CRY associated proteins modulate circadian transcription by regulating CRY stability

Abstract

Circadian clocks have evolved in all light sensitive organisms from cyanobacteria to mammals. These timing systems allow the organism to adjust their physiology and behavior to the geo-physical time. In mammals the circadian clocks exist in virtually all body cells, but the system function in a hierarchical manner in which the master pacemaker in the suprachiasmatic nucleus (SCN) sets the pace of the subsidiary peripheral oscillators. SCN is a small, approximately 10 000-20 000 cells, neuroendocrine gland in the hypothalamus. The SCN receives a direct photic input from the retina through the retino-hypothalamic tract and transmits this information to the oscillators in the periphery using neuronal and humoral signals. The molecular clock both in the SCN and in the peripheral oscillators is thought to consist of negative transcriptional and translational feedback loops. The PAS domain basic helix-loop-helix transcription factors BMAL1 and CLOCK bind to the promoters and transactivate two cryptochrome (cry) and two period (per) genes. Once CRY and PER proteins reach the threshold concentration they translocate into the nucleus and inhibit the activity of BMAL1-CLOCK heterodimer and repress their own genes. In addition, Bmal1 is rhythmically activated and repressed by orphan nuclear receptors RORs and REV-ERB? respectively in the interconnecting loop. Post-translational modifications such as phosphorylation, acetylation, sumoylation, and ubiquitination play an important role in fine-tuning the oscillator to measure 24 hour periodicity. The regulation of CRY protein stability and accumulation is particularly important for functional circadian oscillator. CRYs are ubiquitinated by the SCF-FBXL3 ubiquitin E3-ligase in timely regulated manner and subsequently degraded by the proteasome.