The Phospho-Code Determining Circadian Feedback Loop Closure and Output in Neurospora.
The Phospho-Code Determining Circadian Feedback Loop Closure and Output in Neurospora.
复制标题
DOI：
10.1016/j.molcel.2019.03.003
复制
发表时间：
2019-05
期刊：
影响因子：
16
通讯作者：
Bin Wang;A. Kettenbach;Xiaoying Zhou;J. Loros;J. Dunlap
中科院分区：
文献类型：
--
作者：
Bin Wang;A. Kettenbach;Xiaoying Zhou;J. Loros;J. Dunlap
在驱动真菌和动物昼夜节律振荡器的负反馈回路中，负因子（FREQUENCY [FRQ]、PERIODS [PERs]和CRYPTOCHROMES [CRYs]）被认为可以抑制其自身的表达，部分原因是通过促进其异二体转录激活因子的磷酸化（例如，White Collar-1 [WC-1]-WC-2 [White Collar complex； WCC]和BMAL1/ circadian Locomotor Output Cycles Kaput [CLOCK]）。然而，异源二聚体活性与磷酸化之间的相关性很弱，存在矛盾，并且几乎完全缺乏机制细节。我们报告了WC-1上的80个磷酸化位点和WC-2上的15个磷酸化位点的定位，并阐明了一天中特定时间的编码，这需要WC-1上的一组磷酸化事件和WC-2上的两个不同的集群，这些磷酸化事件控制着昼夜节律抑制，导致反馈回路关闭。通过磷酸化的组合控制也控制了WCC与时钟控制基因启动子的节律性结合，这些启动子介导了昼夜节律输出的重要第一步，这是一组编码转录因子和信号蛋白的基因。这些数据为昼夜节律负反馈和输出的基本事件提供了基本的机制理解，这是昼夜节律生物学的关键方面。
In the negative feedback loop driving fungal and animal circadian oscillators, negative elements (FREQUENCY [FRQ], PERIODS [PERs], and CRYPTOCHROMES [CRYs]) are understood to inhibit their own expression, in part by promoting the phosphorylation of their heterodimeric transcriptional activators (e.g., White Collar-1 [WC-1]-WC-2 [White Collar complex; WCC] and BMAL1/Circadian Locomotor Output Cycles Kaput [CLOCK]). However, correlations between heterodimer activity and phosphorylation are weak, contradictions exist, and mechanistic details are almost wholly lacking. We report mapping of 80 phosphosites on WC-1 and 15 on WC-2 and elucidation of the time-of-day-specific code, requiring both a group of phosphoevents on WC-1 and two distinct clusters on WC-2, that governs circadian repression, leading to feedback loop closure. Combinatorial control via phosphorylation also governs rhythmic WCC binding to the promoters ofclock-controlled genesmediating the essential first step in circadian output, a group encoding both transcription factors and signaling proteins. These data provide a basic mechanistic understanding for fundamental events underlying circadian negative feedback and output, key aspects of circadian biology.