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Quantitative Analysis of a Dynamic Cell Cycle Regulatory Model of Schizosaccharomyces pombe

Anbumathi P, Sharad Bhartiya and KV Venkatesh

Cell cycle is the central process that regulates growth and division in all eukaryotes. Based on the environmental condition sensed, the cell lies in a resting phase G0 or proceeds through the cyclic cell division process (G1->S->G2- >M). These series of events and the irreversible phase transitions are governed mainly by the highly conserved Cyclin dependent kinases (Cdks) and its positive and negative regulators which results in a highly interconnected network. The dynamics of the cell cycle regulation is due to this underlying complex network that governs this process. In in silico models it is the parameter set that directly reflects the characteristics of the system. Synthesis rate constants indirectly represent the source of complexity. Therefore, a recently developed model for fission yeast Schizosaccharomyces pombe cell cycle regulation was utilized to investigate the influence of synthesis level regulation on the overall cell cycle period. A systematic local and the global perturbation of sixteen synthesis rate constants of the model were performed to study the synthesis level influence of these regulators on (i) viability, (ii) cell cycle period and (iii) robustness. The results of sensitivity analysis indicates that the cell cycle time is robust to perturbation in the synthesis rate constant of single regulators but fragile to simultaneous perturbation of the multiple regulators. In addition, a perspective on emergence of robustness with respect to multiple layers of complex regulators over a fragile core network is demonstrated based on a systematic regulator deletion and addition analysis. Some of the key predictions that emerge from this study includes, that (i) seven regulatory components Slp1, Cdc2, Cdc13, PP1, APC, and Cdc25 along with Mik1 or Wee1 are sufficient to drive cell cycle regulation. This can be verified by designing appropriate synthetic biology experiments; (ii) either one of the G2 regulatory kinases Wee1 or Mik1 could have emerged through whole chromosome duplication events during evolution which can be tested experimentally to arrive with a conclusive proof.