Diurnal oscillations of endogenous HO sustained by p66 regulate circadian clocks.

Redox balance, an essential feature of healthy physiological steady states, is regulated by circadian clocks, but whether or how endogenous redox signalling conversely regulates clockworks in mammals remains unknown. Here, we report circadian rhythms in the levels of endogenous HO in mammalian cells and mouse livers. Using an unbiased method to screen for HO-sensitive transcription factors, we discovered that rhythmic redox control of CLOCK directly by endogenous HO oscillations is required for proper intracellular clock function. Importantly, perturbations in the rhythm of HO levels induced by the loss of p66, which oscillates rhythmically in the liver and suprachiasmatic nucleus (SCN) of mice, disturb the rhythmic redox control of CLOCK function, reprogram hepatic transcriptome oscillations, lengthen the circadian period in mice and modulate light-induced clock resetting. Our findings suggest that redox signalling rhythms are intrinsically coupled to the circadian system through reversible oxidative modification of CLOCK and constitute essential mechanistic timekeeping components in mammals.