It has long been known that organisms exhibit a multiplicity of physiological and behavioral rhythms that recur every 24 h. This in turn gave rise to speculation over the existence of a biological clock able to “tell the time” from the ambient day/night cycle. In the 1950s, the term “circadian” was coined to denote these daily cycles, and clock theory was consolidated (1). Experimental data and mathematical modeling proposed that an oscillator generates a characteristic sine-wave output with a regular cycle length, or period, responsible for repeating 24-h rhythms. Crucially, the clock is endogenous, not reactive. It does not merely passively respond to environmental changes but sustains free-running cycles that persist even when organisms are housed in constant darkness in deprivation of external time cues. Such time cues are called Zeitgebers, and by a process of phase-shifting they may reset or entrain the clock to a new environmental rhythm. The master Zeitgeber is light. The output of the clock had thus been described in sophisticated terms before its source was discovered. In 1972, it was shown that a central master clock resides in the suprachiasmatic nucleus (SCN) of the hypothalamus and receives photic inputs via the retinohypothalamic tract that enable it to synchronize to light (2, 3). The molecular mechanism underlying clock function was seen in Drosophila in the early 1970s (4), but mammalian homologs proved elusive until the generation in 1994 of the ClockΔ19 mouse, an animal with a dominant negative mutation of a core clock gene (5).
The cogs of the molecular clock (Fig. 1) are now known to consist of a negative feedback system of transcription factors whose transcription and translation oscillates slowly over the magic number of 24 h to create a regular, repetitive, self-sustaining cycle. The core system has a positive limb, dimers of BMAL1 with either CLOCK or NPAS2, which act on E-box elements to promote transcription of PER and CRY (period and cryptochrome) genes, which in turn form the negative limb of the cycle by feeding back to inhibit CLOCK and BMAL1 transcription (6). It is increasingly clear that this is an oversimplification: the system is complicated by a secondary tier of accessory genetic feedback loops, posttranslational protein modifications governing stability and subcellular localization, and interactions of accessory regulatory proteins (7). The output of the system is composed of clock-controlled genes, whose transcription is regulated by the core clock genes and which can be identified on microarray studies by their robust circadian cycling. The effect of a malfunction in the core clock machinery with respect to these clock-controlled genes is more than just a flattening of daily fluctuations; gene transcription tends to be suppressed to the daily minimum level with a consequent severe loss of function of the resultant protein.
The molecular clock. Positive limb: BMAL1 and CLOCK are transcribed and form complexes that act upon E-box elements to promote the transcription of PER and CRY genes. Negative limb: PER and CRY form complexes that feed back to inhibit the transcription of BMAL1 and CLOCK. Clock proteins induce cyclical transcription of clock-controlled genes, propagating circadian rhythms in cellular physiology. Posttranslational protein modifications regulate clock protein function including phosphorylation (P), acetylation (A), ubiquitination (U), and sumoylation (S).
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