Bistable Mitotic Switch Governs Cell Division Cycle in Fission Yeast

Core Concepts

The mitotic control system in fission yeast is governed by a bistable switch that regulates the abrupt transition between interphase and mitosis.

Abstract

The content discusses the bistable nature of the mitotic control system in fission yeast cells. Key highlights:

Eukaryotic cell division cycle (G1-S-G2-M) is maintained by irreversible transitions governed by bistable switching mechanisms at key checkpoints.

The authors developed a computational model of the mitotic control system in fission yeast, which includes the regulation of cyclin-dependent kinase (CDK) by inhibitory kinases (Wee1/Mik1) and activating phosphatase (Cdc25).

Stochastic simulations of the model show that the dose-response curves of CDK activity versus fusion protein (non-degradable cyclin) level exhibit bistability, with cells existing in either a low (interphase) or high (mitotic) CDK activity state.

The bistable behavior is dependent on cell size, with larger cells activating CDK at lower fusion protein levels compared to smaller cells.

The authors argue that the experimental data of Patterson et al. (2021) only probed the activation side of the bistable switch and did not provide unequivocal evidence for bistability, as the observations could also be explained by a reversible, size-dependent sigmoidal switch.

To conclusively demonstrate bistability, the authors propose a modified experimental protocol using degradable fusion protein, which would allow observing both the activation and inactivation thresholds of the mitotic switch.

Stats

The level of the active form of CDK increases linearly with fusion protein level, even though the CDK activity sensor saturates at high fusion protein levels.
The cyclin (fusion protein) threshold for CDK activation decreases as a function of cell size, while the threshold for CDK inactivation is less size-dependent.

Quotes

"Bistability of cell cycle transitions has been confirmed experimentally in frog egg extracts, in budding yeast cells and in mammalian cells."
"Interestingly, our model suggests that their experimental data could also be explained by a reversible/sigmoidal switch, and stochastic simulations confirm this supposition."
"To resolve this uncertainty, we propose a simple modification to Patterson's protocol that would allow the C-CDK level to both rise and fall and thereby provide unequivocal evidence for or against a bistable mitotic switch."

Key Insights Distilled From

The bistable mitotic switch in fission yeast

by Novak,B., Ty... at www.biorxiv.org 01-24-2024

https://www.biorxiv.org/content/10.1101/2024.01.23.576917v1

Deeper Inquiries

What other cellular processes or checkpoints in fission yeast or other eukaryotes might also be governed by bistable switches

In addition to the bistable mitotic switch in fission yeast, other cellular processes or checkpoints in eukaryotes might also be governed by bistable switches. For example, the G1/S transition in the cell cycle, where the cell decides whether to commit to DNA replication, could be regulated by a bistable switch. The transition from metaphase to anaphase during mitosis, where the sister chromatids are separated, is another critical checkpoint that could be controlled by a bistable switch. Furthermore, the restriction point in the mammalian cell cycle, which determines whether a cell will proceed through the cell cycle or exit into a quiescent state, could also be governed by a bistable switch mechanism.

How might the bistable mitotic switch be perturbed or disrupted in fission yeast mutants or under different environmental conditions, and what would be the consequences for cell division

The bistable mitotic switch in fission yeast could be perturbed or disrupted in mutants that affect the levels or activities of key components involved in the switch. For example, mutations that alter the expression or function of cyclins or cyclin-dependent kinases (CDKs) could disrupt the bistable behavior of the switch. Additionally, mutations in regulatory proteins such as Wee1, Cdc25, or PP2A, which control the phosphorylation status of CDKs, could also impact the bistability of the switch. Under different environmental conditions, such as changes in nutrient availability or stress, the activity of the mitotic switch components could be altered, leading to dysregulation of the switch. The consequences of perturbing or disrupting the bistable mitotic switch could include aberrant cell cycle progression, failure to properly enter or exit mitosis, and potential genomic instability.

Given the evolutionary conservation of the mitotic control network, how do the insights from fission yeast apply to the regulation of the cell cycle in higher eukaryotes, including humans

The insights gained from studying the bistable mitotic switch in fission yeast can be applied to understanding the regulation of the cell cycle in higher eukaryotes, including humans. The evolutionary conservation of the mitotic control network suggests that similar regulatory mechanisms may be at play in different organisms. For example, the concept of bistability in the control of cell cycle transitions, such as the G2/M checkpoint, is likely to be conserved across species. Understanding how the bistable switch operates in fission yeast can provide valuable insights into the regulation of the cell cycle in higher eukaryotes. This knowledge can be particularly relevant in the context of cancer research, where dysregulation of cell cycle control mechanisms is a hallmark of the disease. By elucidating the principles of bistability in cell cycle regulation, researchers can potentially identify new therapeutic targets for cancer treatment.