Zhou, M., Diwu, Z., Panchuk-Voloshina, N. SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging. Red fluorescent genetically encoded indicator for intracellular hydrogen peroxide. NRF2 regulates core and stabilizing circadian clock loops, coupling redox and timekeeping in Mus musculus. Mammalian circadian period, but not phase and amplitude, is robust against redox and metabolic perturbations. In vitro and in vivo phase changes of the mouse circadian clock by oxidative stress. Cellular mechanisms and physiological consequences of redox-dependent signalling. ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis. Hydrogen peroxide: a metabolic by-product or a common mediator of ageing signals? Nat. Reconciling the chemistry and biology of reactive oxygen species. Circadian clocks in human red blood cells. Metabolic and nontranscriptional circadian clocks: eukaryotes. Transcriptional architecture of the mammalian circadian clock. Plant circadian clocks increase photosynthesis, growth, survival, and competitive advantage. Circadian integration of metabolism and energetics. All other data supporting the findings of this study are available from the corresponding authors on reasonable request.īass, J. Unprocessed blots are provided in the Source Data. Source data are available online for Figs. Mass spectrometry data generated for the H 2O 2-sensitive TF screen and mass spectrometry data for purified CLOCK protein have been deposited to the ProteomeXchange Consortium ( ) through the iProX partner repository with the dataset identifiers PXD015265 and PXD015266, respectively. 36) and in the Protein Data Bank (PDB) under accession code 4F3L (ref. Previously published ChIP-seq data and crystal structure that were reanalysed here are available in the Gene Expression Omnibus (GEO) under accession code GSE39860 (ref. RNA-seq data that support the findings of this study have been deposited in the Sequence Read Archive (SRA) under accession code PRJNA449625. 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. Importantly, perturbations in the rhythm of H 2O 2 levels induced by the loss of p66 Shc, 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. Using an unbiased method to screen for H 2O 2-sensitive transcription factors, we discovered that rhythmic redox control of CLOCK directly by endogenous H 2O 2 oscillations is required for proper intracellular clock function. Here, we report circadian rhythms in the levels of endogenous H 2O 2 in mammalian cells and mouse livers. 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.
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