Clock genes: from Drosophila to humans

Abstract

The circadian clock that governs sleep-wake rhythms stems from a small set of genes, called clock genes, that are highly conserved during evolution. In insects as in mammals, a transcriptional feedback loop generates 24 h molecular oscillations. Two major transcrip- tional activators direct the expression of genes encoding repressors the accumulation of which leads afew hours later to transcriptional inhibition. This cyclic transcription is the core of the circadian oscillator and controls a large number of target genes (about 5 % of the genome), the nature of which varies from one organ to another depending on the physiology of the tissues. The period of the molecular oscillations relies on the accumulation rate of the repressors, their transfer into the cell nucleus, their ability to inhibit transcription, and their lifetime. These various parameters are largely based on post-translational regula- tions that depend on genes encoding kinases, phosphatases and ubiquitin ligases for a large fraction of them. Several syndromes that affect the sleep-wake rhythm were characterized in the human population. Inparticula; shifts of the sleep-wake rhythms compared to day-night cycles have been identifed and associated with mutations in clock genes. These mutations disrupt not only the brain clock that governs sleep-wake rhythms but also the temporal organization of many physiological processes (metabolism, detoxification etc.) through the clocks that are present in the different cell types of the body.