Peter Thorpe

Mitotic Control Laboratory

We study the process of chromosome segregation when newly copied genetic material must be divided equally between the two nascent daughter cells. If this process is perturbed then the resulting cells do not inherit the correct complement of chromosomes and this is a hallmark of cancer cells.

We also explore the impact of asymmetric cell division on chromosome segregation. Asymmetric cell division is the process that underlies development and stem cell homeostasis. For example, in adult stem cell populations repeated asymmetric divisions maintain the stem cell population while simultaneously generating new, differentiated cells.

The goal of our lab is to determine how the mitotic spindle - the machinery that segregates chromosomes during division - maintains the integrity of the genome. Further, we seek to establish how spindle asymmetry is established and maintained over multiple divisions to create cell lineages.

Our model system is the budding yeast, Saccharomyces cerevisiae, which shows patterns of asymmetric division like those of more complex organisms. We employ high-throughput fluorescence microscopy techniques that allow us to rapidly screen the localisation, levels and dynamics of all yeast proteins. We have also developed systems to allow us to control the location of proteins within the cell, since a number of pathologies, including cancer, result in the alteration of protein localisation within the cell. Using these tools, we aim to identify the conserved mechanisms controlling mitotic spindle function, asymmetric division and lineage specification.

Fluorescent labelling of cellular components allows us to identify changes in the structure and function of the machinery required to segregate chromosomes

Figure 1. Fluorescent labelling of cellular components allows us to identify changes in the structure and function of the machinery required to segregate chromosomes

For example, we are testing how components of the kinetochore, a protein complex that anchors chromosomes to the spindle, are regulated by phosphorylation and ubiquitylation. We are also exploring emerging links between the kinetochore and the process of DNA repair.

As part of these studies we are working to construct systems-level datasets that describe the localisation and concentration of every protein, throughout the cell cycle and in every viable yeast mutant. We are also making a topographical database of all protein localisations that lead to growth defects. These bioinformatic resources would help us understand how proteins operate together spatially to control cellular functions.

High-density arrays of yeast allow us to identify changes in protein location that affect cell growth

Figure 2. High-density arrays of yeast allow us to identify changes in protein location that affect cell growth

Peter Thorpe

peter.thorpe@crick.ac.uk
+44 (0)20 379 62403