The period of the circadian oscillator is primarily determined by the balance between casein kinase 1 and protein phosphatase 1

Abstract

Mounting evidence suggests that PERIOD (PER) proteins play a central role in setting the speed (period) and phase of the circadian clock. Pharmacological and genetic studies have shown that changes in PER phosphorylation kinetics are associated with changes in circadian rhythm period and phase, which can lead to sleep disorders such as Familial Advanced Sleep Phase Syndrome in humans. We and others have shown that casein kinase 1delta and epsilon (CK1delta/epsilon) are essential PER kinases, but it is clear that additional, unknown mechanisms are also crucial for regulating the kinetics of PER phosphorylation. Here we report that circadian periodicity is determined primarily through PER phosphorylation kinetics set by the balance between CK1delta/epsilon and protein phosphatase 1 (PP1). In CK1delta/epsilon-deficient cells, PER phosphorylation is severely compromised and nonrhythmic, and the PER proteins are constitutively cytoplasmic. However, when PP1 is disrupted, PER phosphorylation is dramatically accelerated; the same effect is not seen when PP2A is disrupted. Our work demonstrates that the speed and rhythmicity of PER phosphorylation are controlled by the balance between CK1delta/epsilon and PP1, which in turn determines the period of the circadian oscillator. Thus, our findings provide clear insights into the molecular basis of how the period and phase of our daily rhythms are determined.