Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan.
Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
RNA Biol. 2022;19(1):703-718. doi: 10.1080/15476286.2022.2071026. Epub 2021 Dec 31.
Circadian clocks are an endogenous internal timekeeping mechanism that drives the rhythmic expression of genes, controlling the 24 h oscillatory pattern in behaviour and physiology. It has been recently shown that post-transcriptional mechanisms are essential for controlling rhythmic gene expression. Controlling the stability of mRNA through poly(A) tail length modulation is one such mechanism. In this study, we show that , encoding the scaffold protein of the CCR4-NOT deadenylase complex, is highly expressed in the suprachiasmatic nucleus, the master timekeeper. CNOT1 deficiency in mice results in circadian period lengthening and alterations in the mRNA and protein expression patterns of various clock genes, mainly mRNA exhibited a longer poly(A) tail and increased mRNA stability in mice. CNOT1 is recruited to mRNA through BRF1 (ZFP36L1), which itself oscillates in antiphase with mRNA. Upon knockdown, mRNA is stabilized leading to increased PER2 expression levels. This suggests that CNOT1 plays a role in tuning and regulating the mammalian circadian clock.
生物钟是一种内源性的计时机制，它驱动基因的节律表达，控制行为和生理的 24 小时振荡模式。最近的研究表明，转录后机制对于控制节律基因表达是必不可少的。通过调节聚腺苷酸 (poly(A)) 尾的长度来控制 mRNA 的稳定性就是这样一种机制。在这项研究中，我们表明，编码 CCR4-NOT 脱腺苷酸化复合物支架蛋白的 ，在主生物钟视交叉上核中高度表达。小鼠中 CNOT1 的缺失导致生物钟周期延长，并改变了各种时钟基因的 mRNA 和蛋白表达模式，主要是 mRNA 的 poly(A) 尾更长，mRNA 稳定性增加。CNOT1 通过 BRF1（ZFP36L1）被招募到 mRNA 上，BRF1 本身与 mRNA 呈反相振荡。在 敲低后， mRNA 稳定，导致 PER2 表达水平增加。这表明 CNOT1 在调节和控制哺乳动物生物钟方面发挥作用。
