period and timeless Tango: A dance of two clock genes

Circadian rhythms are genetically determined biological oscillations evident in virtually all plants and animals, and even some prokaryotes. Circadian rhythms are generated by endogenous timing mechanisms referred to as biological or circadian clocks. Signature features of circadian clocks include an endogenous cycle length (period) of about 24 hr, daily sensitivity to resetting (entraining) stimuli, and relative insensitivity of period to changes in temperature (temperature compensation). Circadian clocks are normally set or entrained by periodic environmental cues, with the daily light-dark cycle being the most pervasive and potent entraining stimulus. An entrained circadian clock ensures that expressed rhythms are coordinated to one another and to the 24 hr day, conferring temporal order among biological processes. An issue of central importance to the field of circadian biology is defining the molecular mechanisms underlying circadian clocks. Over the past two years, genetic, biochemical, and molecular analyses of these clocks have accelerated at a phenomenal rate. Much of this activity centers on Drosophila melanogaster, the premier species for genetic analysis of neural circadian clocks. Here we review the recent advances in understanding the Drosophila circadian system, focusing on the clock genes period (per) and timeless (tim) and highlighting the newly discovered biochemical and molecular interactions between these two clock elements. per Is an Essential Clock Element The per locus of Drosophila was discovered by Konopka and Benzer in 1971 and shown to be essential for circadian rhythms in adult eclosion behavior and locomotor activity. Nonsense mutations of per (per °) cause arrhythmicity in these behaviors, while missense mutations can either shorten (per s) or lengthen (per L) the period of circadian rhythms. Soon after its molecular cloning, functions were ascribed to the per protein (PER) that have since been disproven, such as PER's function as a proteoglycan or its involvement in gap junction-mediated intercellular communication (reviewed in Hall, 1995). Although the precise biochemical functions of PER still remain to be defined, a firm working hypothesis of PER function has emerged for which there is staggering evidence. This hypothesis proposes that PER is a negative regulator of its own transcription, forming an autoregulatory feedback loop that constitutes the molecular oscilla-