The temporal coordination of biological processes by the circadian clock is an important mechanism, and its disruption has negative health outcomes, including cancer. Experimental and theoretical evidence suggests that the oscillators driving the circadian clock and the cell cycle are coupled through phase locking. We present a detailed and documented SBGN PD map of known mechanisms related to the regulation of the circadian clock, and its coupling with an existing cell cycle SBGN PD map which includes main interactions of the mammalian cell cycle. The coherence of the merged map has been validated with a qualitative dynamics analysis. We verified that the coupled circadian clock and cell cycle maps allow reproducing the observed sequence of phase markers. Moreover, we predicted mutations that contribute to regulating checkpoints of the two oscillators. Strikingly, our approach underlines the potential key role of the core clock protein NR1D1 in regulating cell cycle progression. We predicted that its activity influences negatively the progression of the cell cycle from phase G2 to M. It is consistent with the earlier experimental finding that pharmacological activation of NR1D1 inhibits tumour cell proliferation and shows that our approach can identify biologically relevant species in the context of large and complex networks.

中文翻译：

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昼夜节律时钟和细胞周期耦合的详细图，并进行定性动力学验证

昼夜节律对生物过程的时间协调是一个重要的机制，其破坏具有负面的健康后果，包括癌症。实验和理论证据表明，驱动生物钟和单元周期的振荡器是通过锁相耦合的。我们提出了详细的和已记录的SBGN PD图，涉及与生物钟调节有关的已知机制，以及它与现有细胞周期SBGN PD图的耦合，其中包括哺乳动物细胞周期的主要相互作用。合并图的相干性已通过定性动力学分析得到验证。我们验证了耦合的生物钟和细胞周期图可以重现观察到的相位标记序列。此外，我们预测了有助于调节两个振荡器检查点的突变。令人惊讶的是，我们的方法强调了核心时钟蛋白NR1D1在调节细胞周期进程中的潜在关键作用。我们预测它的活性会对细胞周期从G2期到M期的发展产生负面影响。这与早期的实验发现一致，即NR1D1的药理学激活会抑制肿瘤细胞的增殖，并表明我们的方法可以在生物学背景下鉴定生物学上相关的物种。大型而复杂的网络。