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Cell size at S phase initiation: an emergent property of the G1/S network.

Barberis M, Klipp E, Vanoni M, Alberghina L - PLoS Comput. Biol. (2007)

Bottom Line: The model was tested by simulation in several genetic and nutritional setups and was found to be neatly consistent with experimental data.To estimate PS, the authors developed a hybrid model including a probabilistic component for firing of DNA replication origins.Sensitivity analysis of PS provides a novel relevant conclusion: PS is an emergent property of the G1 to S network that strongly depends on growth rate.

View Article: PubMed Central - PubMed

Affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.

ABSTRACT
The eukaryotic cell cycle is the repeated sequence of events that enable the division of a cell into two daughter cells. It is divided into four phases: G1, S, G2, and M. Passage through the cell cycle is strictly regulated by a molecular interaction network, which involves the periodic synthesis and destruction of cyclins that bind and activate cyclin-dependent kinases that are present in nonlimiting amounts. Cyclin-dependent kinase inhibitors contribute to cell cycle control. Budding yeast is an established model organism for cell cycle studies, and several mathematical models have been proposed for its cell cycle. An area of major relevance in cell cycle control is the G1 to S transition. In any given growth condition, it is characterized by the requirement of a specific, critical cell size, PS, to enter S phase. The molecular basis of this control is still under discussion. The authors report a mathematical model of the G1 to S network that newly takes into account nucleo/cytoplasmic localization, the role of the cyclin-dependent kinase Sic1 in facilitating nuclear import of its cognate Cdk1-Clb5, Whi5 control, and carbon source regulation of Sic1 and Sic1-containing complexes. The model was implemented by a set of ordinary differential equations that describe the temporal change of the concentration of the involved proteins and protein complexes. The model was tested by simulation in several genetic and nutritional setups and was found to be neatly consistent with experimental data. To estimate PS, the authors developed a hybrid model including a probabilistic component for firing of DNA replication origins. Sensitivity analysis of PS provides a novel relevant conclusion: PS is an emergent property of the G1 to S network that strongly depends on growth rate.

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Main Events That Occur during the Yeast Cell Cycle(A) General representation of the cell cycle showing the discontinuous events that have to take place only once per cell cycle, namely the S phase and the M phase, spaced with G1 and G2 phases that allow increase of the cell size before DNA replication and cell division, respectively.(B) During the dynamics of the cell cycle, RNA and proteins increase exponentially, while the DNA content show a typical doubling amount until the cell divides to generate a newborn daughter. From G1 to M phases, the cell increases continuously in mass.(C) Typical representation of the cell cycle that points out the coordination of the increase in cell mass with DNA replication and cell division in order to maintain size homeostasis. DNA replication and cell division start only when cells have reached a critical cell size (PS and PM, respectively).(D) General representation of the molecular threshold. It involves two molecules, an activator and an inhibitor. When the activator increases with growth, the threshold is overcome when enough molecules of the activator are made to exceed the inhibitor.
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pcbi-0030064-g001: Main Events That Occur during the Yeast Cell Cycle(A) General representation of the cell cycle showing the discontinuous events that have to take place only once per cell cycle, namely the S phase and the M phase, spaced with G1 and G2 phases that allow increase of the cell size before DNA replication and cell division, respectively.(B) During the dynamics of the cell cycle, RNA and proteins increase exponentially, while the DNA content show a typical doubling amount until the cell divides to generate a newborn daughter. From G1 to M phases, the cell increases continuously in mass.(C) Typical representation of the cell cycle that points out the coordination of the increase in cell mass with DNA replication and cell division in order to maintain size homeostasis. DNA replication and cell division start only when cells have reached a critical cell size (PS and PM, respectively).(D) General representation of the molecular threshold. It involves two molecules, an activator and an inhibitor. When the activator increases with growth, the threshold is overcome when enough molecules of the activator are made to exceed the inhibitor.

Mentions: Typical pie chart representation of the cell cycle (Figure 1A) stresses the discontinuous events that have to take place only once per cell cycle (i.e., S and M phases), but fails to show that proliferating somatic cells are continuously increasing in their mass throughout the cell cycle (Figure 1B). As pointed out as early as 1971 by Mitchinson [1], the “continuous events of the growth cycle” (i.e., increase in cell mass) and the “discontinuous events of the DNA division cycle” (i.e., DNA replication, mitosis, and cell division) need to be tightly coordinated in order to maintain cell size homeostasis. It has been proposed that coordination of mass accumulation with cell cycle progression relies on a sizer mechanism, so that DNA replication and/or cell division start only when cells have reached a critical cell size (see [2] for a review). In this way, tiny newborn cells will have to grow more than mother cells before being able to overcome the cell size checkpoint. Conversely, a larger cell will overcome the cell size checkpoint earlier than the “normal, average” cell. As a result, both small and large cells will stabilize cell size to the “normal, average” value (Figure 1C).


