Cyclin/Forkhead-mediated coordination of cyclin waves: an autonomous oscillator rationalizing the quantitative model of Cdk control for budding yeast

Abstract

Networks of interacting molecules organize topology, amount, and timing of biological functions. Systems biology concepts required to pin down ‘network motifs’ or ‘design principles’ for time-dependent processes have been developed for the cell division cycle, through integration of predictive computer modeling with quantitative experimentation. A dynamic coordination of sequential waves of cyclin-dependent kinases (cyclin/Cdk) with the transcription factors network offers insights to investigate how incompatible processes are kept separate in time during the eukaryotic cell cycle. Here this coordination is discussed for the Forkhead transcription factors in light of missing gaps in the current knowledge of cell cycle control in budding yeast. An emergent design principle is proposed where cyclin waves are synchronized by a cyclin/Cdk-mediated feed-forward regulation through the Forkhead as a transcriptional timer. This design is rationalized by the bidirectional interaction between mitotic cyclins and the Forkhead transcriptional timer, resulting in an autonomous oscillator that may be instrumental for a well-timed progression throughout the cell cycle. The regulation centered around the cyclin/Cdk–Forkhead axis can be pivotal to timely coordinate cell cycle dynamics, thereby to actuate the quantitative model of Cdk control.

Unveiling Forkhead-mediated regulation of yeast cell cycle and metabolic networks

“…This regulatory mode, together with the activation of Fkh2 through phosphorylation mediated by the progressive accumulation of successive Clb/Cdk1 complexes [50] , [56] , may be in place to timely transcribe CLB genes. This mechanism can guarantee self-sustained, autonomous oscillations of Clb/Cdk1 activities [57] , [58] , thereby the unidirectionality of cell cycle progression.…”

Characterization and functional analysis of chicken CDK protein

“…The mammalian CDK family comprises proteins ranging from CDK1 to CDK20 ( Swaffer et al, 2016 ). Originally discovered through genetic and bioinformatic studies in yeasts and frogs, the functional interaction of CDKs with the cyclin subunits, which regulate the cell cycle, was subsequently verified ( Barberis, 2021 ). These interactions underscore the pivotal role of CDKs in signal transduction, modulating gene transcription and cell cycle progression, thereby establishing their importance in cellular functioning ( Malumbres and Barbacid, 2005 ).…”

New roles of DNA‐binding and forkhead‐associated domains of Fkh1 and Fkh2 in cellular functions

“…However, Ndd1 is only required for the Fkh2‐regulated CLB2 cluster gene transcription, but not for the Fkh1‐regulated CLB2 cluster gene transcription, the latter being independent of Ndd1 11 . The complex of Fkh2/Ndd1 may be regulated by all Clb/Cdk1complexes for the activation of CLB2 and CLB3 promoters, 8 and the Clb3/Fkh2 axis has been shown to synchronize autonomous oscillations of Clb/Cdk1 complexes 12,13 . Another significant difference between Fkh1 and Fkh2 is that the lethality incurred by the deletion of NDD1 can be rescued through the deletion of FKH2 , but not of FKH1 14 .…”

“…11 The complex of Fkh2/Ndd1 may be regulated by all Clb/Cdk1complexes for the activation of CLB2 and CLB3 promoters, 8 and the Clb3/Fkh2 axis has been shown to synchronize autonomous oscillations of Clb/Cdk1 complexes. 12,13 Another significant difference between Fkh1 and Fkh2 is that the lethality incurred by the deletion of NDD1 can be Cell Biochem Funct. 2022;40:888-902. wileyonlinelibrary.com/journal/cbf rescued through the deletion of FKH2, but not of FKH1.…”