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  • Published:

Post-translational modifications regulate the ticking of the circadian clock

Nature Reviews Molecular Cell Biology volume 8, pages 139–148 (2007)Cite this article

Key Points

  • Post-translational modifications are as, or even more, important than transcriptional regulation to finely tune circadian rhythms. Oscillations in period (PER) and cryptochrome (CRY) protein abundance levels might be sufficient to establish cycling.

  • Post-translation regulation of the localization, degradation and activity of circadian regulators by phosphorylation, sumoylation and histone acetylation all determine the length of the biological day.

  • Mutations in kinases and phosphatases alter both the core clock, and its ability to respond to environmental (light) cues.

  • The ubiquitin–proteasome pathway controls the degradation of most of the circadian regulatory proteins. Both slimb (SLMB) and β-transducin repeat-containing protein (βTrCP) and the newly identified jetlag are members of the SCF (SKP1–Cullin1–F-box protein) family of ubiquitin ligases that regulate rhythms.

  • Clock components do not exist independently of each other, but rather interact in large multiprotein complexes in which each protein's activity can regulate and be regulated by the others. The PER proteins are scaffolds that physically interact with a large number of other circadian regulators.

  • Sleep disorders are the consequence of misalignments between the endogenous circadian clock and the external environment. Many of the mutations and polymorphisms associated with circadian rhythms disorders affect either the clock kinases casein kinase Iɛ/δ or their substrates, the PER proteins.

Abstract

Getting a good night's sleep is on everyone's to-do list. So is, no doubt, staying awake during late afternoon seminars. Our internal clocks control these and many more workings of the body, and disruptions of the circadian clocks predispose individuals to depression, obesity and cancer. Mutations in kinases and phosphatases in hamsters, flies, fungi and humans highlight how our timepieces are regulated and provide clues as to how we might be able to manipulate them.

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Figure 1: Feedback loops control the mammalian circadian core clock.
Figure 2: Conservation of mechanism in the Drosophila melanogaster and Neurospora crassa circadian clocks.
Figure 3: Multiple roles of casein kinase I in the mammalian circadian clock.
Figure 4: Reversible phosphorylation regulates the degradation of Drosophila melanogaster PER.

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  1. Department of Pediatrics, University of Utah, Salt Lake City, Utah 84112, USA. David.Virshup@hci.utah.edu

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  1. Center for Children, Huntsman Cancer Institute, Salt Lake City, 84112, Utah, USA

    Monica Gallego & David M. Virshup

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  1. Monica Gallego
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Glossary

Suprachiasmatic nucleus

(SCN). Paired hypothalamic collection of neurons that receive signals from the retina and regulate circadian behaviour. Destruction of the SCN causes arrhythmic behaviour.

PAS domain

Protein domain first identified in period, arnt, and simple-minded; it mediates protein–protein interactions.

Stabilizing loop

A separate interacting transcription–translation loop that reinforces the oscillations that are driven by a core loop.

Locomotor activity

Circadian rhythms cause changes in activity (along with many other changes). Wheel running in a cage is a form of locomotor activity.

Eclosion

Hatching of an insect larva from an egg.

Free-running period

Rhythms observed in nature continue in the laboratory even under constant experimental conditions such as constant light or constant dark. The persistence of these rhythms is seen as proof of endogenous biological clocks. When in constant conditions away from any external cues, these rhythms are called free runs.

Familial advanced sleep-phase syndrome

(FASPS). A dominantly inherited short-circadian-period disorder.

Conidation

Conidation is asexual reproduction in Ascomycetes by the formation of asexual, non-motile spores.

Delayed sleep-phase syndrome

(DSPS). Patients with DSPS have late sleep-onset and the inability to wake up at a conventional time.

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Gallego, M., Virshup, D. Post-translational modifications regulate the ticking of the circadian clock. Nat Rev Mol Cell Biol 8, 139–148 (2007). https://doi.org/10.1038/nrm2106

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