Volume 1 • Issue 1 • 1000105 Curr Synthetic Sys Biol ISSN: 2332-0737 CSSB, an open access journal Research Article Open Access Anbumathi et al., Curr Synthetic Sys Biol 2013, 1:1 DOI: 10.4172/2332-0737.1000105 Research Article Open Access Quantitative Analysis of a Dynamic Cell Cycle Regulatory Model of Schizosaccharomyces pombe Anbumathi P*, Sharad Bhartiya and KV Venkatesh Department of Chemical Engineering, Indian Institute of Technology Bombay, Mumbai, India *Corresponding author: Anbumathi P, School of Chemical and Biotechnology, SASTRA University, Thanjavur, 613401, India, Tel: +91-4362-264101-108; Extn: 3657; E-mail: anbumathi_p@iitb.ac.in Received June 24, 2013; Accepted September 10, 2013; Published September 12, 2013 Citation: Anbumathi P, Bhartiya S, Venkatesh KV (2013) Quantitative Analysis of a Dynamic Cell Cycle Regulatory Model of Schizosaccharomyces pombe. Curr Synthetic Sys Biol 1: 105. doi: 10.4172/2332-0737.1000105 Copyright: © 2013 Anbumathi P, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract 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 refects the characteristics of the system. Synthesis rate constants indirectly represent the source of complexity. Therefore, a recently developed model for fssion yeast Schizosac- charomyces pombe cell cycle regulation was utilized to investigate the infuence 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 infuence 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 suffcient to drive cell cycle regulation. This can be verifed by design- ing 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. Keywords: Cell cycle; S. pombe; Yeast; Cell Signaling; Evolution; Sensitivity; Robustness Introduction Te series of process by which a cell replicates its genetic material (S phase) and divides (M Phase) it equally between its daughter is known as cell cycle. Tis process underlies growth and development in all eukaryotes and is central to their heredity and evolution [1]. Cell cycle regulation is driven primarily by the enzymatic activity of Cyclin dependent kinases (Cdks) and its activation partner cyclin which is universally conserved across eukaryotes [2]. Additional regulations are exerted by several activators and inhibitors through interlinked feedback loops. Information related to the interaction of individual regulators is available through experimental studies and recent times are witnessing the overfow of high throughput experimental data [3-6]. Terefore, systematic modeling approaches that explain the relevance of the underlying biochemical interactions are necessary to better understand the working of the cell cycle network [7]. Teoretical studies have contributed extensively to explore several emerging properties of the cell cycle regulatory networks [8- 11]. Robust nature of the biological systems are known, however, the exact underlying mechanisms that contribute towards maintaining robustness is still not well understood and the mathematical foundation is yet to be established [12]. Tere are very few theoretical studies that investigate the robustness characteristics of the cell cycle through parameter analysis since most of the mathematical studies rely on semi quantitative experimental data for model building [13,14]. Complex systems both engineered and biological are linked with robust yet fragile characteristics that are observed due to modularity. Fragility or failure of a single cell’s robust control system leads to fatal disease like cancer [15,16]. It is difcult or almost impossible to experimentally deduce these robust/fragility core of a biological system which could provide insights for drug development studies in complex diseases like cancer [12]. Nevertheless, mathematical models of complex biological processes can be utilized to understand these crucial properties of biological systems. Te present study utilizes a fssion yeast S. pombe cell cycle regulatory model developed by our group which employed synthesis level regulation for all the regulators [17]. Tis model demonstrated the wild type dynamics of fssion yeast S. pombe cell cycle regulators and through simulations predicted the underlying regulatory dynamics of various single, double, temperature sensitive, over-expression and structural mutants. Trough structural perturbation studies this model explored the crucial role of multiple phosphatases in imparting specifc phenotypic characterizes during cell cycle progression and discussed the ambiguities in the identity and roles of the diferent phosphatases. In this study through sensitivity analysis the regulatory role of individual regulators and their contribution towards maintaining robust control of fssion yeast S. pombe cell cycle progression is examined. Oscillatory nature of this dynamic interaction network is known and this study considers it as a measure of viability. We also attempt to integrate this Current Synthetic and Systems Biology C u r r e n t S y n t h e t i c a n d S y s t e m s B i o l o g y ISSN: 2332-0737