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

AbstractNetworks 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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Quantitative model of eukaryotic Cdk control through the Forkhead CONTROLLER

npj Systems Biology and Applications ◽

10.1038/s41540-021-00187-5 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Matteo Barberis

Keyword(s):

Cell Cycle ◽

Transcription Factors ◽

Cell Division ◽

Design Principle ◽

Budding Yeast ◽

Eukaryotic Cell ◽

Quantitative Model ◽

Sequential Order ◽

Forkhead Transcription Factors

AbstractIn budding yeast, synchronization of waves of mitotic cyclins that activate the Cdk1 kinase occur through Forkhead transcription factors. These molecules act as controllers of their sequential order and may account for the separation in time of incompatible processes. Here, a Forkhead-mediated design principle underlying the quantitative model of Cdk control is proposed for budding yeast. This design rationalizes timing of cell division, through progressive and coordinated cyclin/Cdk-mediated phosphorylation of Forkhead, and autonomous cyclin/Cdk oscillations. A “clock unit” incorporating this design that regulates timing of cell division is proposed for both yeast and mammals, and has a DRIVER operating the incompatible processes that is instructed by multiple CLOCKS. TIMERS determine whether the clocks are active, whereas CONTROLLERS determine how quickly the clocks shall function depending on external MODULATORS. This “clock unit” may coordinate temporal waves of cyclin/Cdk concentration/activity in the eukaryotic cell cycle making the driver operate the incompatible processes, at separate times.

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Quantitative Characterization of a Mitotic Cyclin Threshold Regulating Exit from Mitosis

Molecular Biology of the Cell ◽

10.1091/mbc.e04-10-0897 ◽

2005 ◽

Vol 16 (5) ◽

pp. 2129-2138 ◽

Cited By ~ 32

Author(s):

Frederick R. Cross ◽

Lea Schroeder ◽

Martin Kruse ◽

Katherine C. Chen

Keyword(s):

Cell Cycle ◽

Budding Yeast ◽

Cell Cycle Control ◽

Predictive Ability ◽

Eukaryotic Cell ◽

Model Predictions ◽

Mitotic Cyclin ◽

Constitutive Overexpression

Regulation of cyclin abundance is central to eukaryotic cell cycle control. Strong overexpression of mitotic cyclins is known to lock the system in mitosis, but the quantitative behavior of the control system as this threshold is approached has only been characterized in the in vitro Xenopus extract system. Here, we quantitate the threshold for mitotic block in budding yeast caused by constitutive overexpression of the mitotic cyclin Clb2. Near this threshold, the system displays marked loss of robustness, in that loss or even heterozygosity for some regulators becomes deleterious or lethal, even though complete loss of these regulators is tolerated at normal cyclin expression levels. Recently, we presented a quantitative kinetic model of the budding yeast cell cycle. Here, we use this model to generate biochemical predictions for Clb2 levels, asynchronous as well as through the cell cycle, as the Clb2 overexpression threshold is approached. The model predictions compare well with biochemical data, even though no data of this type were available during model generation. The loss of robustness of the Clb2 overexpressing system is also predicted by the model. These results provide strong confirmation of the model's predictive ability.

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Genetic control of mitosis, meiosis and cellular differentiation during mammalian spermatogenesis

Reproduction Fertility and Development ◽

10.1071/rd9950669 ◽

1995 ◽

Vol 7 (4) ◽

pp. 669 ◽

Cited By ~ 28

Author(s):

DJ Wolgemuth ◽

K Rhee ◽

S Wu ◽

SE Ravnik

Keyword(s):

Cell Cycle ◽

Genetic Control ◽

Current Knowledge ◽

Cell Cycle Control ◽

Mitotic Cell ◽

Eukaryotic Cell ◽

Model Systems ◽

Regulatory Processes ◽

Mammalian Cell Lines ◽

Unique Cell

Gametogenesis in both the male and female mammal represents a specialized and highly regulated series of cell cycle events, involving both mitosis and meiosis as well as subsequent differentiation. Recent advances in our understanding of the genetic control of the eukaryotic cell cycle have underscored the evolutionarily-conserved nature of these regulatory processes. However, most of the data have been obtained from yeast model systems and mammalian cell lines. Furthermore, most of the observations focus on regulation of mitotic cell cycles. In the present paper: (i) aspects of gametogenesis in mammals that represent unique cell-cycle control points are highlighted; (ii) current knowledge on the regulation of the germ cell cycle, in the context of what is known in yeast and other model eukaryotic systems, is summarized; and (iii) strategies that can be used to identify additional cell cycle regulating genes are outlined.

