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NPJ Syst Biol Appl. 2017 Mar 6;3:7. doi: 10.1038/s41540-017-0008-1. eCollection 2017.

A Clb/Cdk1-mediated regulation of Fkh2 synchronizes CLB expression in the budding yeast cell cycle.

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Synthetic Systems Biology and Nuclear Organization, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, 1098 XH The Netherlands.
Max Planck Institute for Molecular Genetics, Berlin, 14195 Germany.
Vital-IT group, Swiss Institute of Bioinformatics, University of Lausanne, CH-1015 Lausanne, Switzerland.
Cell Signaling Unit, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, 08003 Spain.
Institute for Biology, Theoretical Biophysics, Humboldt University Berlin, Berlin, 10115 Germany.
Institute of Technology, University of Tartu, Tartu, 50411 Estonia.
Contributed equally


Precise timing of cell division is achieved by coupling waves of cyclin-dependent kinase (Cdk) activity with a transcriptional oscillator throughout cell cycle progression. Although details of transcription of cyclin genes are known, it is unclear which is the transcriptional cascade that modulates their expression in a timely fashion. Here, we demonstrate that a Clb/Cdk1-mediated regulation of the Fkh2 transcription factor synchronizes the temporal mitotic CLB expression in budding yeast. A simplified kinetic model of the cyclin/Cdk network predicts a linear cascade where a Clb/Cdk1-mediated regulation of an activator molecule drives CLB3 and CLB2 expression. Experimental validation highlights Fkh2 as modulator of CLB3 transcript levels, besides its role in regulating CLB2 expression. A Boolean model based on the minimal number of interactions needed to capture the information flow of the Clb/Cdk1 network supports the role of an activator molecule in the sequential activation, and oscillatory behavior, of mitotic Clb cyclins. This work illustrates how transcription and phosphorylation networks can be coupled by a Clb/Cdk1-mediated regulation that synchronizes them.

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