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

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. Cell cycle control: Order in time achieved by dynamic coupling A dynamic coupling of cyclin-dependent kinase with transcription factors in yeast offers insights into the timely cell cycle progression. An international team lead by Matteo Barberis from University of Amsterdam in The Netherlands studied the molecular mechanisms responsible for the coordination of DNA replication with cell division. The researchers have demonstrated how the sequential order of waves of mitotic cyclins activating cyclin-dependent kinase, or Cdk, is achieved by synchronizing Cdk with transcriptional activities. They have generated a mathematical model that predicts a cyclin/Cdk-mediated regulation of an activator molecule to stimulate mitotic cyclin expression. This prediction was successfully validated experimentally, identifying Forkhead transcription factors, or Fkh, as pivotal molecules. Cyclin waves are temporally synchronized by Fkh, and a mitotic Clb/Cdk1-mediated regulation of Fkh modulates cyclin expression. The findings reveal a novel principle of design, with kinase and transcription activities interlocked to guarantee a timely cell cycle.