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在时空逻辑模型中统一有丝分裂退出控制机制。

Unifying the mechanism of mitotic exit control in a spatiotemporal logical model.

作者信息

Howell Rowan S M, Klemm Cinzia, Thorpe Peter H, Csikász-Nagy Attila

机构信息

The Francis Crick Institute, London, United Kingdom.

Randall Centre for Cell and Molecular Biophysics, King's College London, London, United Kingdom.

出版信息

PLoS Biol. 2020 Nov 12;18(11):e3000917. doi: 10.1371/journal.pbio.3000917. eCollection 2020 Nov.

Abstract

The transition from mitosis into the first gap phase of the cell cycle in budding yeast is controlled by the Mitotic Exit Network (MEN). The network interprets spatiotemporal cues about the progression of mitosis and ensures that release of Cdc14 phosphatase occurs only after completion of key mitotic events. The MEN has been studied intensively; however, a unified understanding of how localisation and protein activity function together as a system is lacking. In this paper, we present a compartmental, logical model of the MEN that is capable of representing spatial aspects of regulation in parallel to control of enzymatic activity. We show that our model is capable of correctly predicting the phenotype of the majority of mutants we tested, including mutants that cause proteins to mislocalise. We use a continuous time implementation of the model to demonstrate that Cdc14 Early Anaphase Release (FEAR) ensures robust timing of anaphase, and we verify our findings in living cells. Furthermore, we show that our model can represent measured cell-cell variation in Spindle Position Checkpoint (SPoC) mutants. This work suggests a general approach to incorporate spatial effects into logical models. We anticipate that the model itself will be an important resource to experimental researchers, providing a rigorous platform to test hypotheses about regulation of mitotic exit.

摘要

在芽殖酵母中,从有丝分裂过渡到细胞周期的第一个间隙期是由有丝分裂退出网络(MEN)控制的。该网络解读有关有丝分裂进程的时空线索,并确保Cdc14磷酸酶仅在关键有丝分裂事件完成后才释放。人们对MEN进行了深入研究;然而,对于其定位和蛋白质活性如何作为一个系统共同发挥作用,仍缺乏统一的认识。在本文中,我们提出了一个MEN的分区逻辑模型,该模型能够在控制酶活性的同时,并行表示调控的空间方面。我们表明,我们的模型能够正确预测我们测试的大多数突变体的表型,包括导致蛋白质定位错误的突变体。我们使用该模型的连续时间实现来证明Cdc14早期后期释放(FEAR)确保了后期的稳健时间,并在活细胞中验证了我们的发现。此外,我们表明我们的模型可以表示纺锤体位置检查点(SPoC)突变体中测量到的细胞间差异。这项工作提出了一种将空间效应纳入逻辑模型的通用方法。我们预计该模型本身将成为实验研究人员的重要资源,为测试有关有丝分裂退出调控的假设提供一个严谨的平台。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e0ad/7685450/0e1f2d64023a/pbio.3000917.g001.jpg

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