Molecular mechanism of the repressive phase of the mammalian circadian clock

The mammalian circadian clock consists of a transcription-translation feedback loop (TTFL) composed of CLOCK-BMAL1 transcriptional activators and CRY-PER transcriptional repressors. Previous work showed that CRY inhibits CLOCK-BMAL1-activated transcription by a blocking-type mechanism and that CRY-PER inhibits CLOCK-BMAL1 by a displacement-type mechanism. While the mechanism of CRY-mediated repression was explained by both in vitro and in vivo experiments, the CRY-PER-mediated repression in vivo seemed in conflict with the in vitro data demonstrating PER removes CRY from the CLOCK-BMAL1-E-box complex. Here, we show that CRY-PER participates in the displacement-type repression by recruiting CK1 delta to the nucleus and mediating an increased local concentration of CK1 delta at CLOCK-BMAL1-bound promoters/enhancers and thus promoting the phosphorylation of CLOCK and dissociation of CLOCK-BMAL1 along with CRY from the E-box. Our findings bring clarity to the role of PER in the dynamic nature of the repressive phase of the TTFL.

Automated summary

The mammalian circadian clock is regulated by a transcription-translation feedback loop involving CLOCK-BMAL1 activators and CRY-PER repressors. Previous studies have shown that CRY and CRY-PER inhibit CLOCK-BMAL1 in different mechanisms. This study reveals the involvement of CRY-PER in displacing CLOCK-BMAL1 by recruiting CK1 delta, leading to the dissociation of CLOCK-BMAL1 from the E-box.