Modeling the Effects of Cell Cycle M-phase Transcriptional Inhibition on Circadian Oscillation

Circadian clocks are endogenous time-keeping systems that temporally organize biological processes. Gating of cell cycle events by a circadian clock is a universal observation that is currently considered a mechanism serving to protect DNA from diurnal exposure to ultraviolet radiation or other mutagens. In this study, we put forward another possibility: that such gating helps to insulate the circadian clock from perturbations induced by transcriptional inhibition during the M phase of the cell cycle. We introduced a periodic pulse of transcriptional inhibition into a previously published mammalian circadian model and simulated the behavior of the modified model under both constant darkness and light–dark cycle conditions. The simulation results under constant darkness indicated that periodic transcriptional inhibition could entrain/lock the circadian clock just as a light–dark cycle does. At equilibrium states, a transcriptional inhibition pulse of certain periods was always locked close to certain circadian phases where inhibition on Per and Bmal1 mRNA synthesis was most balanced. In a light–dark cycle condition, inhibitions imposed at different parts of a circadian period induced different degrees of perturbation to the circadian clock. When imposed at the middle- or late-night phase, the transcriptional inhibition cycle induced the least perturbations to the circadian clock. The late-night time window of least perturbation overlapped with the experimentally observed time window, where mitosis is most frequent. This supports our hypothesis that the circadian clock gates the cell cycle M phase to certain circadian phases to minimize perturbations induced by the latter. This study reveals the hidden effects of the cell division cycle on the circadian clock and, together with the current picture of genome stability maintenance by circadian gating of cell cycle, provides a more comprehensive understanding of the phenomenon of circading gating of cell cycle.Author Summary: Circadian clock and cell cycle are two important biological processes that are essential for nearly all eukaryotes. The circadian clock governs day and night 24 h periodic molecular processes and physiological behaviors, while cell cycle controls cell division process. It has been widely observed that cell division does not occur randomly across day and night, but instead is normally confined to specific times during day and night. These observations suggest that cell cycle events are gated by the circadian clock. Regarding the biological benefit and rationale for this intriguing gating phenomena, it has been postulated that circadian gating helps to maintain genome stability by confining radiation-sensitive cell cycle phases to night. Bearing in mind the facts that global transcriptional inhibition occurs at cell division and transcriptional inhibition shifts circadian phases and periods, we postulate that confining cell division to specific circadian times benefits the circadian clock by removing or minimizing the side effects of cell division on the circadian clock. Our results based on computational simulation in this study show that periodic transcriptional inhibition can perturb the circadian clock by altering circadian phases and periods, and the magnitude of the perturbation is clearly circadian phase dependent. Specifically, transcriptional inhibition initiated at certain circadian phases induced minimal perturbation to the circadian clock. These results provide support for our postulation. Our postulation and results point to the importance of the effect of cell division on the circadian clock in the interaction between circadian and cell cycle and suggest that it should be considered together with other factors in the exploitation of circadian cell cycle interaction, especially the phenomena of circadian gating of cell cycle.