scholarly journals Abundances of transcripts, proteins, and metabolites in the cell cycle of budding yeast reveals coordinate control of lipid metabolism

2019 ◽  
Author(s):  
Heidi M. Blank ◽  
Ophelia Papoulas ◽  
Nairita Maitra ◽  
Riddhiman Garge ◽  
Brian K. Kennedy ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Lipid Metabolism ◽  
Cell Division ◽  
Ribosome Biogenesis ◽  
Budding Yeast ◽  
Eukaryotic Cell ◽  
Yeast Cells ◽  
Protein Levels ◽  
Coordinate Control ◽  
Cycle Dependent

ABSTRACTEstablishing the pattern of abundance of molecules of interest during cell division has been a long-standing goal of cell cycle studies. In several systems, including the budding yeast Saccharomyces cerevisiae, cell cycle-dependent changes in the transcriptome are well studied. In contrast, few studies queried the proteome during cell division, and they are often plagued by low agreement with each other and with previous transcriptomic datasets. There is also little information about dynamic changes in the levels of metabolites and lipids in the cell cycle. Here, for the first time in any system, we present experiment-matched datasets of the levels of RNAs, proteins, metabolites, and lipids from un-arrested, growing, and synchronously dividing yeast cells. Overall, transcript and protein levels were correlated, but specific processes that appeared to change at the RNA level (e.g., ribosome biogenesis), did not do so at the protein level, and vice versa. We also found no significant changes in codon usage or the ribosome content during the cell cycle. We describe an unexpected mitotic peak in the abundance of ergosterol and thiamine biosynthesis enzymes. Although the levels of several metabolites changed in the cell cycle, by far the most significant changes were in the lipid repertoire, with phospholipids and triglycerides peaking strongly late in the cell cycle. Our findings provide an integrated view of the abundance of biomolecules in the eukaryotic cell cycle and point to a coordinate mitotic control of lipid metabolism.

scholarly journals Abundances of transcripts, proteins, and metabolites in the cell cycle of budding yeast reveal coordinate control of lipid metabolism

2020 ◽  
Vol 31 (10) ◽  
pp. 1069-1084 ◽  
Author(s):  
Heidi M. Blank ◽  
Ophelia Papoulas ◽  
Nairita Maitra ◽  
Riddhiman Garge ◽  
Brian K. Kennedy ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Lipid Metabolism ◽  
Cell Division ◽  
Yeast Cell ◽  
Budding Yeast ◽  
Yeast Cells ◽  
Dynamic Changes ◽  
Coordinate Control ◽  
Cycle Dependent ◽  
Budding Yeast Cell Cycle

In several systems, including budding yeast, cell cycle-dependent changes in the transcriptome are well studied. In contrast, few studies queried the proteome during cell division. There is also little information about dynamic changes in metabolites and lipids in the cell cycle. Here, the authors present such information for dividing yeast cells.

scholarly journals Effects of cell-cycle-dependent expression on random fluctuations in protein levels

2016 ◽  
Vol 3 (12) ◽  
pp. 160578 ◽  
Author(s):  
Mohammad Soltani ◽  
Abhyudai Singh
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Protein Levels ◽  
Stochastic Component ◽  
Stochastic Expression ◽  
A Cell ◽  
Intrinsic Stochasticity ◽  
Cycle Dependent ◽  
Random Fluctuations ◽  
Cell To Cell Variability

Expression of many genes varies as a cell transitions through different cell-cycle stages. How coupling between stochastic expression and cell cycle impacts cell-to-cell variability (noise) in the level of protein is not well understood. We analyse a model where a stable protein is synthesized in random bursts, and the frequency with which bursts occur varies within the cell cycle. Formulae quantifying the extent of fluctuations in the protein copy number are derived and decomposed into components arising from the cell cycle and stochastic processes. The latter stochastic component represents contributions from bursty expression and errors incurred during partitioning of molecules between daughter cells. These formulae reveal an interesting trade-off: cell-cycle dependencies that amplify the noise contribution from bursty expression also attenuate the contribution from partitioning errors. We investigate the existence of optimum strategies for coupling expression to the cell cycle that minimize the stochastic component. Intriguingly, results show that a zero production rate throughout the cell cycle, with expression only occurring just before cell division, minimizes noise from bursty expression for a fixed mean protein level. By contrast, the optimal strategy in the case of partitioning errors is to make the protein just after cell division. We provide examples of regulatory proteins that are expressed only towards the end of the cell cycle, and argue that such strategies enhance robustness of cell-cycle decisions to the intrinsic stochasticity of gene expression.

scholarly journals Schizosaccharomyces pombe Noc3 Is Essential for Ribosome Biogenesis and Cell Division but Not DNA Replication

2008 ◽  
Vol 7 (9) ◽  
pp. 1433-1440 ◽  
Author(s):  
Christopher R. Houchens ◽  
Audrey Perreault ◽  
François Bachand ◽  
Thomas J. Kelly
Keyword(s):  
Cell Division ◽  
Dna Replication ◽  
Schizosaccharomyces Pombe ◽  
Fission Yeast ◽  
Ribosome Biogenesis ◽  
Budding Yeast ◽  
Ribosomal Subunit ◽  
Dna Helicase ◽  
Yeast Cells ◽  
Direct Role

