A circadian sleep disorder reveals a complex clock

Abstract

Circadian rhythms are established by transcription of clock genes and autoregulatory transcriptional feedback loops. In this issue, Xu et al. (2007) characterize mice expressing a human Per2 mutation identified in patients with familial advanced sleep phase syndrome. Their results reveal that PER2 phosphorylation, by CK1delta and other kinases, is surprisingly complex and has opposite effects on PER2 levels and period length.

Figure 1. The primary negative feedback loop of the circadian clock

Clock/BMAL1 activate Per and Cry transcription. PER and CRY form a complex in the cytoplasm. Phosphorylation of PER by CK1ε/δ mediates PER degradation by the proteosome. Phosphorylation of PER2 on S662 (by an unidentified kinase) stabilizes PER2 potentially by causing its nuclear translocation or increased transcription. CRY and CK1 are also translocated into the nucleus. PER/CRY complexes inhibit the activity of CLOCK:BMAL1 as part of a negative feedback loop.