MRC Laboratory of Molecular Biology, Cambridge, UK.
Biozentrum Universität, Würzburg, Germany.
EMBO J. 2021 Apr 1;40(7):e106745. doi: 10.15252/embj.2020106745. Epub 2021 Jan 25.
Circadian rhythms are a pervasive property of mammalian cells, tissues and behaviour, ensuring physiological adaptation to solar time. Models of cellular timekeeping revolve around transcriptional feedback repression, whereby CLOCK and BMAL1 activate the expression of PERIOD (PER) and CRYPTOCHROME (CRY), which in turn repress CLOCK/BMAL1 activity. CRY proteins are therefore considered essential components of the cellular clock mechanism, supported by behavioural arrhythmicity of CRY-deficient (CKO) mice under constant conditions. Challenging this interpretation, we find locomotor rhythms in adult CKO mice under specific environmental conditions and circadian rhythms in cellular PER2 levels when CRY is absent. CRY-less oscillations are variable in their expression and have shorter periods than wild-type controls. Importantly, we find classic circadian hallmarks such as temperature compensation and period determination by CK1δ/ε activity to be maintained. In the absence of CRY-mediated feedback repression and rhythmic Per2 transcription, PER2 protein rhythms are sustained for several cycles, accompanied by circadian variation in protein stability. We suggest that, whereas circadian transcriptional feedback imparts robustness and functionality onto biological clocks, the core timekeeping mechanism is post-translational.
昼夜节律是哺乳动物细胞、组织和行为的普遍特征，确保了生理适应太阳时间。细胞计时模型围绕转录反馈抑制，即 CLOCK 和 BMAL1 激活 PERIOD (PER) 和 CRYPTOCHROME (CRY) 的表达，而 CRY 蛋白反过来又抑制 CLOCK/BMAL1 的活性。因此，CRY 蛋白被认为是细胞时钟机制的重要组成部分，这一观点得到了 CRY 缺失（CKO）小鼠在恒定条件下行为节律失常的支持。然而，与这一解释相悖的是，我们发现 CRY 缺失的成年 CKO 小鼠在特定环境条件下存在运动节律，并且在 CRY 缺失时细胞 PER2 水平存在昼夜节律。无 CRY 调节的振荡在表达上具有可变性，其周期比野生型对照更短。重要的是，我们发现经典的昼夜节律特征，如温度补偿和 CK1δ/ε 活性决定的周期，得到了维持。在缺乏 CRY 介导的反馈抑制和周期性 Per2 转录的情况下，PER2 蛋白节律持续几个周期，伴随着蛋白稳定性的昼夜变化。我们认为，虽然昼夜转录反馈赋予生物钟稳健性和功能性，但核心计时机制是翻译后。