ABSTRACT The initiation of eukaryotic DNA replication is preceded by the assembly of prereplication complexes (pre-RCs) at chromosomal origins of DNA replication. Pre-RC assembly requires the essential DNA replication proteins ORC, Cdc6, and Cdt1 to load the MCM DNA helicase onto chromatin. Saccharomyces cerevisiae Noc3 (ScNoc3), an evolutionarily conserved protein originally implicated in 60S ribosomal subunit trafficking, has been proposed to be an essential regulator of DNA replication that plays a direct role during pre-RC formation in budding yeast. We have cloned Schizosaccharomyces pombe noc3 + (Spnoc3 +), the S. pombe homolog of the budding yeast ScNOC3 gene, and functionally characterized the requirement for the SpNoc3 protein during ribosome biogenesis, cell cycle progression, and DNA replication in fission yeast. We showed that fission yeast SpNoc3 is a functional homolog of budding yeast ScNoc3 that is essential for cell viability and ribosome biogenesis. We also showed that SpNoc3 is required for the normal completion of cell division in fission yeast. However, in contrast to the proposal that ScNoc3 plays an essential role during DNA replication in budding yeast, we demonstrated that fission yeast cells do enter and complete S phase in the absence of SpNoc3, suggesting that SpNoc3 is not essential for DNA replication in fission yeast.

scholarly journals Using Budding Yeast to Identify Molecules That Block Cancer Cell ‘Mitotic Slippage’ Only in the Presence of Mitotic Poisons

2021 ◽  
Vol 22 (15) ◽  
pp. 7985
Author(s):  
Scott C. Schuyler ◽  
Hsin-Yu Chen
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Drug Targets ◽  
Budding Yeast ◽  
Eukaryotic Cell ◽  
Mitotic Checkpoint ◽  
Chemotherapeutic Agents ◽  
Cell Cycle Checkpoints ◽  
Yeast Saccharomyces Cerevisiae ◽  
Mitotic Slippage

Research on the budding yeast Saccharomyces cerevisiae has yielded fundamental discoveries on highly conserved biological pathways and yeast remains the best-studied eukaryotic cell in the world. Studies on the mitotic cell cycle and the discovery of cell cycle checkpoints in budding yeast has led to a detailed, although incomplete, understanding of eukaryotic cell cycle progression. In multicellular eukaryotic organisms, uncontrolled aberrant cell division is the defining feature of cancer. Some of the most successful classes of anti-cancer chemotherapeutic agents are mitotic poisons. Mitotic poisons are thought to function by inducing a mitotic spindle checkpoint-dependent cell cycle arrest, via the assembly of the highly conserved mitotic checkpoint complex (MCC), leading to apoptosis. Even in the presence of mitotic poisons, some cancer cells continue cell division via ‘mitotic slippage’, which may correlate with a cancer becoming refractory to mitotic poison chemotherapeutic treatments. In this review, knowledge about budding yeast cell cycle control is explored to suggest novel potential drug targets, namely, specific regions in the highly conserved anaphase-promoting complex/cyclosome (APC/C) subunits Apc1 and/or Apc5, and in a specific N-terminal region in the APC/C co-factor cell division cycle 20 (Cdc20), which may yield molecules which block ‘mitotic slippage’ only in the presence of mitotic poisons.

scholarly journals Quantitative model of eukaryotic Cdk control through the Forkhead CONTROLLER

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.

scholarly journals TORC1 and PKA activity towards ribosome biogenesis oscillates in synchrony with the budding yeast cell cycle

2021 ◽  
Author(s):  
Paolo Guerra ◽  
Luc-Alban Vuillemenot ◽  
Marije Been ◽  
Andreas Milias-Argeits
Keyword(s):  
Cell Cycle ◽  
Mammalian Cells ◽  
Ribosome Biogenesis ◽  
Growth Regulation ◽  
Budding Yeast ◽  
Time Lapse ◽  
Yeast Cells ◽  
Dynamic Coupling ◽  
External Conditions ◽  
Budding Yeast Cell Cycle

Recent studies have revealed that the growth rate of budding yeast and mammalian cells varies during the cell cycle. By linking a multitude of signals to cell growth, the highly conserved Target of Rapamycin Complex 1 (TORC1) and Protein Kinase A (PKA) pathways are prime candidates for mediating the dynamic coupling between growth and division. However, measurements of TORC1 and PKA activity during the cell cycle are still lacking. Following the localization dynamics of two TORC1 and PKA targets via time-lapse microscopy in hundreds of yeast cells, we found that the activity of these pathways towards ribosome biogenesis fluctuates in synchrony with the cell cycle even under constant external conditions. Mutations of upstream TORC1 and PKA regulators suggested that internal metabolic signals partially mediate these activity changes. Our study reveals a new aspect of TORC1 and PKA signaling, which will be important for understanding growth regulation during the cell cycle.

