Diurnal oscillations of endogenous H 2 O 2 sustained by p66 Shc regulate circadian clocks

Nat Cell Biol. 2019 Dec;21(12):1553-1564. doi: 10.1038/s41556-019-0420-4. Epub 2019 Nov 25.


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 H2O2 in mammalian cells and mouse livers. Using an unbiased method to screen for H2O2-sensitive transcription factors, we discovered that rhythmic redox control of CLOCK directly by endogenous H2O2 oscillations is required for proper intracellular clock function. Importantly, perturbations in the rhythm of H2O2 levels induced by the loss of p66Shc, 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Circadian Clocks / physiology*
  • Circadian Rhythm / physiology*
  • Female
  • Hydrogen Peroxide / metabolism*
  • Liver / metabolism
  • Liver / physiology
  • Male
  • Mammals / metabolism
  • Mammals / physiology
  • Mice
  • Mice, Knockout
  • Oxidation-Reduction
  • Period Circadian Proteins / metabolism
  • Signal Transduction / physiology
  • Src Homology 2 Domain-Containing, Transforming Protein 1 / metabolism*
  • Suprachiasmatic Nucleus / metabolism
  • Suprachiasmatic Nucleus / physiology


  • Period Circadian Proteins
  • Shc1 protein, mouse
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Hydrogen Peroxide