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.

中文翻译：

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p66Shc 维持的内源性 H2O2 的昼夜振荡调节生物钟。

氧化还原平衡是健康生理稳态的基本特征，受生物钟调节，但内源性氧化还原信号是否或如何反过来调节哺乳动物的发条机制仍然未知。在这里，我们报告了哺乳动物细胞和小鼠肝脏中内源性 H2O2 水平的昼夜节律。使用公正的方法筛选 H2O2 敏感转录因子，我们发现正常的细胞内时钟功能需要通过内源性 H2O2 振荡直接对 CLOCK 进行有节奏的氧化还原控制。重要的是，由 p66Shc 的丢失引起的 H2O2 水平节律的扰动，它在小鼠的肝脏和视交叉上核 (SCN) 有节奏地振荡，扰乱了 CLOCK 功能的节律性氧化还原控制，重新编程肝脏转录组振荡，延长小鼠的昼夜节律并调节光诱导的时钟重置。我们的研究结果表明，氧化还原信号节律通过 CLOCK 的可逆氧化修饰与昼夜节律系统内在耦合，并构成哺乳动物中必不可少的机械计时组件。