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Faculty Opinions recommendation of Control of cyclin G2 mRNA expression by forkhead transcription factors: novel mechanism for cell cycle control by phosphoinositide 3-kinase and forkhead.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1017747.205418 ◽

2004 ◽

Author(s):

Andrius Kazlauskas

Keyword(s):

Cell Cycle ◽

Transcription Factors ◽

Mrna Expression ◽

Cell Cycle Control ◽

Forkhead Transcription Factors ◽

Cyclin G2 ◽

Phosphoinositide 3 Kinase

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Dual control by Cdk1 phosphorylation of the budding yeast APC/C ubiquitin ligase activator Cdh1

Molecular Biology of the Cell ◽

10.1091/mbc.e15-11-0787 ◽

2016 ◽

Vol 27 (14) ◽

pp. 2198-2212 ◽

Cited By ~ 15

Author(s):

Sebastian Höckner ◽

Lea Neumann-Arnold ◽

Wolfgang Seufert

Keyword(s):

Cell Cycle ◽

Ubiquitin Ligase ◽

Budding Yeast ◽

Cell Cycle Control ◽

Eukaryotic Cell ◽

Negative Control ◽

Nuclear Localization Sequence ◽

Phosphorylation Sites ◽

Localization Sequence ◽

Cdk Phosphorylation

The antagonism between cyclin-dependent kinases (Cdks) and the ubiquitin ligase APC/C-Cdh1 is central to eukaryotic cell cycle control. APC/C-Cdh1 targets cyclin B and other regulatory proteins for degradation, whereas Cdks disable APC/C-Cdh1 through phosphorylation of the Cdh1 activator protein at multiple sites. Budding yeast Cdh1 carries nine Cdk phosphorylation sites in its N-terminal regulatory domain, most or all of which contribute to inhibition. However, the precise role of individual sites has remained unclear. Here, we report that the Cdk phosphorylation sites of yeast Cdh1 are organized into autonomous subgroups and act through separate mechanisms. Cdk sites 1–3 had no direct effect on the APC/C binding of Cdh1 but inactivated a bipartite nuclear localization sequence (NLS) and thereby controlled the partitioning of Cdh1 between cytoplasm and nucleus. In contrast, Cdk sites 4–9 did not influence the cell cycle–regulated localization of Cdh1 but prevented its binding to the APC/C. Cdk sites 4–9 reside near two recently identified APC/C interaction motifs in a pattern conserved with the human Cdh1 orthologue. Thus a Cdk-inhibited NLS goes along with Cdk-inhibited APC/C binding sites in yeast Cdh1 to relay the negative control by Cdk1 phosphorylation of the ubiquitin ligase APC/C-Cdh1.

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ChIP-exo analysis highlights Fkh1 and Fkh2 transcription factors as hubs that integrate multi-scale networks in budding yeast

Nucleic Acids Research ◽

10.1093/nar/gkz603 ◽

2019 ◽

Vol 47 (15) ◽

pp. 7825-7841 ◽

Cited By ~ 1

Author(s):

Thierry D G A Mondeel ◽

Petter Holland ◽

Jens Nielsen ◽

Matteo Barberis

Keyword(s):

