文章基本信息

标题：A feedback loop of conditionally stable circuits drives the cell cycle from checkpoint to checkpoint
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作者：Dávid Deritei ; Jordan Rozum ; Erzsébet Ravasz Regan 等
期刊名称：Scientific Reports
电子版ISSN：2045-2322
出版年度：2019
卷号：9
期号：1
页码：1-19
DOI：10.1038/s41598-019-52725-1
出版社：Springer Nature
摘要：We perform logic-based network analysis on a model of the mammalian cell cycle. This model is composed of a Restriction Switch driving cell cycle commitment and a Phase Switch driving mitotic entry and exit. By generalizing the concept of stable motif, i.e., a self-sustaining positive feedback loop that maintains an associated state, we introduce the concept of a conditionally stable motif, the stability of which is contingent on external conditions. We show that the stable motifs of the Phase Switch are contingent on the state of three nodes through which it receives input from the rest of the network. Biologically, these conditions correspond to cell cycle checkpoints. Holding these nodes locked (akin to a checkpoint-free cell) transforms the Phase Switch into an autonomous oscillator that robustly toggles through the cell cycle phases G1, G2 and mitosis. The conditionally stable motifs of the Phase Switch Oscillator are organized into an ordered sequence, such that they serially stabilize each other but also cause their own destabilization. Along the way they channel the dynamics of the module onto a narrow path in state space, lending robustness to the oscillation. Self-destabilizing conditionally stable motifs suggest a general negative feedback mechanism leading to sustained oscillations.