Cell Cycle Model
Cell cycle model: a noisy yet robust network
A cell cycle model can help better understand the property of this complex regulatory network. The cell cycle is the process by which a growing cell replicates its genome and partitions the two copies of each chromosome to two daughter cells at division. It is of utmost importance to the perpetuation of life that these processes of replication (DNA synthesis) and partitioning (mitosis) be carried out with great fidelity. In eukaryotic cells, DNA synthesis (S phase) and mitosis (M phase) are separated in time by two gaps (G1 and G2). Proper alternation of S phase and M phase is enforced by ‘checkpoints’ that block progression through the cell cycle if the genomic integrity of the cell is compromised in any way. For example, if DNA is damaged in G1 phase, a checkpoint blocks progression into S phase until the damage can be repaired.
The molecular mechanisms that govern each of these checkpoints have a peculiar property called ‘bistability.’ Under physiological conditions, the control mechanism can persist indefinitely in either of two characteristic states: the off state, which corresponds to holding the cell cycle in the pre-transition phase, and the on state, which corresponds to pushing the cell cycle into the post-transition phase. Checkpoint stop signals seem to act by stabilizing the appropriate bistable switch in its off state. Because these checkpoints are crucial to maintaining the integrity of an organism’s genome from one generation of cells to the next, it is vital that they function reliably even in the face of random molecular fluctuations that are inevitable in a cell as small as a yeast cell (30 fL).
The cell cycle model we are developing along with the experimental data we collect help us understand how cell cycle checkpoints operate reliably in wild-type yeast cells and how they fail in mutant cells. This project relies on new advances in stochastic modeling and in the technology of measuring mRNA and protein molecules in single yeast cells.
Because all eukaryotic organisms seem to employ the same fundamental molecular machinery that governs progression through the cell division cycle, the cell cycle model developed for yeast cells will translate into a better understanding of checkpoint functions and failures in other types of cells, most notably human cells.
Sources of Funding
- 2015-present: National Institute of Health Grant 2R01GM078989-09
- 2011-present: National Institute of Health Grant 5R01GM095955-02
- 2006-2015: National Institute of Health Grant 5R01GM078989-07
- John Tyson, Department of Biological Sciences, Virginia Tech
- Kathy Chen, Department of Biological Sciences, Virginia Tech
- T.M. Murali, Department of Computer Sciences, Virginia Tech
- Bill Baumann, Department of Electrical and Computer Engineering, Virginia Tech
- Ball DA, Ahn TH, Wang P, Chen KC, Cao Y, Tyson JJ, Peccoud J, Baumann WT (2011) Stochastic Exit from Mitosis in Budding Yeast: Model Predictions and Experimental Observations Cell Cycle 10 (6):999-1009
- Ball DA, Marchand J, Poulet M, Baumann WT, Chen KC, Tyson JJ, Peccoud J. (2011) Oscillatory dynamics of cell cycle proteins in single yeast cells analyzed by imaging cytometry. PLoS ONE 6:e26272
- Ball DA, Adames NR, Reischmann N, Barik D, Franck CT, Tyson JJ, Peccoud J (2013) Measurement and modeling of transcriptional noise in the cell cycle regulatory network Cell Cycle 12 (19), 3203 – 3218