Novak, Pataki, Ciliberto, Tyson, 2001

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 units have been checked and are consistent.

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:

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 majority of dividing eukaryotic cells fulfill these three criteria. However, budding yeast are unusual in that they divide asymmetrically. At the Start of the cell cycle, a bud emerges from the mother cell. S and M phases are completed before the bud can grow as large as the mother cell and consequently, budding produces a large mother cell and a small daughter cell. Following division the daughter cell enters an extended G1 phase during which it has to grow to a critical size before it can produce a bud itself. A second anomaly of yeast budding is that the cells pass through the S and M phases of the cell cycle without their chromatin condensing into discrete chromosomes. In addition, DNA replication does not have to be complete before the cell passes into the M-phase of division.

It has been suggested that the budding yeast cycle is an alternation between two self-maintaining states:

the G1 state in which APC is active, CDK activity is low, and origins are licensed; and
the S/M state in which the APC is inactive, CDK activity is high, and origins are fired and incapable of firing again.

The G1 state is self-reinforcing because APC destroys S-phase and M-phase cyclins. The S/M state is self-reinforcing because CDKs inactivate APC.

The molecular mechanisms underlying the cell cycle have been schematically summarised in the figure below. In turn, the reactions dipicted in this diagram have been converted into a series of differential and algebraic equations. The model has been described here in CellML (the raw CellML description of the Novak and Pataki 2001 model can be downloaded in various formats as described in ).

The complete original paper reference is cited below:

Mathematical model of the cell division cycle of fission yeast, Bela Novak, and Zsuzsa Pataki, 2001, CHAOS , 11, 277-286. (A PDF version of the article is available to subscribers on the CHAOS website.) PubMed ID: 12779461

Diagram of the fission-yeast cell cycle. In the middle of the diagram is Cdc2/Cdc13 (MPF), which is regulated by proteolysis of the Cdc13 component, phosphorylation of the Cdc2 component, and stoichiometric inhibition of the complex.

Using bifuraction analysis of the model's equations, the authors describe the unusual features of the fission yeast cell cycle.