The Faculty of Life Sciences and the Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat-Gan 5290002, Israel.
Department of Physiology and Pharmacology, Sackler Faculty of Medicine, and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv-Yafo 69978, Israel.
Mol Cell. 2021 Dec 16;81(24):4979-4993.e7. doi: 10.1016/j.molcel.2021.10.026. Epub 2021 Nov 18.
The characteristics of the sleep drivers and the mechanisms through which sleep relieves the cellular homeostatic pressure are unclear. In flies, zebrafish, mice, and humans, DNA damage levels increase during wakefulness and decrease during sleep. Here, we show that 6 h of consolidated sleep is sufficient to reduce DNA damage in the zebrafish dorsal pallium. Induction of DNA damage by neuronal activity and mutagens triggered sleep and DNA repair. The activity of the DNA damage response (DDR) proteins Rad52 and Ku80 increased during sleep, and chromosome dynamics enhanced Rad52 activity. The activity of the DDR initiator poly(ADP-ribose) polymerase 1 (Parp1) increased following sleep deprivation. In both larva zebrafish and adult mice, Parp1 promoted sleep. Inhibition of Parp1 activity reduced sleep-dependent chromosome dynamics and repair. These results demonstrate that DNA damage is a homeostatic driver for sleep, and Parp1 pathways can sense this cellular pressure and facilitate sleep and repair activity.
睡眠驱动因素的特征以及睡眠缓解细胞稳态压力的机制尚不清楚。在果蝇、斑马鱼、小鼠和人类中，清醒时 DNA 损伤水平增加，而睡眠时则减少。在这里，我们表明，6 小时的整合睡眠足以减少斑马鱼背侧脑皮层中的 DNA 损伤。神经元活动和诱变剂诱导的 DNA 损伤引发睡眠和 DNA 修复。DNA 损伤反应 (DDR) 蛋白 Rad52 和 Ku80 的活性在睡眠期间增加，并且染色体动力学增强了 Rad52 的活性。DDR 起始子聚 (ADP-核糖) 聚合酶 1 (Parp1) 的活性在睡眠剥夺后增加。在幼虫斑马鱼和成年小鼠中，Parp1 促进睡眠。Parp1 活性的抑制减少了睡眠依赖性染色体动力学和修复。这些结果表明 DNA 损伤是睡眠的一种稳态驱动因素，而 Parp1 途径可以感知这种细胞压力，并促进睡眠和修复活动。
