The right place at the right time: regulation of daily timing by phosphorylation

Each day we perform a ritual: We sleep for ~8 h, awaken and rise, and ~16 h later, we sleep again. This ritual is based on a temporal program that continues, although not necessarily exactly every 24 h, even if we are shielded from environmental signals such as light and dark, scheduled meals, or any social “rituals” such as work schedules. This endogenous, ~24-h oscillation, is called a circadian rhythm. Circadian clocks regulate processes from gene expression to behavior, and have been observed in all phyla. As such, the circadian system is a fundamental biological process—a part of life like reproduction or cell division. Because daily temporal structure is fundamental to, for instance, medicine or work schedules, an understanding of the underlying biochemical mechanism is highly relevant to human health and quality of life.

A genetic approach to the clock mechanism has revealed a network of genes (clock genes) that function as a transcriptional–translational negative feedback loop, with at least one protein feeding back to inhibit the transcriptional activator of its own gene (Hardin et al. 1990). In mice, CRYPTOCHROME (CRY) and PERIOD (PER) form heterodimers and down-regulate their activators, CLOCK (CLK) and BRAIN AND MUSCLE ARNT-LIKE-1 (BMAL-1) (see Fig. 1A). It is an elegantly simple molecular mechanism implemented in animals, plants, fungi, and cyanobacteria by sets of clock genes unique to each group. Common to all these circadian systems is phosphorylation of one or several of the clock proteins (Vanselow et al. 2006). This post-translational modification is apparently critical to all circadian clock mechanisms—in some cases even more important than regulated transcription.