Modeling the control of DNA replication in fission yeast

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

The molecular mechanisms which underlie the control of the eukaryotic cell cycle are beginning to be elucidated by studies of fission yeast. One event of particular importance is the initiation of DNA replication (the S phase). Tight controls usually exist to prevent repeated phases of DNA replication without nuclear (mitosis) and cellular (cytokinesis) division occurring. Similarly, until DNA replication is complete, the initiation of mitosis is inhibited.

Fission yeast cells carrying the mutant genes wee1^- and cdc25^OP initiate mitosis before DNA replication is complete, suggesting that the products of the wild type genes play an essential role in the G₂ checkpoint controls that delay division until DNA replication is complete. Similarly, in cells with a mutant copy of either the cdc2, cdc13, or Rum1 genes, the G₁ checkpoint fails, and DNA synthesis begins before the cell has divided, resulting in a polyploid cell.

Based on this experimental data, Bela Novak and John Tyson have developed a mathematical model describing the control of DNA replication in fission yeast. Using principles of biochemical kinetics (mass action and Michaelis-Menten reaction kinetics), the reaction mechanism shown in the figure below is converted into a set of differential equations. These rate equations describe how the concentrations of the main control variables change over time.

The complete original paper reference is cited below:

Modeling the control of DNA replication in fission yeast, Bela Novak and John J. Tyson, 1997, Proceedings of the National Academy of Sciences , 94, 9147-9152. (A PDF version of the article is available to subscribers on the journal website.) PubMed ID: 9256450

A schematic diagram of the reaction mechanism which describes the G₁/S and G₂/M controls in fission yeast.

Please note that the following switches in the published model are not included in the CellML description:

(i) When SPF crosses 0.1 from below, S phase is initiated (Start).
(ii) When UbE crosses 0.1 from above, the cell divides functionally (mass->mass/2), although visible cytokinesis may be delayed.
(iii) 60 min after Start, kp is divided by 2, and at cell division kp is multiplied by 2.

(taken from Table 1 of the cited reference).