Toggle switches are widely used to make critical all-or-none decisions such as cell differentiation or apoptosis. While the toggle switch can be generated by using a single-type positive feedback loop (PFL), a natural toggle switch frequently emerges from interlocked PFLs composed of two different types of PFLs: one with two mutually activated units and the other with two mutually inhibiting units. To investigate the advantage of the interlocked PFL over the single type of PFL, here, we carefully analyze how the interlocked PFLs generate bistability and thus the toggle switch. We find that in the interlocked PFLs, mutual activation and mutual inhibition cooperate to generate a robust merged bistability. Interestingly, we also find that turning-on and turning-off of the merged bistability can be flexibly controlled by using the balance between the strengths of two competing PFLs. We illustrate the role of such robust and tunable joint toggle switches of the interlocked PFLs in the DNA damage checkpoint control of G2/M transition. Our work describes how natural toggle switches achieve two critical properties, robustness and tunability, simultaneously by merging opposite types of PFLs.

中文翻译：

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具有互锁正反馈回路的稳健且可调的拨动开关

切换开关广泛用于做出关键的全有或全无决策，例如细胞分化或细胞凋亡。虽然可以使用单一类型的正反馈回路 (PFL) 生成拨动开关，但自然拨动开关经常从由两种不同类型的 PFL 组成的互锁 PFL 中出现：一种具有两个相互激活的单元，另一个具有两个相互抑制的单元单位。为了研究互锁 PFL 相对于单一类型 PFL 的优势，在这里，我们仔细分析了互锁 PFL 如何产生双稳态，从而产生拨动开关。我们发现在互锁的 PFL 中，相互激活和相互抑制合作产生强大的合并双稳态。有趣的是，我们还发现，通过利用两个相互竞争的 PFL 的强度之间的平衡，可以灵活地控制合并双稳态的开启和关闭。我们说明了互锁 PFL 的这种稳健且可调的关节拨动开关在 G2/M 过渡的 DNA 损伤检查点控制中的作用。我们的工作描述了自然拨动开关如何通过合并相反类型的 PFL 来同时实现两个关键特性，即稳健性和可调谐性。