From START to FINISH: computational analysis of cell cycle control in budding yeast

In the cell division cycle of budding yeast, START refers to a set of tightly linked events that prepare a cell for budding and DNA replication, and FINISH denotes the interrelated events by which the cell exits from mitosis and divides into mother and daughter cells. On the basis of recent progress made by molecular biologists in characterizing the genes and proteins that control START and FINISH, we crafted a new mathematical model of cell cycle progression in yeast. Our model exploits a natural separation of time scales in the cell cycle control network to construct a system of differential-algebraic equations for protein synthesis and degradation, post-translational modifications, and rapid formation and dissociation of multimeric complexes. The model provides a unified account of the observed phenotypes of 257 mutant yeast strains (98% of the 263 strains in the data set used to constrain the model). We then use the model to predict the phenotypes of 30 novel combinations of mutant alleles. Our comprehensive model of the molecular events controlling cell cycle progression in budding yeast has both explanatory and predictive power. Future experimental tests of the model’s predictions will be useful to refine the underlying molecular mechanism, to constrain the adjustable parameters of the model, and to provide new insights into how the cell division cycle is regulated in budding yeast. Cell cycle modeling: Accounting for different rates A model of yeast cell cycling developed by US and Thai researchers replicates lab results by modeling reactions on separate time scales. The network of genes and proteins that regulates cell growth and division is immensely complex and requires mathematical models to link all the underlying processes. John Tyson and Pavel Kraikivski at Virginia Tech and co-workers improved an existing model for budding yeast, Saccharomyces cerevisiae , by classifying reactions into three types based on their speed. These ranged from slow (protein synthesis and degradation) through moderate (protein modification such as phosphorylation) to fast (the formation of multi-protein complexes). The researchers verified their model by using it to account for 257 of the 263 observed genetic strains of yeast, and were also able to predict the phenotypes of 30 new mutant strains.