Dynamics of cell cycle controls
Co-workers: Dr. Stefan Heldt, Lukas Hutter, Scott Rata, Michael Hopkins
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).
1. 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:
2. Rattani, A., Vinod, P.K., Godwin, J., Tachibana-Konwalski, K., Wolna, M., Malumbres, M. Novák, B. & Nasmyth, K. (2014): Dependency of the Spindle Assembly Checkpoint on Cdk1 Renders the Anaphase Transition Irreversible.
Current Biology 24: 630-637.
3. 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.
4. Hellmuth, S., Rata, S., Brown, A., Heidmann, S., Novák, B. & Stemmann, O. (2015): Human chromosome
segregation involves multi-layered regulation of separase by the peptidyl-prolyl-isomerase pin1. Molecular Cell 58:
5. Mirkovic, M., Hutter, L.H., Novák, B. & Oliveira, R.A. (2015): Premature Sister Chromatid Separation Is Poorly
Detected by the Spindle Assembly Checkpoint as a Result of System-Level Feedback. Cell Report 13: 469-478.
6. Barr, A.R., Frank S. Heldt, F.S., Zhang, T., Bakal, C. & Novák, B. (2016): A Dynamical Framework for the All-or-
None G1/S Transition. Cell Systems 2: 27–37.
7. Chica, N., Rozalén, A.E., Pérez-Hidalgo, L., Rubio, A., Novák. B. & Moreno, S. (2016): Nutritional Control of Cell
Size by the Greatwall-Endosulfine-PP2A·B55 Pathway. Current Biology (in press)
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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