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.

This work was supported by the SILS Starting Grant of the University of Amsterdam, UvA to M.B., by the UvA-Systems Biology Research Priority Area grant to M.B., and by the ENFIN Network of Excellence grant funded by the European Commission to M.B. (within contract number LSHG-CT-2005-518254 to E.K.). We also acknowledge the grant from the European Commission UNICELLSYS, contract number HEALTH-2007-201142 to E.K., S.K., and F.P.); the Spanish Ministry of Economy and Competitiveness (BFU2012-33503 and FEDER) and by Fundación Botín, by Banco Santander through its Santander Universities Global Division to F.P.; the SNSF Swiss National Science Foundation (contract number 132392, SYNERGIA) and State Secretariat for Science Research and Innovation (SEFRI) to I.X.