The positive circadian regulators CLOCK and BMAL1 control G2/M cell cycle transition through Cyclin B1 FarshadiElham YanJie LeclerePierre GoldbeterAlbert ChavesInĂªs van der HorstGijsbertus T. J. 2019 <p>We previously identified a tight bidirectional phase coupling between the circadian clock and the cell cycle. To understand the role of the CLOCK/BMAL1 complex, representing the main positive regulator of the circadian oscillator, we knocked down <i>Bmal1</i> or <i>Clock</i> in NIH3T3<sup>3C</sup> mouse fibroblasts (carrying fluorescent reporters for clock and cell cycle phase) and analyzed timing of cell division in individual cells and cell populations. Inactivation of <i>Bmal1</i> resulted in a loss of circadian rhythmicity and a lengthening of the cell cycle, originating from delayed G2/M transition. Subsequent molecular analysis revealed reduced levels of Cyclin B1, an important G2/M regulator, upon suppression of <i>Bmal1</i> gene expression. In complete agreement with these experimental observations, simulation of <i>Bmal1</i> knockdown in a computational model for coupled mammalian circadian clock and cell cycle oscillators (now incorporating <i>Cyclin B1</i> induction by BMAL1) revealed a lengthening of the cell cycle. Similar data were obtained upon knockdown of <i>Clock</i> gene expression. In conclusion, the CLOCK/BMAL1 complex controls cell cycle progression at the level of G2/M transition through regulation of <i>Cyclin B1</i> expression.</p>