Design Principles of the Yeast G1/S Switch

Yang, Xiaojing; Lau, Kai-Yeung; Sevi̇m, Volkan; Tang, Chao

doi:10.1371/journal.pbio.1001673

Cited by 54 publications

(71 citation statements)

References 47 publications

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“…Likewise, we saw that Cln3 is not as proficient as Cln2 at driving extensive Whi5 modification in vivo, and the superior activity of Cln2 depends at least in part on docking. Whi5 might be phosphorylated via a two-stage relay, first by Cln3 and then more completely by Cln1/2; this would be analogous to Rb phosphorylation by cyclins D and E in animal cells [43], and to the sequential phosphorylation of Sic1 by Cln1/2 and Clb5 in yeast [14, 16]. Yet, while our results clearly reveal phosphorylation of Whi5 by Cln1/2, there is scant (if any) evidence that Cln3 can do so, and hence this remains an important issue for future studies.…”

Section: Discussionmentioning

confidence: 99%

“…Key CDK substrates in this period are inhibitors of cell cycle entry such as Whi5, a repressor of G1/S transcription [9, 10], as well as Cdh1 and Sic1, which prevent the expression and activity of Clb cyclins, respectively [1]. Notably, each of these substrates has multiple CDK phosphorylation sites [11–13], which may place unique demands on the cyclin-CDK complex to ensure complete phosphorylation and also dictate the threshold CDK levels required to trigger the regulatory effect [11, 14–16]. …”

Section: Introductionmentioning

confidence: 99%

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A Docking Interface in the Cyclin Cln2 Promotes Multi-site Phosphorylation of Substrates and Timely Cell-Cycle Entry

et al. 2015

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Summary Background Eukaryotic cell division is driven by cyclin-dependent kinases (CDKs). Distinct cyclin-CDK complexes are specialized to drive different cell cycle events, though the molecular foundations for these specializations are only partly understood. In budding yeast, the decision to begin a new cell cycle is regulated by three G1 cyclins (Cln1–Cln3). Recent studies revealed that some CDK substrates contain a novel docking motif that is specifically recognized by Cln1 and Cln2, and not by Cln3 or later S- or M-phase cyclins, but the responsible cyclin interface was unknown. Results Here, to explore the role of this new docking mechanism in the cell cycle, we first show that it is conserved in a distinct cyclin subtype (Ccn1). Then, we exploit phylogenetic variation to identify cyclin mutations that disrupt docking. These mutations disrupt binding to multiple substrates as well as the ability to use docking sites to promote efficient, multi-site phosphorylation of substrates in vitro. In cells where the Cln2 docking function is blocked, we observed reductions in the polarized morphogenesis of daughter buds and reduced ability to fully phosphorylate the G1/S transcriptional repressor Whi5. Furthermore, disruption of Cln2 docking perturbs the coordination between cell size and division, such that the G1/S transition is delayed. Conclusions The findings point to a novel substrate interaction interface on cyclins, with patterns of conservation and divergence that relate to functional distinctions among cyclin subtypes. Furthermore, this docking function helps ensure full phosphorylation of substrates with multiple phosphorylation sites, and this contributes to punctual cell cycle entry.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Docking Interface in the Cyclin Cln2 Promotes Multi-site Phosphorylation of Substrates and Timely Cell-Cycle Entry

et al. 2015

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“…This degradation is required for the sudden activation of Cdc28-Clb5, which phosphorylates the prereplicative complex components Sld2 and Sld3 (24,25), thereby licensing DNA replication origins for firing. It has been recently demonstrated that Clb5 is also involved in the phosphorylation of Sic1, creating another positive-feedback loop (26).…”

mentioning

confidence: 99%

Hog1 Targets Whi5 and Msa1 Transcription Factors To Downregulate Cyclin Expression upon Stress

González-Novo

Jiménez

Clotet

et al. 2015

Molecular and Cellular Biology

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“…Motivated by some previous works [5][6][7]10], a full mathematical model is built by combining the schematic diagrams in Figure 1A and Figure 1B. Several assumptions, which are listed below, simplify the model.…”

