Regulation of the circadian clock by animal cryptochromes. (a) In Drosophila, Cry suppresses the negative feedback loop of the circadian clock by binding to Tim in a light-dependent manner; this results in the proteosome-dependent ubiquitin-mediated degradation of Tim (Ubq, ubiquitination) and thus to inhibition of the action of the Per-Tim heterodimer. Without Cry, the Per-Tim heterodimer would enter the nucleus and inhibit the binding of clock-cycle proteins (Per, Clk and Bmal1) to the E-box in the promoters of clock genes, preventing their expression. (b) In mammals, cryptochromes are integral parts of the negative feedback loop. The Cry protein interacts with Per to repress the activity of the transcription factors Clk and Bmal1 and thus to repress transcription. Cryptochromes may also be involved in the photo-entrainment of the mammalian circadian clock; clock genes are known to be regulated in response to neural signals from the retina in response to light, but it is not yet clear whether this involves cryptochromes.