Poly(ADP-Ribose) Polymerase 1 Participates in the Phase Entrainment of Circadian Clocks to Feeding
Poly(ADP-Ribose) Polymerase 1 Participates in the Phase Entrainment of Circadian Clocks to Feeding
复制标题
DOI：
10.1016/j.cell.2010.08.016
复制
发表时间：
2010-09-17
期刊：
影响因子：
64.5
通讯作者：
Schibler, Ueli
中科院分区：
文献类型：
--
作者：
Asher, Gad;Reinke, Hans;Schibler, Ueli
外周器官中的昼夜节律钟与细胞代谢紧密耦合，并且容易被进食-禁食周期所携带。然而，所涉及的分子机制在很大程度上是未知的。在这里，我们表明，在肝脏中的PARP-1，NAD（+）依赖的ADP-核糖基转移酶的活性，每天振荡的方式，并通过喂养调节。我们提供的生化证据表明，PARP-1结合和聚（ADP-核糖基）在光相开始时的时钟。PARP-1的缺失增强了CLOCK-BMAL 1与DNA的结合，并导致CLOCK-BMAL 1与PER和CRY阻遏蛋白相互作用的相移。因此，在PARP-1缺陷小鼠中，CLOCK-BMAL 1依赖性基因表达发生改变，特别是对喂养时间变化的反应。我们的研究结果表明，PARP-1基因敲除小鼠表现出受损的食物夹带外周生物钟和支持的作用PARP-1连接喂养与哺乳动物的定时系统。
Circadian clocks in peripheral organs are tightly coupled to cellular metabolism and are readily entrained by feeding-fasting cycles. However, the molecular mechanisms involved are largely unknown. Here we show that in liver the activity of PARP-1, an NAD(+)-dependent ADP-ribosyltransferase, oscillates in a daily manner and is regulated by feeding. We provide biochemical evidence that PARP-1 binds and poly(ADP-ribosyl)ates CLOCK at the beginning of the light phase. The loss of PARP-1 enhances the binding of CLOCK-BMAL1 to DNA and leads to a phase-shift of the interaction of CLOCK-BMAL1 with PER and CRY repressor proteins. As a consequence, CLOCK-BMAL1-dependent gene expression is altered in PARP-1-deficient mice, in particular in response to changes in feeding times. Our results show that Parp-1 knockout mice exhibit impaired food entrainment of peripheral circadian clocks and support a role for PARP-1 in connecting feeding with the mammalian timing system.