CNOT1 regulates circadian behaviour through <i>Per2</i> mRNA decay in a deadenylation-dependent manner

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 <i>Cnot1</i>, 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 <i>Per2. Per2</i> mRNA exhibited a longer poly(A) tail and increased mRNA stability in <i>Cnot1^+/−</i> mice. CNOT1 is recruited to <i>Per2</i> mRNA through BRF1 (ZFP36L1), which itself oscillates in antiphase with <i>Per2</i> mRNA. Upon <i>Brf1</i> knockdown, <i>Per2</i> mRNA is stabilized leading to increased PER2 expression levels. This suggests that CNOT1 plays a role in tuning and regulating the mammalian circadian clock.