Stability of Wake-Sleep Cycles Requires Robust Degradation of the PERIOD Protein
Stability of Wake-Sleep Cycles Requires Robust Degradation of the PERIOD Protein
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DOI：
10.1016/j.cub.2017.10.014
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发表时间：
2017-11-20
期刊：
影响因子：
9.2
通讯作者：
Lee, Choogon
中科院分区：
文献类型：
--
作者：
D'Alessandro, Matthew;Beesley, Stephen;Lee, Choogon
生物学中的稳健性是在不同的遗传和/或环境扰动下表型的稳定性。与其他生物钟不同的是，生物钟具有显著的周期和相位稳定性，在各种条件下都能维持。在这里，我们表明，高保真的昼夜节律系统源于强大的降解的时钟蛋白周期。我们表明，周期降解是由泛素化和去泛素化之间的平衡调节，这种平衡的破坏可以破坏时钟。在E3连接酶基因β-Trcp 2功能缺失突变的小鼠中，PERIOD降解的平衡被扰乱，生物钟变得非常不稳定，呈现出与其他昼夜节律突变动物模型不同的独特行为表型。我们相信，我们的数据为昼夜节律阶段（如觉醒-睡眠开始时间）如何在人类中变得不稳定提供了分子解释，我们提出了一种独特的小鼠模型来研究具有不稳定昼夜节律阶段的人类昼夜节律紊乱。
Robustness in biology is the stability of phenotype under diverse genetic and/or environmental perturbations. The circadian clock has remarkable stability of period and phase that-unlike other biological oscillators-is maintained over a wide range of conditions. Here, we show that the high fidelity of the circadian system stems from robust degradation of the clock protein PERIOD. We show that PERIOD degradation is regulated by a balance between ubiquitination and deubiquitination, and that disruption of this balance can destabilize the clock. In mice with a loss-of-function mutation of the E3 ligase gene beta-Trcp2, the balance of PERIOD degradation is perturbed and the clock becomes dramatically unstable, presenting a unique behavioral phenotype unlike other circadian mutant animal models. We believe that our data provide a molecular explanation for how circadian phases, such as wake-sleep onset times, can become unstable in humans, and we present a unique mouse model to study human circadian disorders with unstable circadian rhythm phases.