Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Cell Cycle. 2012 Sep 15;11(18):3481-91. doi: 10.4161/cc.21771. Epub 2012 Aug 23.
The circadian clock is a global regulatory mechanism that confers daily rhythmicity on many biochemical and physiological functions, including DNA excision repair in mammalian organisms. Here, we investigated the effect of the circadian clock on the major DNA damage response pathways by using mouse cell lines mutated in genes encoding proteins in the positive (Bmal1, CLOCK) or negative (Cry 1/2, Per 1/2) arms of the transcription-translation feedback loop that generates the circadian clock. We find that cells mutated in these genes are indistinguishable from wild-type in their response to UV, ionizing radiation and mitomycin C. We conclude that either the majority of DNA damage response reactions are not controlled by the circadian clock or that, even if such a control exists at the organism level, it is supplanted by homeostatic control mechanisms at the cellular level in tissue culture. We suggest that caution must be exercised in extrapolating from experiments in tissue culture to whole animals with respect to the effect of the circadian clock on cellular response to DNA damaging agents.
生物钟是一种全球调节机制，赋予许多生化和生理功能以昼夜节律，包括哺乳动物生物体内的 DNA 切除修复。在这里，我们通过使用编码转录 - 翻译反馈环正（Bmal1，CLOCK）或负（Cry1/2，Per1/2）臂中蛋白质的基因突变的小鼠细胞系，研究了生物钟对主要 DNA 损伤反应途径的影响。我们发现，这些基因突变的细胞与野生型细胞在对 UV、电离辐射和丝裂霉素 C 的反应中没有区别。我们得出结论，要么大多数 DNA 损伤反应不受生物钟控制，要么即使在生物体水平上存在这种控制，它也被组织培养中的细胞水平的体内平衡控制机制所取代。我们建议，在将组织培养中的实验外推到整个动物时，必须谨慎对待生物钟对细胞对 DNA 损伤剂的反应的影响。
