ArticlePLoS biology2013
Design principles of the yeast G1/S switch.
Article in PLoS biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 55 citations in OpenAlex.
- Initial nutrient condition determines the recovery speed of quiescent cells in fission yeast.Heliyon · 2024Article
- Network regulation meets substrate modification chemistry.Journal of the Royal Society, Interface · 2023Article
- The regulatory mechanism of the yeast osmoresponse under different glucose concentrations.iScience · 2023Article
- Article
- Quantitative model of eukaryotic Cdk control through the Forkhead CONTROLLER.NPJ systems biology and applications · 2021Review
- Comprehensive Analysis of G1 Cyclin Docking Motif Sequences that Control CDK Regulatory Potency In Vivo.Current biology : CB · 2020Article
- Life span extension by glucose restriction is abrogated by methionine supplementation: Cross-talk between glucose and methionine and implication of methionine as a key regulator of life span.Science advances · 2020Article
- A processive phosphorylation circuit with multiple kinase inputs and mutually diversional routes controls G1/S decision.Nature communications · 2020Article
- The Design Principles of Biochemical Timers: Circuits that Discriminate between Transient and Sustained Stimulation.Cell systems · 2019Article
- Multisite phosphorylation code of CDK.Nature structural & molecular biology · 2019Article
- Multiple Mechanisms Inactivate the LIN-41 RNA-Binding Protein To Ensure a Robust Oocyte-to-Embryo Transition inGenetics · 2018Article
- CDK and MAPK Synergistically Regulate Signaling Dynamics via a Shared Multi-site Phosphorylation Region on the Scaffold Protein Ste5.Molecular cell · 2018Article
- Cell-cycle transitions: a common role for stoichiometric inhibitors.Molecular biology of the cell · 2017Article
- Firing of Replication Origins Frees Dbf4-Cdc7 to Target Eco1 for Destruction.Current biology : CB · 2017Article
- Using Microfluidic Devices to Measure Lifespan and Cellular Phenotypes in Single Budding Yeast Cells.Journal of visualized experiments : JoVE · 2017Article
- Parallel arrangements of positive feedback loops limit cell-to-cell variability in differentiation.PloS one · 2017Article
- A Stochastic Model of the Yeast Cell Cycle Reveals Roles for Feedback Regulation in Limiting Cellular Variability.PLoS computational biology · 2016Article
- Switch-like Transitions Insulate Network Motifs to Modularize Biological Networks.Cell systems · 2016Article
- Cell-Size Control.Cold Spring Harbor perspectives in biology · 2016Review
- Noise Reduction in Complex Biological Switches.Scientific reports · 2016Article
Corrections and comments
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Authors and funding
4 authors at 3 institutions in 2 countries.
Funding
Abstract
A hallmark of the G1/S transition in budding yeast cell cycle is the proteolytic degradation of the B-type cyclin-Cdk stoichiometric inhibitor Sic1. Deleting SIC1 or altering Sic1 degradation dynamics increases genomic instability. Certain key facts about the parts of the G1/S circuitry are established: phosphorylation of Sic1 on multiple sites is necessary for its destruction, and both the upstream kinase Cln1/2-Cdk1 and the downstream kinase Clb5/6-Cdk1 can phosphorylate Sic1 in vitro with varied specificity, cooperativity, and processivity. However, how the system works as a whole is still controversial due to discrepancies between in vitro, in vivo, and theoretical studies. Here, by monitoring Sic1 destruction in real time in individual cells under various perturbations to the system, we provide a clear picture of how the circuitry functions as a switch in vivo. We show that Cln1/2-Cdk1 sets the proper timing of Sic1 destruction, but does not contribute to its destruction speed; thus, it acts only as a trigger. Sic1's inhibition target Clb5/6-Cdk1 controls the speed of Sic1 destruction through a double-negative feedback loop, ensuring a robust all-or-none transition for Clb5/6-Cdk1 activity. Furthermore, we demonstrate that the degradation of a single-phosphosite mutant of Sic1 is rapid and switch-like, just as the wild-type form. Our mathematical model confirms our understanding of the circuit and demonstrates that the substrate sharing between the two kinases is not a redundancy but a part of the design to overcome the trade-off between the timing and sharpness of Sic1 degradation. Our study provides direct mechanistic insight into the design features underlying the yeast G1/S switch.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.