Molecular mechanism of the repressive phase of the mammalian circadian clock

Significance The circadian clock mechanism is a daily rhythmic activation of circadian gene transcription by the CLOCK–BMAL1 heterodimer and repression by CRYs (CRY1 and CRY2) and PERs (PER1 and PER2). CRYs and PERs are highly expressed around predawn, when they begin repressing transcription of cry and per and other clock genes, leading to a nadir of CRYs and PERs in the afternoon. CRY represses by simply binding to the CLOCK–BMAL1 heterodimer on DNA, and PER represses by removing CLOCK–BMAL1 from DNA in a CRY-dependent manner. This work shows that removal of CLOCK–BMAL1 involves phosphorylation of CLOCK, which is accomplished by CK1δ when CRY and PER deliver CK1δ to the CLOCK–BMAL1 complex in the nucleus.