Gauger Michele A, Sancar Aziz
Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA.
Cancer Res. 2005 Aug 1;65(15):6828-34. doi: 10.1158/0008-5472.CAN-05-1119.
It has been reported that disruption of the circadian clock may lead to increased risk of breast cancer in humans and to a high rate or ionizing radiation-induced tumors and mortality in mice. Cryptochrome 1 and cryptochrome 2 proteins are core components of the mammalian circadian clock and mice mutated in both genes are arrhythmic. We tested Cry1-/- Cry2-/- mice and fibroblasts derived from these mice for radiation-induced cancer and killing and DNA damage checkpoints and killing, respectively. We find that the mutant mice are indistinguishable from the wild-type controls with respect to radiation-induced morbidity and mortality. Similarly, the Cry1-/- Cry2-/-mutant fibroblasts are indistinguishable from the wild-type controls with respect to their sensitivity to ionizing radiation and UV radiation and ionizing radiation-induced DNA damage checkpoint response. Our data suggest that disruption of the circadian clock in itself does not compromise mammalian DNA repair and DNA damage checkpoints and does not predispose mice to spontaneous and ionizing radiation-induced cancers. We conclude that the effect of circadian clock disruption on cellular response to DNA damage and cancer predisposition in mice may depend on the mechanism by which the clock is disrupted.
据报道，昼夜节律时钟紊乱可能会增加人类患乳腺癌的风险，并导致小鼠中电离辐射诱发肿瘤的高发生率和死亡率。隐花色素1和隐花色素2蛋白是哺乳动物昼夜节律时钟的核心成分，两个基因均发生突变的小鼠没有节律。我们分别测试了Cry1-/- Cry2-/-小鼠及其来源的成纤维细胞在辐射诱发癌症、杀伤以及DNA损伤检查点和杀伤方面的情况。我们发现，在辐射诱发的发病率和死亡率方面，突变小鼠与野生型对照没有区别。同样，Cry1-/- Cry2-/-突变成纤维细胞在对电离辐射和紫外线辐射的敏感性以及电离辐射诱发的DNA损伤检查点反应方面，与野生型对照没有区别。我们的数据表明，昼夜节律时钟本身的紊乱不会损害哺乳动物的DNA修复和DNA损伤检查点，也不会使小鼠易患自发和电离辐射诱发的癌症。我们得出结论，昼夜节律时钟紊乱对小鼠细胞对DNA损伤的反应和癌症易感性的影响可能取决于时钟紊乱的机制。
