Nuclear CK1δ as a Critical Determinant of PER:CRY Complex Dynamics and Circadian Period

The mammalian circadian clock is governed by a feedback loop in which the transcription activator CLOCK:BMAL1 induces expression of its inhibitors, PERs and CRYs, which form a complex with CK1δ, the main circadian kinase. The spatiotemporal dynamics of this feedback mechanism and the precise role of CK1δ remain incompletely understood. Using an inducible cell system, we demonstrate that nuclear CK1δ is a key determinant of circadian period. The availability of CK1δ is limited due to rapid degradation and export of unassembled active kinase. Our findings reveal that active CK1δ promotes cytoplasmic localization of the PER2:CRY1 complex and triggers the dissociation of CRY1, which subsequently accumulates in the nucleus. We propose that late in the circadian cycle, cytoplasmic PER:CRY:CK1δ complexes may serve as a reservoir, gradually releasing CRY1 into the nucleus. This mechanism ensures rebinding of CLOCK:BMAL1 to DNA and prolonged attenuation of transcriptional activity after the degradation of PER proteins.