scholarly journals How the cell cycle clock ticks

2019 ◽  
Vol 30 (2) ◽  
pp. 169-172 ◽  
Author(s):  
Mihkel Örd ◽  
Mart Loog
Keyword(s):  
Cell Cycle ◽  
Control System ◽  
Cell Division ◽  
Control Process ◽  
Eukaryotic Cell ◽  
Yeast Cells ◽  
Molecular Events ◽  
Core Elements ◽  
Mitotic Cyclin ◽  
Cellular Control

Eukaryotic cell division has been studied thoroughly and is understood in great mechanistic detail. Paradoxically, however, we lack an understanding of its core control process, in which the master regulator of the cell cycle, cyclin-dependent kinase (CDK), temporally coordinates an array of complex molecular events. The core elements of the CDK control system are conserved in eukaryotic cells, which contain multiple cyclin–CDK forms that have poorly defined and partially overlapping responsibilities in the cell cycle. However, a single CDK can drive all events of cell division in both mammalian and yeast cells, and in fission yeast a single mitotic cyclin can drive the cell cycle without major problems. But how can the same CDK induce different events when activated at different times during the cell cycle? This question, which has bewildered cell cycle researchers for decades, now has a sufficiently clear mechanistic answer. This Perspective aims to provide a synthesis of recent data to facilitate a better understanding of this central cellular control system.

scholarly journals Systems Level Modeling of the Cell Cycle Using Budding Yeast

2007 ◽  
Vol 3 ◽  
pp. 117693510700300 ◽  
Author(s):  
B.P. Ingalls ◽  
B.P. Duncker ◽  
D.R. Kim ◽  
B.J. McConkey
Keyword(s):  
Cell Cycle ◽  
Budding Yeast ◽  
Human Cancer ◽  
Quality Data ◽  
Cell Cycle Gene ◽  
Mathematical Framework ◽  
Gene Transcript ◽  
Proteomics Data ◽  
Yeast Saccharomyces Cerevisiae ◽  
Protein Levels

Proteins involved in the regulation of the cell cycle are highly conserved across all eukaryotes, and so a relatively simple eukaryote such as yeast can provide insight into a variety of cell cycle perturbations including those that occur in human cancer. To date, the budding yeast Saccharomyces cerevisiae has provided the largest amount of experimental and modeling data on the progression of the cell cycle, making it a logical choice for in-depth studies of this process. Moreover, the advent of methods for collection of high-throughput genome, transcriptome, and proteome data has provided a means to collect and precisely quantify simultaneous cell cycle gene transcript and protein levels, permitting modeling of the cell cycle on the systems level. With the appropriate mathematical framework and sufficient and accurate data on cell cycle components, it should be possible to create a model of the cell cycle that not only effectively describes its operation, but can also predict responses to perturbations such as variation in protein levels and responses to external stimuli including targeted inhibition by drugs. In this review, we summarize existing data on the yeast cell cycle, proteomics technologies for quantifying cell cycle proteins, and the mathematical frameworks that can integrate this data into representative and effective models. Systems level modeling of the cell cycle will require the integration of high-quality data with the appropriate mathematical framework, which can currently be attained through the combination of dynamic modeling based on proteomics data and using yeast as a model organism.

scholarly journals The Small Subunit Processome Is Required for Cell Cycle Progression at G1

2004 ◽  
Vol 15 (11) ◽  
pp. 5038-5046 ◽  
Author(s):  
Kara A. Bernstein ◽  
Susan J. Baserga
Keyword(s):  
Cell Cycle ◽  
Ribosome Biogenesis ◽  
Cell Cycle Progression ◽  
Small Subunit ◽  
Cellular Growth ◽  
Yeast Cells ◽  
G1 Phase ◽  
Relay Cell ◽  
Ssu Processome ◽  
Nucleolar Rna

Without ribosome biogenesis, translation of mRNA into protein ceases and cellular growth stops. We asked whether ribosome biogenesis is cell cycle regulated in the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, and we determined that it is not regulated in the same manner as in metazoan cells. We therefore turned our attention to cellular sensors that relay cell size information via ribosome biogenesis. Our results indicate that the small subunit (SSU) processome, a complex consisting of 40 proteins and the U3 small nucleolar RNA necessary for ribosome biogenesis, is not mitotically regulated. Furthermore, Nan1/Utp17, an SSU processome protein, does not provide a link between ribosome biogenesis and cell growth. However, when individual SSU processome proteins are depleted, cells arrest in the G1 phase of the cell cycle. This arrest was further supported by the lack of staining for proteins expressed in post-G1. Similarly, synchronized cells depleted of SSU processome proteins did not enter G2. This suggests that when ribosomes are no longer made, the cells stall in the G1. Therefore, yeast cells must grow to a critical size, which is dependent upon having a sufficient number of ribosomes during the G1 phase of the cell cycle, before cell division can occur.

scholarly journals Quantitative Characterization of a Mitotic Cyclin Threshold Regulating Exit from Mitosis

2005 ◽  
Vol 16 (5) ◽  
pp. 2129-2138 ◽  
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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