Phase resetting of the mammalian circadian clock by DNA damage
Phase resetting of the mammalian circadian clock by DNA damage
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DOI：
10.1016/j.cub.2008.01.047
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发表时间：
2008-02-26
期刊：
影响因子：
9.2
通讯作者：
van der Horst, Gijsbertus T. J.
中科院分区：
文献类型：
--
作者：
Oklejewicz, Malgorzata;Destici, Eugin;van der Horst, Gijsbertus T. J.
为了预测一天的动力，大多数生物体已经发展出一种内部时钟来驱动新陈代谢、生理和行为方面的昼夜节律。最近的研究表明，细胞周期进程和dna损伤反应途径受昼夜节律控制[2-4]。由于昼夜节律输出过程可以反馈到生物钟中，我们研究了DNA损伤是否会影响哺乳动物的生物钟。通过使用表达mPer2启动子驱动的荧光素酶报告基因的大鼠-1成纤维细胞，我们发现电离辐射以剂量和时间依赖的方式推进昼夜节律。值得注意的是，这一体外发现也适用于活体动物，因为电离辐射也会使小鼠的行为节律提前。潜在的机制涉及atm介导的损伤信号，因为辐射诱导的相移在癌症易感共济失调、毛细血管扩张和奈梅亨断裂综合征患者的成纤维细胞中被抑制。电离辐射诱导的相移既不依赖于时钟基因表达的上调或下调，也不依赖于从头蛋白合成，因此在机制上不同于地塞米松和福斯克林引发的时钟重置[5]。有趣的是，紫外光和过氧化叔丁基也能引起相推进效应。综上所述，我们的数据提供了证据，证明哺乳动物的生物钟，如低等真核生物Neurospora[6]的生物钟，对DNA损伤有反应，并表明生物钟重置是DNA损伤的普遍特性。
To anticipate the momentum of the day, most organisms have developed an internal clock that drives circadian rhythms in metabolism, physiology, and behavior [1]. Recent studies indicate that cell-cycle progression and DNA-damage-response pathways are under circadian control [2-4]. Because circadian output processes can feed back into the clock, we investigated whether DNA damage affects the mammalian circadian clock. By using Rat-1 fibroblasts expressing an mPer2 promoter-driven luciferase reporter, we show that ionizing radiation exclusively phase advances circadian rhythms in a dose- and time-dependent manner. Notably, this in vitro finding translates to the living animal, because ionizing radiation also phase advanced behavioral rhythms in mice. The underlying mechanism involves ATM-mediated damage signaling as radiation-induced phase shifting was suppressed in fibroblasts from cancer-predisposed ataxia telangiectasia and Nijmegen breakage syndrome patients. Ionizing radiation-induced phase shifting depends on neither upregulation or downregulation of clock gene expression nor on de novo protein synthesis and, thus, differs mechanistically from dexamethasone- and forskolin-provoked clock resetting [5]. Interestingly, ultraviolet light and tert-butyl hydroperoxide also elicited a phase-advancing effect. Taken together, our data provide evidence that the mammalian circadian clock, like that of the lower eukaryote Neurospora [6], responds to DNA damage and suggest that clock resetting is a universal property of DNA damage.