The Cdk1–APC/C cell cycle oscillator circuit functions as a time-delayed, ultrasensitive switch

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Abstract
Frog embryonic cell cycles are driven by oscillations in the activity of cyclin B–Cdk1. This complex activates the E3 ligase APC/CCdc20, which in turn causes cyclin B degradation, creating a negative feedback loop. Yang and Ferrell combine experimentation and mathematical modelling to demonstrate that the loop functions as a time-delayed ultrasensitive switch that promotes robust oscillations. Despite the complexity and variety of biological oscillators, their core design invariably includes an essential negative feedback loop. In the Xenopus laevis embryonic cell cycle oscillator, this loop consists of the kinase cyclin B–Cdk1 and the ubiquitin ligase APC/CCdc20; active Cdk1 activates APC/CCdc20, which then brings about cyclin B degradation and inactivates Cdk1. Here we ask how this negative feedback loop functions quantitatively, with the aim of understanding what mechanisms keep the Cdk1–APC/CCdc20 system from settling into a stable steady state with intermediate levels of Cdk1 and APC/CCdc20 activity. We found that the system operates as a time-delayed, digital switch, with a time lag of ∼ 15 min between Cdk1 and APC/CCdc20 activation and a tremendously high degree of ultrasensitivity (nH≈17). Computational modelling shows how these attributes contribute to the generation of robust, clock-like oscillations. Principles uncovered here may also apply to other activator–repressor oscillators and help in designing robust synthetic clocks.

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