Coupling between the Circadian Clock and Cell Cycle Oscillators: Implication for Healthy Cells and Malignant Growth

Abstract

Uncontrolled cell proliferation is one of the key features leading to cancer. Seminal works in chronobiology have revealed that disruption of the circadian timing system in mice, either by surgical, genetic, or environmental manipulation, increased tumor development. In humans, shift work is a risk factor for cancer. Based on these observations, the link between the circadian clock and cell cycle has become intuitive. But despite identification of molecular connections between the two processes, the influence of the clock on the dynamics of the cell cycle has never been formally observed. Recently, two studies combining single live cell imaging with computational methods have shed light on robust coupling between clock and cell cycle oscillators. We recapitulate here these novel findings and integrate them with earlier results in both healthy and cancerous cells. Moreover, we propose that the cell cycle may be synchronized or slowed down through coupling with the circadian clock, which results in reduced tumor growth. More than ever, systems biology has become instrumental to understand the dynamic interaction between the circadian clock and cell cycle, which is critical in cellular coordination and for diseases such as cancer.

Keywords: cancer; cell cycle; circadian desynchrony; coupling; mathematical modeling.

Figure 1

Image acquisition, fluorescence quantification, period, and phase dynamics in non-synchronized NIH3T3-REVERBα:VENUS_FUCCI cells. (A) Time series of a representative single cycle for the various fluorescent reporters and respective quantified traces: from top to bottom: Cell Cycle_G1 (red) = CDT1:mKO2, Cell Cycle_S/G2/M (blue) = GEMININ:E2CRIMSON, Circadian Clock (green) = REVERBα:VENUS, Merge = fluorescent channels combined with the corresponding brightfield image. Arrows point to tracked cell nuclei. Images are 2.5 h apart. Traces at the bottom have been plotted from measured intensities extracted from tracking with the LineageTracker plugin for ImageJ. (B) Histograms showing distribution of periods for both the clock (green) and cell cycle (red) in the whole population. In non-synchronized cells, mean clock period (19.4 ± 0.5 h) is not significantly different from mean cell cycle period: (18.6 ± 0.6 h). (C) Phase histograms for the same cells. Gray histogram and trace show random background densities. Colored histogram and trace show the observed phase of the clock at division. We observe a preferred clock phase for performing cell division (phase locking).