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Review
. 2021 Dec 13;7(1):48.
doi: 10.1038/s41540-021-00201-w.

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

Matteo Barberis  1   2   3
Affiliations
Review

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

Matteo Barberis. NPJ Syst Biol Appl. .

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.

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Conflict of interest statement

The author declares no competing interests.

Figures

Fig. 1
Fig. 1. Waves of mitotic (Clb) cyclins throughout cell cycle progression.
a Qualitative description of alternating waves of expression of mitotic cyclin/Cdk1 complexes and of their stoichiometric inhibitor Cki throughout the cell cycle phases. In budding yeast: (i) Cki indicates Sic1 (black color), which is expressed maximally in G1 phase and at a low level in the other cell cycle phases; (ii) Clb indicates mitotic cyclins: Clb5,6 (red color) trigger DNA replication in S phase; Clb3,4 (blue color) trigger completion of S phase and early mitotic events in G2 phase; Clb1,2 (green color) trigger late mitotic events and cell division in M phase. b Scheme of regulations connecting cyclin transcription and Clb/Cdk1 complexes through the Fkh2 transcription factor. The synchronization of Clb cyclins occurs in steps: (i) Clb5 promotes CLB3 transcription (solid red line); (ii) Clb3 promotes CLB2 transcription (solid blue line); (iii) Clb2 further promotes CLB2 transcription through a Clb2-mediated positive feedback loop (solid green line) (adapted from Linke et al.). Dashed colored arrows indicate regulations that may occur between Fkh2/Ndd1 and Clb cyclins, following the physical interactions that have been shown experimentally. For simplicity, Cdk1 has been omitted.
Fig. 2
Fig. 2. Design principle underlying the minimal model of cell cycle control in budding yeast.
a Coherent type II feed-forward loop (FFL, black lines) generated among the Anaphase-Promoting Complex/Cyclosome activated by Cdh1 (APC/CCdh1), Ndd1 and their target Clb2 (adapted from). b Coherent type I FFL (black arrows) proposed to occur among the mitotic Clb cyclins: Clb5 activates Clb3, and Clb5 activates Clb2 together with Clb3. c Detailed regulations occurring within the coherent type I FFL in b, through the Fkh2/Ndd1 transcriptional complex. The Clb5 → Clb2 regulatory activation is shown in dotted arrow, to indicate its possible less relevance within the FFL. Clb2-mediated inhibitory regulations of Clb3 and Clb5 (through APC/C, not visualized) identified in autonomous Clb/Cdk1 oscillators are indicated by bar-headed black lines. d, e Most frequently dominant regulations underlying autonomous oscillations,. d Two Fkh2-mediated activatory regulations (Clb3 → Clb2 and Clb3 PFL) and two APC/C-mediated regulatory inhibitions (Clb3 ⊦ Clb2 and Clb5 ⊦ Clb2). e Three Fkh2-mediated activatory regulations (Clb5 → Clb3, Clb3 → Clb2 and Clb3 PFL) and two APC/C-mediated regulatory inhibitions (Clb3 ⊦ Clb2 and Clb5 ⊦ Clb2). f The ‘negative feedback with positive feedback loop’ (NF-PFL) design: two Fkh2-mediated activatory regulations (Clb3 → Clb2 and Clb3 PFL) and one APC/C-mediated regulatory inhibition (Clb3 ⊦ Clb2). a–e For clarity, Clb cyclins and APC/C that drive post-transcriptional regulations are indicated with ovals, whereas Fkh2 and Ndd1 that promote transcriptional regulations are indicated within squares. Bar-headed black lines indicate APC/C-mediated inhibitory reactions, whereas red arrows indicate positive feedback loops (PFLs). For simplicity, Cdk1 has been omitted.
Fig. 3
Fig. 3. Gear shifter mechanism of Clb-centered cell cycle control.
An autonomous pattern of alternating waves of mitotic cyclins over time may occur through a gear shifter mechanism. Clb cyclins ‘read’ the cell’s state and the Cdk1 kinase ‘writes’ that state by modulating its activity. The ‘readers’ (Clb)–centered gear shifter is realized through a scaffold formed by three schafts (yellow vertical pipes) each corresponding to the main mitotic Clb cyclins: Clb5 (red disc), Clb3 (blue disc), and Clb2 (green disc). Of note, a yellow and a green vertical pipes are connected through a catch-and-release mechanism (little horizontal black line), which allows the two pipes to move together. When the gear shifter is actioned (through the black crank), movement of Clb5 activates the coordinates motion of Clb3 and, in turn, of Clb2 through two black bands, thus resembling the two Fkh2-mediated regulations occurring within the linear CLB cascade, Clb5 → Clb3 and Clb3 → Clb2 (black arrows in Fig. 2e). When movement of Clb3 is required to be further expedite, the catch-and-release mechanism connecting the yellow and green vertical pipes of Clb3 is removed from a fixed position (through the blue crank that sets in motion the green cogs). This step allows the green pipe to function independently from the yellow pipe and to further boost Clb2 movement (through the black band connecting Clb3 and Clb2), thus resembling the activation of the PFL mediated by Clb3/Cdk1 on CLB3 synthesis (Clb3 PFL) (red arrow in Fig. 2e). The gear shifter mechanism also includes a brake system connecting the three Clb disks that is activated by the move of Clb2, which progressively reduces the move of Clb3 and of Clb5, thus resembling the two APC/C-mediated regulatory inhibitions, Clb3 ⊦ Clb2 and Clb5 ⊦ Clb2 (bar-headed black lines in Fig. 2e) driven by Clb2. Altogether, modulation of the gear shifter mechanism on Clb3 allows for the maintenance of an autonomous coordination of the three Clb disks.
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