Our research questions:
Cell Division and Cancer
Errors in chromosome transmission alter the balance of tumour suppressor and tumour promoter genes to facilitate subsequent changes in genome composition in the ensuing cell divisions that can ultimately lead to transformation and cancer.
Cell cycle controls ensure that a cell does not commit to the segregation of its replicated genomes in mitosis until a number of criteria have been fulfilled. Mechanisms that couple mitotic commitment to growth and external stimuli are complimented by DNA integrity checkpoint pathways that block commitment when DNA is damaged or replication is incomplete. Once cells have entered mitosis, the spindle assembly checkpoint (SAC) ensures that the two chromatids are not separated until all of the chromosomes are appropriately attached to both spindle poles.
SAC signalling is generated from unattached kinetochores. Only when kinetochores are fully attached and correctly aligned, do the inhibitory SAC signals subside. The persistent SAC activation that arises from severe errors in chromosome segregation triggers apoptotic cell death to clear the damaged cell from the body. Because cancers are invariably aneuploid, they have an abnormally high load on their spindle assembly checkpoint. This excessive loading renders them especially sensitive to drugs that enhance SAC stimulation to extend the arrest to the point at which death is triggered. Consequently, the anti-mitotic impact of microtubule stabilisation by Taxol has been widely exploited in the clinic. Inappropriate entrance into mitosis with incompletely replicated or damaged DNA is equally effective at generating mitotic errors that extend SAC signalling into the death zone. Drugs that promote inappropriate mitotic commitment are therefore showing great promise as either single agents or in combination with DNA damaging agents in pre-clinical models.
Understanding Cancer through Model Systems
Simple, malleable model systems, such as the yeasts, worms and flies have exceptional track records in the discovery of the central players in many cellular and developmental processes. They have proved equally invaluable in defining the molecular function and control of individual components. It is becoming increasingly common to directly move from the definition of the function of an individual molecule in a model system to tackling the complexity of human cells without the intermediate step of defining the composition and control of the networks in the model before the move. While this may be beneficial in some instances, progress may well be more efficient when the questions/issues are clearly defined by exploiting the speed, simplicity and agility of the model before the move to the complexity of the human context.
Fission Yeast and Cell Cycle Control
Fission yeast are unicellular, free living, fungi whose prime objective is to grow and divide. They have a short cell division cycle of 2-4 hours, excellent cytology, exceptional mendelian genetics, biochemistry and molecular manipulation of the genome is routine. Most importantly, simple genetic crosses can combine mutations in a single haploid yeast in less than a week. Cell cycle progression can be synchronised throughout the population by either size selection, drug arrest/release or mutant manipulation. Biochemical changes in such bulk cultures accurately reflect the molecular changes occurring in each individual members of the culture. As the principle molecules that regulate progression through the cell division cycle are essentially the same in eukaryotes from yeast to man, many of the molecules that regulate cell division in humans were first identified in fission yeast (e.g. Cdk1, Wee1 and Cdc25). Equally importantly, the definition of principle cell cycle concepts such as checkpoint control emerged from studies in these malleable fungi.
Blue - cell wall, yellow - chromatin
The reduced complexity of yeasts avoids much of the molecular redundancy that can obscure key switches in human cells. The ability to manipulate genes at will and combine them in a virtually infinite spectrum of combinations in a simple organism, whose primary purpose is to divide, enables us to both define unanticipated key principles of division and explore the finer points of the pathways that co-ordinate a successful cell division. Many of the ground rules that are defined in yeast can be applied in a highly focused manner to direct the interrogation of the analogous process in human cell lines through targeted genome editing. Findings in human cell lines, in turn, raise questions that can be most readily tested in yeast in re-iterative cycles of comparative studies that greatly accelerate our understanding of the complex signalling networks of human cells.