Mechanisms of signalling-memory governing progression through the eukaryotic cell cycle

Novák, Béla; Tyson, John J.

doi:10.1101/2020.08.20.259671

Cited by 4 publications

(5 citation statements)

References 42 publications

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“…This transition is characterized by the establishment of gap phases and slowing down of the cell cycle, resulting in a higher resemblance to the cell cycle as typically studied in yeast and mammalian somatic cells. Remarkably, many of the transitions between these additional cell cycle phases are—just like the G2-M transition—governed by bistable switches [ 26 ].…”

Section: Resultsmentioning

confidence: 99%

“…Once these are correctly attached, the cohesin rings that are keeping the sister chromatids together can be cleaved, upon which the chromatids are separated by the mitotic spindle. Although some experimental studies question the all-or-none nature of the SAC [ 21 , 22 ], indirect experimental and theoretical findings support the idea that this transition is also centered around a bistable switch [ 23 – 26 ]. Given the recurring occurrence of all-or-none transitions throughout the cell cycle, the latter has been envisioned as a chain of interlinked bistable switches ( Fig 1B ) [ 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

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A modular approach for modeling the cell cycle based on functional response curves

2021

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Modeling biochemical reactions by means of differential equations often results in systems with a large number of variables and parameters. As this might complicate the interpretation and generalization of the obtained results, it is often desirable to reduce the complexity of the model. One way to accomplish this is by replacing the detailed reaction mechanisms of certain modules in the model by a mathematical expression that qualitatively describes the dynamical behavior of these modules. Such an approach has been widely adopted for ultrasensitive responses, for which underlying reaction mechanisms are often replaced by a single Hill function. Also time delays are usually accounted for by using an explicit delay in delay differential equations. In contrast, however, S-shaped response curves, which by definition have multiple output values for certain input values and are often encountered in bistable systems, are not easily modeled in such an explicit way. Here, we extend the classical Hill function into a mathematical expression that can be used to describe both ultrasensitive and S-shaped responses. We show how three ubiquitous modules (ultrasensitive responses, S-shaped responses and time delays) can be combined in different configurations and explore the dynamics of these systems. As an example, we apply our strategy to set up a model of the cell cycle consisting of multiple bistable switches, which can incorporate events such as DNA damage and coupling to the circadian clock in a phenomenological way.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A modular approach for modeling the cell cycle based on functional response curves

2021

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“…On another note, a recent study suggested that CycD/Cdk4,6 mono-phosphorylates but does not inhibit Rb, and it meanwhile activates CycE/Cdk2 via an unidentified mechanism [54]. Although this new finding and the classic model differ in whether CycD/Cdk4,6 directly inhibits Rb, they are consistent in the role of CycD/Cdk4,6 in leading to CycE/Cdk2 activation and initiating the positive mutual-inhibition loop between Rb and E2f, which eventually leads to E2f activation and the passage of the restriction point during the quiescence-to-proliferation transition [55][56][57][58][59][60].…”

Section: Discussionmentioning

confidence: 79%

Circadian Proteins Cry and Rev-erb Converge to Deepen Cellular Quiescence by Downregulating Cyclin D and Cdk4,6

Wang

Pan

et al. 2021

Preprint

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The proper balance and transition between cellular quiescence and proliferation are critical to tissue homeostasis, and their deregulations are commonly found in many human diseases, including cancer and aging. Recent studies showed that the reentry of quiescent cells to the cell cycle is subjected to circadian regulation. However, the underlying mechanisms are largely unknown. Here, we report that two circadian proteins, Cryptochrome (Cry) and Rev-erb, deepen cellular quiescence in rat embryonic fibroblasts, resulting in stronger serum stimulation required for cells to exit quiescence and reenter the cell cycle. This finding was opposite from what we expected from the literature. By modeling a library of possible regulatory topologies linking Cry and Rev-erb to a bistable Rb-E2f gene network switch that controls the quiescence-to-proliferation transition and by experimentally testing model predictions, we found Cry and Rev-erb converge to downregulate Cyclin D/Cdk4,6 activity, leading to an ultrasensitive increase of the serum threshold to activate the Rb-E2f bistable switch. Our findings suggest a mechanistic role of circadian proteins in modulating the depth of cellular quiescence, which may have implications in the varying potentials of tissue repair and regeneration at different times of the day.

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“…This process is governed by the orderly progression through different phases of the cell cycle. The eukaryotic cell cycle contains various checkpoints and transitions in which bistability plays a role ( Fig 1C), and can even be viewed as a chain of sequentially activated bistable switches [16][17][18][19]. These switches provide robustness and directionality to the cell cycle and ensure the genome's integrity.…”

Section: Introductionmentioning

confidence: 99%

Dynamic bistable switches enhance robustness and accuracy of cell cycle transitions

Rombouts

Gelens

2021

PLoS Comput Biol

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Bistability is a common mechanism to ensure robust and irreversible cell cycle transitions. Whenever biological parameters or external conditions change such that a threshold is crossed, the system abruptly switches between different cell cycle states. Experimental studies have uncovered mechanisms that can make the shape of the bistable response curve change dynamically in time. Here, we show how such a dynamically changing bistable switch can provide a cell with better control over the timing of cell cycle transitions. Moreover, cell cycle oscillations built on bistable switches are more robust when the bistability is modulated in time. Our results are not specific to cell cycle models and may apply to other bistable systems in which the bistable response curve is time-dependent.

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Mechanisms of signalling-memory governing progression through the eukaryotic cell cycle

Cited by 4 publications

References 42 publications

A modular approach for modeling the cell cycle based on functional response curves

A modular approach for modeling the cell cycle based on functional response curves

Circadian Proteins Cry and Rev-erb Converge to Deepen Cellular Quiescence by Downregulating Cyclin D and Cdk4,6

Dynamic bistable switches enhance robustness and accuracy of cell cycle transitions

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