Section: Mathematical Modelmentioning

confidence: 99%

“…A recent study demonstrated that the switch-like G1/S transition is driven by the degradation of Sic1 and that the timing of Sic1 destruction is set by Cln1/2-Cdc28 [10]. Due to the mutual inhibition between Sic1 and Clb5/6, the level of Sic1 decreases steeply while the level of Clb5/6 increases sharply at the G1/S transition point [10]. It is reasonable to suppose that the crossing point of the two levels is the G1/S transition point in our study ( Figure 2A).…”

Section: Determination Of the G1/s Transition Pointmentioning

confidence: 99%

Mathematical modeling reveals the mechanisms of feedforward regulation in cell fate decisions in budding yeast

Zou

2015

Quant. Biol.

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The determination of cell fate is one of the key questions of developmental biology. Recent experiments showed that feedforward regulation is a novel feature of regulatory networks that controls reversible cellular transitions. However, the underlying mechanism of feedforward regulation-mediated cell fate decision is still unclear. Therefore, using experimental data, we develop a full mathematical model of the molecular network responsible for cell fate selection in budding yeast. To validate our theoretical model, we first investigate the dynamical behaviors of key proteins at the Start transition point and the G1/S transition point; a crucial three-node motif consisting of cyclin (Cln1/2), Substrate/Subunit Inhibitor of cyclin-dependent protein kinase (Sic1) and cyclin B (Clb5/6) is considered at these points. The rapid switches of these important components between high and low levels at two transition check points are demonstrated reasonably by our model. Many experimental observations about cell fate decision and cell size control are also theoretically reproduced. Interestingly, the feedforward regulation provides a reliable separation between different cell fates. Next, our model reveals that the threshold for the amount of WHIskey (Whi5) removed from the nucleus is higher at the Reentry point in pheromone-arrested cells compared with that at the Start point in cycling cells. Furthermore, we analyze the hysteresis in the cell cycle kinetics in response to changes in pheromone concentration, showing that Cln3 is the primary driver of reentry and Cln1/2 is the secondary driver of reentry. In particular, we demonstrate that the inhibition of Cln1/2 due to the accumulation of Factor ARrest (Far1) directly reinforces arrest. Finally, theoretical work verifies that the three-node coherent feedforward motif created by cell FUSion (Fus3), Far1 and STErile (Ste12) ensures the rapid arrest and reversibility of a cellular state. The combination of our theoretical model and the previous experimental data contributes to the understanding of the molecular mechanisms of the cell fate decision at the G1 phase in budding yeast and will stimulate further biological experiments in future.Keywords: cell fate decision; feedforward mechanism; mathematical modeling; hysteresis; reversibility INTRODUCTIONCells from across biological kingdoms are continuously engaged in the process of decision making. Through decision making, unicellular and multicellular organisms take information from their surroundings (including neighboring cells) and process these data through complex signal transduction and genetic circuits to further modulate cellular phenotypes. Therefore, the selection of cell fate in response to both internal and external stimuli is essential in a cell's life [1]. Much progress in understanding the circuitry underlying decision making, as well as the advantages of the underlying strategic logic implemented therein, has come from budding yeast, the simplest eukaryote [2].Mathematical modelling is an important method in ©...

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Design Principles of the Yeast G1/S Switch

Abstract: Single-cell microscopy and computational modeling offer novel mechanistic insight into the G1/S switch that initiates DNA replication in budding yeast, revealing a Clb5/6-Cdk1 and Sic1 feedback loop and new rules of biochemical circuit design.

Cited by 54 publications

References 47 publications

A Docking Interface in the Cyclin Cln2 Promotes Multi-site Phosphorylation of Substrates and Timely Cell-Cycle Entry

A Docking Interface in the Cyclin Cln2 Promotes Multi-site Phosphorylation of Substrates and Timely Cell-Cycle Entry

Hog1 Targets Whi5 and Msa1 Transcription Factors To Downregulate Cyclin Expression upon Stress

Mathematical modeling reveals the mechanisms of feedforward regulation in cell fate decisions in budding yeast

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