Robust synchronization of the cell cycle and the circadian clock through bidirectional coupling

Sep 12, 2019Journal of the Royal Society, Interface

Strong two-way coordination between the cell cycle and the body’s daily clock

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Abstract

Bidirectional coupling of the cell cycle and circadian clock can lead to robust synchronization of these cellular rhythms.

The circadian factor BMAL1 regulates cell cycle proteins like Cyclin E and WEE1, which influences the G2/M transition.
CDK1, a kinase involved in the cell cycle, directly affects REV-ERBα, which negatively regulates BMAL1, indicating a feedback loop.
Weak coupling allows the two rhythms to oscillate independently, while stronger coupling in either direction can lead to synchronization.
Synchronization can occur at periods within or even outside the range defined by the two autonomous periods prior to coupling.
Complex oscillations are less likely with bidirectional coupling compared to unidirectional coupling, which enhances stability in synchronization.
Multiple modes of synchronization, such as birhythmicity or trirhythmicity, may coexist under certain conditions.

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The cell cycle and the circadian clock represent major cellular rhythms, which appear to be coupled. Thus the circadian factor BMAL1 controls the level of cell cycle proteins such as Cyclin E and WEE1, the latter of which inhibits the kinase CDK1 that governs the G2/M transition. In reverse the cell cycle impinges on the circadian clock through direct control by CDK1 of REV-ERBα, which negatively regulates BMAL1. These observations provide evidence for bidirectional coupling of the cell cycle and the circadian clock. By merging detailed models for the two networks in mammalian cells, we previously showed that unidirectional coupling to the circadian clock can entrain the cell cycle to 24 or 48 h, depending on the cell cycle autonomous period, while complex oscillations occur when entrainment fails. Here we show that the reverse unidirectional coupling via phosphorylation of REV-ERBα or via mitotic inhibition of transcription, both controlled by CDK1, can elicit entrainment of the circadian clock by the cell cycle. We then determine the effect of bidirectional coupling of the cell cycle and circadian clock as a function of their relative coupling strengths. In contrast to unidirectional coupling, bidirectional coupling markedly reduces the likelihood of complex oscillations. While the two rhythms oscillate independently as long as both couplings are weak, one rhythm entrains the other if one of the couplings dominates. If the couplings in both directions become stronger and of comparable magnitude, the two rhythms synchronize, generally at an intermediate period within the range defined by the two autonomous periods prior to coupling. More surprisingly, synchronization may also occur at a period slightly below or above this range, while in some conditions the synchronization period can even be much longer. Two or even three modes of synchronization may sometimes coexist, yielding examples of birhythmicity or trirhythmicity. Because synchronization readily occurs in the form of simple periodic oscillations over a wide range of coupling strengths and in the presence of multiple connections between the two oscillatory networks, the results indicate that bidirectional coupling favours the robust synchronization of the cell cycle and the circadian clock.

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Robust synchronization of the cell cycle and the circadian clock through bidirectional coupling

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