Cell size at S phase initiation: an emergent property of the G1/S network.

Barberis M, Klipp E, Vanoni M, Alberghina L - PLoS Comput. Biol. (2007)

Main Events That Occur during the Yeast Cell Cycle(A) General representation of the cell cycle showing the discontinuous events that have to take place only once per cell cycle, namely the S phase and the M phase, spaced with G1 and G2 phases that allow increase of the cell size before DNA replication and cell division, respectively.(B) During the dynamics of the cell cycle, RNA and proteins increase exponentially, while the DNA content show a typical doubling amount until the cell divides to generate a newborn daughter. From G1 to M phases, the cell increases continuously in mass.(C) Typical representation of the cell cycle that points out the coordination of the increase in cell mass with DNA replication and cell division in order to maintain size homeostasis. DNA replication and cell division start only when cells have reached a critical cell size (PS and PM, respectively).(D) General representation of the molecular threshold. It involves two molecules, an activator and an inhibitor. When the activator increases with growth, the threshold is overcome when enough molecules of the activator are made to exceed the inhibitor.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1851985&req=5

pcbi-0030064-g001: Main Events That Occur during the Yeast Cell Cycle(A) General representation of the cell cycle showing the discontinuous events that have to take place only once per cell cycle, namely the S phase and the M phase, spaced with G1 and G2 phases that allow increase of the cell size before DNA replication and cell division, respectively.(B) During the dynamics of the cell cycle, RNA and proteins increase exponentially, while the DNA content show a typical doubling amount until the cell divides to generate a newborn daughter. From G1 to M phases, the cell increases continuously in mass.(C) Typical representation of the cell cycle that points out the coordination of the increase in cell mass with DNA replication and cell division in order to maintain size homeostasis. DNA replication and cell division start only when cells have reached a critical cell size (PS and PM, respectively).(D) General representation of the molecular threshold. It involves two molecules, an activator and an inhibitor. When the activator increases with growth, the threshold is overcome when enough molecules of the activator are made to exceed the inhibitor.
Mentions: Typical pie chart representation of the cell cycle (Figure 1A) stresses the discontinuous events that have to take place only once per cell cycle (i.e., S and M phases), but fails to show that proliferating somatic cells are continuously increasing in their mass throughout the cell cycle (Figure 1B). As pointed out as early as 1971 by Mitchinson [1], the “continuous events of the growth cycle” (i.e., increase in cell mass) and the “discontinuous events of the DNA division cycle” (i.e., DNA replication, mitosis, and cell division) need to be tightly coordinated in order to maintain cell size homeostasis. It has been proposed that coordination of mass accumulation with cell cycle progression relies on a sizer mechanism, so that DNA replication and/or cell division start only when cells have reached a critical cell size (see [2] for a review). In this way, tiny newborn cells will have to grow more than mother cells before being able to overcome the cell size checkpoint. Conversely, a larger cell will overcome the cell size checkpoint earlier than the “normal, average” cell. As a result, both small and large cells will stabilize cell size to the “normal, average” value (Figure 1C).

Bottom Line: The model was tested by simulation in several genetic and nutritional setups and was found to be neatly consistent with experimental data.To estimate PS, the authors developed a hybrid model including a probabilistic component for firing of DNA replication origins.Sensitivity analysis of PS provides a novel relevant conclusion: PS is an emergent property of the G1 to S network that strongly depends on growth rate.

View Article: PubMed Central - PubMed

Affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.

ABSTRACT
The eukaryotic cell cycle is the repeated sequence of events that enable the division of a cell into two daughter cells. It is divided into four phases: G1, S, G2, and M. Passage through the cell cycle is strictly regulated by a molecular interaction network, which involves the periodic synthesis and destruction of cyclins that bind and activate cyclin-dependent kinases that are present in nonlimiting amounts. Cyclin-dependent kinase inhibitors contribute to cell cycle control. Budding yeast is an established model organism for cell cycle studies, and several mathematical models have been proposed for its cell cycle. An area of major relevance in cell cycle control is the G1 to S transition. In any given growth condition, it is characterized by the requirement of a specific, critical cell size, PS, to enter S phase. The molecular basis of this control is still under discussion. The authors report a mathematical model of the G1 to S network that newly takes into account nucleo/cytoplasmic localization, the role of the cyclin-dependent kinase Sic1 in facilitating nuclear import of its cognate Cdk1-Clb5, Whi5 control, and carbon source regulation of Sic1 and Sic1-containing complexes. The model was implemented by a set of ordinary differential equations that describe the temporal change of the concentration of the involved proteins and protein complexes. The model was tested by simulation in several genetic and nutritional setups and was found to be neatly consistent with experimental data. To estimate PS, the authors developed a hybrid model including a probabilistic component for firing of DNA replication origins. Sensitivity analysis of PS provides a novel relevant conclusion: PS is an emergent property of the G1 to S network that strongly depends on growth rate.

Show MeSH
Related in: MedlinePlus