Cryptochrome, circadian cycle, cell cycle checkpoints, and cancer
Cryptochrome, circadian cycle, cell cycle checkpoints, and cancer
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DOI：
10.1158/0008-5472.can-05-1119
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发表时间：
2005-08-01
期刊：
影响因子：
11.2
通讯作者：
Sancar, A
中科院分区：
文献类型：
--
作者：
Gauger, MA;Sancar, A
据报告，生物钟的紊乱可能导致人类患乳腺癌的风险增加，并导致电离辐射诱发的小鼠肿瘤和死亡率升高。隐花色素I和隐花色素2蛋白是哺乳动物生物钟的核心组成部分，这两种基因突变的小鼠是哺乳动物。我们分别测试了Cry 1（-/-）Cry 2（-/-）小鼠和来自这些小鼠的成纤维细胞的辐射诱导的癌症和杀伤以及DNA损伤检查点和杀伤。我们发现，突变小鼠是从野生型控制辐射诱导的发病率和死亡率方面无法区分。类似地，Cry 1（-/-）Cry 2（-/-）突变成纤维细胞在其对电离辐射和UV辐射的敏感性以及电离辐射诱导的DNA损伤检查点反应方面与野生型对照无区别。我们的数据表明，生物钟本身的破坏不会损害哺乳动物DNA修复和DNA损伤检查点，也不会使小鼠易患自发性和电离辐射诱导的癌症。我们的结论是，生物钟中断对小鼠细胞对DNA损伤和癌症易感性的反应的影响可能取决于生物钟中断的机制。
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 of ionizing radiation-induced tumors and mortality in mice. Cryptochrome I 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.