Living organisms have intrinsic clocks that have an approximately 24-hour period. The specific biochemical mechanism that sets the pace of the clock, however, has not been fully described. Chiu et al. expand on earlier indications that changes in daily cycles of phosphorylation of PER (which recruits transcriptional repressors controlling the central transcriptional clock mechanism) can alter the period of the clock. Studies using cultured cells and genetically altered Drosophila showed that complex interactions of sequential phosphorylation of multiple clusters of phosphorylation sites on PER by multiple protein kinases dictated the rate at which PER became fully phosphorylated and thus targeted for degradation. The protein kinase NEMO was identified as being critical for an initial phosphorylation event that was permissive for further phosphorylation by the protein kinase DOUBLETIME. Intriguingly, NEMO functions (as do several regulators of the circadian clock) in the Wnt or Wingless signaling pathway. Yu et al. also implicate NEMO in pacing the Drosophila clock and found that NEMO is present in nuclear protein complexes with clock components PER, TIM, and CLK, and appears to influence phosphorylation and abundance of the transcriptional activator CLK.
Cell 145, 357 (2011); Curr. Biol. 21, 756 (2011).
