Dynamics of cell cycle controls
Co-workers: Dr. Vinod P.K., Dr. Tongli Zhang, Lukas Hutter, Scott Rata, Sung Kim
The living cell is a dynamical system of molecular interactions. Most of the physiological characteristics of the cell (movement, growth, and division etc.) are emergent properties of underlying molecular networks rather than being determined by a single molecule. These molecular networks are intrinsically dynamic and they dictate both spatial and temporal behaviour of the cell. In order to understand the physiological consequences of these regulatory molecular networks we use computational methods. Our mathematical modelling focuses on the eukaryotic cell cycle control system, which is responsible for:
Global and local temporal ordering of cell cycle events;
blocking further cell cycle progression in response to checkpoint controls (activated by incomplete cell cycle events);
adjusting the tempo of cell cycle progression to the growth rate of the cell (balanced growth and division).
Using nonlinear differential equations, we build computer models for cell cycle control network of budding and fission yeasts, frog and fruit fly embryos, and human cells. These models accurately reproduce the physiological properties of normal cell cycle progression as well as the bizarre properties of mutant cells that have been studied. Recently, we have developed a quantitative model of the temporal ordering of DNA replication and mitosis for the minimal Cdk control network of fission yeast (Fig. 1). The model also predicts phenotypes of novel mutants and unintuitive properties (bistability, hysteresis etc.) of the cell cycle machinery (see Fig. 2).
We also develop quantitative models for individual cell cycle transitions like (G1/S, G2/M, meta/anaphase and mitotic exit).
Our experimentalist collaborators provide valuable quantitative data in the following areas:
budding yeast cell cycle (Dr Frank Uhlmann, CRUK, LRI) and meiosis (Dr Wolfgang Zachariae, MPI, Martinsried), G1/S transition (Dr Chris Bakal, ICR, London), G2/M transition (Dr Helfrid Hochegger, U Sussex; Dr Sergio Moreno, Salamanca), Spindle Assembly Checkpoint (Dr Daniel Gerlich, IMBA, Vienna; Dr Ulrike Gruneberg, Dunn School, Oxford; Raquel Oliveira, Gulbenkian Inst, Lisbon) and mitotic exit (Prof Francis Barr, Biochemistry, Oxford).
- He, E., Kapuy, O., Oliveira, R.A., Uhlmann, F., Tyson, J.J. & Novák, B. (2011): System-level feedbacks make the anaphase switch irreversible. Proc. Natl. Acad. Sci. USA. 108: 10016-10021.
- Moriya, H., Chino, A., Kapuy, O., Csikasz-Nagy, A. & Novák, B. (2011): Overexpression limits of fission yeast cell-cycle regulators in vivo and in silico. Molecular Systems Biology 7; 556
- Okaz, E., Argüello-Miranda, O., Bogdanova, A., Vinod, P.K., Lipp, J.J., Markova, Z., Zagoriy, I., Novák, B. & Zachariae, W. (2012): Meiotic Prophase Requires Proteolysis of M Phase Regulators Mediated by the Meiosis-Specific APC/C(Ama1). Cell 151: 603-618.
- Zhang, T., Tyson, J.J. & Novák, B. (2013): Role for regulated phosphatase activity in generating mitotic oscillations in Xenopus cell-free extracts. Proc. Natl. Acad. Sci. U S A. 110: 20539-44.
- Cundell, M.J., Bastos, R.N., Zhang, T., Holder, J., Gruneberg, U., Novák, B. & Barr, F.A. (2013): The BEG (PP2A-B55/ENSA/Greatwall) Pathway Ensures Cytokinesis follows Chromosome Separation. Molecular Cell 52: 393-405.
- Rattani, A., Vinod, P.K., Godwin, J., Tachibana-Konwalski, K., Wolna, M., Malumbres, M. Novák, B. and Nasmyth, K. (2014): Dependency of the Spindle Assembly Checkpoint on Cdk1 Renders the Anaphase Transition Irreversible. Current Biology 24: 630-637.
- Gérard, C., Tyson, J.J., Coudreuse, D. & Novák, B. (2015): Cell Cycle Control by a Minimal Cdk Network. PloS Computational Biology 11: e1004056. doi: 10.1371/journal.pcbi.1004056.
More publications: PubMed | Researcher ID
Fig. 1: The molecular mechanism of the minimal Cdk network driving the cell cycle of fission yeast.
Fig. 2: Projection of the cell cycle trajectory on a bifurcation diagram of the minimal Cdk network driving the cell cycle of fission yeast