Ciliberto, Novak, Tyson, 2003

Model Status

This CellML version of the model has been checked in COR and PCEnv and the model runs to replicate the results in the original published paper. The model was checked against the XPP code as there is an inconsistency between the code and the published equation for the variable 'PSwe1'.

ValidateCellML verifies this model as valid CellML with consistent units.

Model Structure

During mitotic cell division, eukaryotic cells will replicate their DNA during the S-phase of the cell cycle, and then divide during the M-phase. S and M phases are temporally separated by gaps, G1 and G2 phases. These discrete phases of the cell cycle are carefully regulated by specific proteins (see below for an illustration of the molecular mechanisms underlying the cell-cycle):

• In order to ensure that DNA replication only occurs once per cell cycle, cyclin-dependent protein kinases (CDKs) control the activity of licensing factors, which in turn bind to the DNA and prime the origins of replication. The CDKs ensure that this only occurs once per cycle.

• It is also important that the cell doesn't begin to divide until DNA replication is complete. Chromosome alignment during the early M phase is required for the activation of the anaphase-promoting complex (APC). In turn, this initiates the degradation of an inhibitor of chromatid separation. APC also mediates the break down of mitotic cyclins, thereby destroying CDK activities and allowing licensing factors to accumulate and origins to be primed for replication.

• Thirdly, the cell must coordinate its DNA replication and division cycle with cell growth. In order to maintain a certain cell size, the cell must reach a critical mass before it divides.

The main transitions of the cell cycle, namely the onset of DNA replication (Start), entry into mitosis (G2-M transition), and exit from mitosis, are controlled by checkpoint mechanisms. The morphogenesis checkpoint in budding yeast arrests the cell cycle at the G2-M transition when bud formation is impaired (perhaps due to environmental stimuli such as heat or osmotic shock). This delay effectively prevents the formation of dinucleated cells, which are less viable than mononucleated cells. However, the arrest in the cycle is not complete; after several hours, the cell cycle will continue and unbudded cells will undergo mitosis and dinucleate cells will be formed.

The complete original paper reference is cited below:

Mathematical model of the morphogenesis checkpoint in budding yeast, Andrea Ciliberto, Bela Novak, and John J. Tyson, 2003, The Journal of Cell Biology , 163, 1243-1254. PubMed ID: 14691135

A schematic diagram of the molecular mechanisms underlying the regulation of the cell cycle in budding yeast.

A schematic diagram of the Swe1 box - a process which is central to the morphogenesis checkpoint in budding yeast.

The model simulations support the idea that the morphogenesis checkpoint increases the cell size threshold for progression from one phase of the cell cycle to the next.