CRYPTOCHROMES confer robustness, not rhythmicity, to circadian timekeeping.
CRYPTOCHROMES confer robustness, not rhythmicity, to circadian timekeeping.
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DOI：
10.15252/embj.2020106745
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发表时间：
2021-04-01
期刊：
影响因子：
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通讯作者：
O'Neill JS
中科院分区：
文献类型：
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作者：
Putker M;Wong DCS;Seinkmane E;Rzechorzek NM;Zeng A;Hoyle NP;Chesham JE;Edwards MD;Feeney KA;Fischer R;Peschel N;Chen KF;Vanden Oever M;Edgar RS;Selby CP;Sancar A;O'Neill JS
昼夜节律是哺乳动物细胞、组织和行为的普遍特性，确保对太阳时间的生理适应。细胞计时的模型围绕转录反馈抑制，由此CLOCK和BMAL 1激活PERIOD（PER）和CRY（CRY）的表达，这反过来抑制CLOCK/BMAL 1活性。因此，CRY蛋白被认为是细胞时钟机制的重要组成部分，这得到了CRY缺陷（CKO）小鼠在恒定条件下的行为稳定性的支持。根据这一解释，我们发现成年CKO小鼠在特定环境条件下的运动节律和CRY不存在时细胞PER 2水平的昼夜节律。无CRY振荡在其表达中是可变的，并且具有比野生型对照更短的周期。重要的是，我们发现经典的昼夜节律特征，如温度补偿和CK 1 δ/ε活性决定的周期得以维持。在不存在CRY介导的反馈抑制和节律性Per 2转录的情况下，PER 2蛋白质节律持续几个周期，伴随着蛋白质稳定性的昼夜变化。我们认为，虽然昼夜转录反馈赋予生物钟鲁棒性和功能性，但核心计时机制是翻译后。在缺乏线粒体色素的情况下的昼夜节律计时为哺乳动物昼夜节律钟机制中翻译后调节的中心作用提供了进一步的支持。
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. Circadian timekeeping in the absence of CRYPTOCHROME provides further support to the central role of post‐translational regulation in the mammalian circadian clock mechanism.