Cell Cycle ◽

Signal Transduction ◽

Transcription Factors ◽

Target Genes ◽

Budding Yeast ◽

Biochemical Networks ◽

Molecular Networks ◽

Forkhead Transcription Factors ◽

Multi Scale ◽

Cellular Environment

AbstractThe understanding of the multi-scale nature of molecular networks represents a major challenge. For example, regulation of a timely cell cycle must be coordinated with growth, during which changes in metabolism occur, and integrate information from the extracellular environment, e.g. signal transduction. Forkhead transcription factors are evolutionarily conserved among eukaryotes, and coordinate a timely cell cycle progression in budding yeast. Specifically, Fkh1 and Fkh2 are expressed during a lengthy window of the cell cycle, thus are potentially able to function as hubs in the multi-scale cellular environment that interlocks various biochemical networks. Here we report on a novel ChIP-exo dataset for Fkh1 and Fkh2 in both logarithmic and stationary phases, which is analyzed by novel and existing software tools. Our analysis confirms known Forkhead targets from available ChIP-chip studies and highlights novel ones involved in the cell cycle, metabolism and signal transduction. Target genes are analyzed with respect to their function, temporal expression during the cell cycle, correlation with Fkh1 and Fkh2 as well as signaling and metabolic pathways they occur in. Furthermore, differences in targets between Fkh1 and Fkh2 are presented. Our work highlights Forkhead transcription factors as hubs that integrate multi-scale networks to achieve proper timing of cell division in budding yeast.

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The Role of Retinoblastoma Protein in Cell Cycle Regulation: An Updated Review

Current Molecular Medicine ◽

10.2174/1566524020666210104113003 ◽

2021 ◽

Vol 20 ◽

Author(s):

Rabih Roufayel ◽

Rabih Mezher ◽

Kenneth B. Storey

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Transcription Factors ◽

Cell Cycle Control ◽

Expression Of Genes ◽

E2f Transcription Factor ◽

Cellular Energetics ◽

Development And Differentiation ◽

E2f Transcription Factors ◽

Rb Phosphorylation

: Selected transcription factors have critical roles to play in organism survival by regulating the expression of genes that control the adaptations needed to handle stress conditions. The retinoblastoma (Rb) protein coupled with the E2F transcription factor family was demonstrated to have roles in controlling the cell cycle during freezing and associated environmental stresses (anoxia, dehydration). Rb phosphorylation or acetylation at different sites provide a mechanism for repressing cell proliferation that is under the control of E2F transcription factors in animals facing stresses that disrupt cellular energetics or cell volume controls. Other central regulators of the cell cycle including Cyclins, Cyclin dependent kinases (Cdks), and checkpoint proteins detect DNA damage or any improper replication, blocking further progression of cell cycle and interrupting cell proliferation. This review provides an insight into the molecular regulatory mechanisms of cell cycle control, focusing on Rb-E2F along with Cyclin-Cdk complexes typically involved in development and differentiation that need to be regulated in order to survive extreme cellular stress.

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Budding yeast relies on G1 cyclin specificity to couple cell cycle progression with morphogenetic development

Science Advances ◽

10.1126/sciadv.abg0007 ◽

2021 ◽

Vol 7 (23) ◽

pp. eabg0007

Author(s):

Deniz Pirincci Ercan ◽

Florine Chrétien ◽

Probir Chakravarty ◽

Helen R. Flynn ◽

Ambrosius P. Snijders ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Budding Yeast ◽

Quantitative Model ◽

Cyclin Dependent Kinase ◽

Cycle Progression ◽

Model Cell ◽

Mitotic Cyclin ◽

Substrate Phosphorylation ◽

The Cost

Two models have been put forward for cyclin-dependent kinase (Cdk) control of the cell cycle. In the qualitative model, cell cycle events are ordered by distinct substrate specificities of successive cyclin waves. Alternatively, in the quantitative model, the gradual rise of Cdk activity from G1 phase to mitosis leads to ordered substrate phosphorylation at sequential thresholds. Here, we study the relative contributions of qualitative and quantitative Cdk control in Saccharomyces cerevisiae. All S phase and mitotic cyclins can be replaced by a single mitotic cyclin, albeit at the cost of reduced fitness. A single cyclin can also replace all G1 cyclins to support ordered cell cycle progression, fulfilling key predictions of the quantitative model. However, single-cyclin cells fail to polarize or grow buds and thus cannot survive. Our results suggest that budding yeast has become dependent on G1 cyclin specificity to couple cell cycle progression to essential morphogenetic events.

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