at division screens carried out in the laboratory. These deletion mutants can be crossed into a strain harbouring the simplified minimalist CDK network with the Cdc2 YF15 mutation. This strain is not subject to much of the CDK regulatory network, but still has a cell size monitoring mechanism. Determining which deletion mutants still have an effect on cell size in this minimalist strain will identify those genes which are involved in the cell size monitoring mechanism.

Establishing nuclear size

A screen for altered nuclear size mutants has identified genes involved in determining nuclear size. Nuclear size is closely correlated with cell size, and a constant nuclear /cytoplasmic ratio is maintained as cells grow during the cell cycle, indicating that there is a mechanism linking cell size and nuclear size. Genes identified will be investigated to determine how they operate in this control. We speculate that the flow of membrane traffic regulates how much membrane is deployed to a specific organelle and that this is controlled by the size of the cell, or cell size regulates transport into the nucleus

CDK substrate phosphorylation turnover

Substrate phosphorylation by the CDK Cdc13-Cdc2 can be determined in vivo by switching off CDK activity using the Shokat inhibitor methodology. Phosphorylation of the proteome during this inhibition is being determined using mass spectrometry in collaboration with Bram Snidjers (Protein Analysis and Proteomics Laboratory). Both direct substrates as well as substrates that are indirectly dependent upon CDK activity are being identified. Inhibition of CDK activity followed by mass spectrometric analysis allows the turnover rate of individual phosphorylation sites to be determined at different stages of the cell cycle.

Cyclins and the minimalist cell cycle

Variations on the theme of the minimalist cell cycle for fission yeast are being investigated using different cyclins. They will be used to determine how they influence progression through the mitotic and meiotic cell cycles. Cyclins and CDK catalytic subunits are also being constructed and investigated using orthologous genes from other organisms.

Cell-cell variability

Molecules present in low copy number often govern cellular processes. As such, small variations in molecule number between cells can have large phenotypic consequences for the organism. Variability between cells in a population as a result of this noise is currently a poorly understood biological phenomenon. We are studying the biological implications of noise using the fission yeast cell cycle. New computational image analysis techniques are being developed to enable the tracking and analysis of hundreds of single cells per experiment, with new transcriptional and translational reporter constructs allowing measurements of gene expression variability in single live cells. The aim is to integrate these dynamic, time-lapse based approaches with imaging flow cytometry to dissect the origins and consequences of cell-cell variability.

New York satellite group

This laboratory is located at Rockefeller University, New York. This group is working on two projects, the spatial and temporal organization of origin firing during DNA replications, and the application of chemical biology techniques to fission yeast for the investigation of cell biology. The laboratory has developed DNA combing methods so that molecules up to 10Mb in length can be analyzed. These methods are being used to map active origin distribution both along chromosomes and during progression through S-Phase. In collaboration with Tarun Kapoor's Laboratory of Chemistry and Cell biology at Rockefeller University, strains have been developed that are more sensitive to drugs. These are being used to identify inhibitors of cell cycle progression and as tools to probe molecular function.

Paul Nurse

Paul.Nurse@crick.ac.uk
+44 (0)20 379 62495

  • Qualifications and History
  • 1973 PhD, University of East Anglia, UK
  • 1984 Imperial Cancer Research Fund (ICRF)  Group leader at Lincoln's Inn Fields (ICRF became Cancer Research UK in 2002
  • 1989 Professor of Microbiology at University of Oxford, UK
  • 1996 Director General of ICRF
  • 2002 Chief Executive Cancer Research UK
  • 2003 President of the Rockefeller University, USA
  • 2010 Director of the Francis Crick Institute