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Multilevel regulation of the circadian clock

Abstract

Living organisms adapt to light–dark rhythmicity using a complex programme based on internal clocks. These circadian clocks, which are regulated by the environment, direct various physiological functions. As the molecular mechanisms that govern clock function are unravelled, we are starting to appreciate simple patterns as well as exquisite layers of regulation.

Key Points

  • Living organisms adapt to light–dark rhythmicity using a complex programme based on internal clocks.

  • In mammals, the central clock structure is located within the suprachiasmatic nucleus (SCN) of the anterior hypothalamus.

  • The clock can be considered as consisting of three overlapping components: the input pathways, the oscillator or pacemaker (which generates rhythmicity autonomously) and the output pathways.

  • Input-gene products are thought to sense external stimuli and relay the message to the oscillator to reset or entrain it.

  • Many pacemaker genes encode transcription factors or proteins that act on gene regulation, emphasizing the idea that the generation and modulation of rhythms relies mainly on transcriptional feedback loops and on activation and repression of gene expression (perhaps through chromatin remodelling).

  • The circadian clock probably uses a number of inter- or intragenic loops organized in networks.

  • Degradation of clock messenger RNAs and proteins is crucial to the control of oscillator periodicity. Entry of clock proteins into the nucleus is another checkpoint for circadian feedback loops.

  • Peripheral clocks may be controlled or synchronized by the SCN through blood-borne signalling factors oscillating in a circadian fashion.

  • Output gene-products, which include peptides and transcription factors, convey rhythmic information to downstream physiological systems.

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Figure 1: Anatomical location of the suprachiasmatic nuclei.
Figure 2: The circadian clock.
Figure 3: Model of the molecular mechanisms involved in the Drosophila circadian clock.
Figure 4: Model of the molecular mechanisms involved in the mammalian circadian clock.
Figure 5: Signalling within a suprachiasmatic nucleus synapse and neuron.

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Acknowledgements

We wish to apologize to all colleagues whose work, because of lack of space, could not be cited. We thank all the members of the Sassone-Corsi laboratory for helpful discussions. N.C. was supported by a Human Frontier Science Program Organization long-term fellowship and a Canadian Institutes of Health Research postdoctoral fellowship. Work in our laboratory is supported by grants from CNRS, INSERM, CHUR, Human Frontier Science Program, Organon Akzo/Nobel, Fondation pour la Recherche Médicale and Association pour la Recherche sur le Cancer.

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Correspondence to Paolo Sassone-Corsi.

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Per

tim

clock

cycle

dbt

Bmal1

PAS domain

AHR

SIM

CRY

bHLH domain

CRY1

CRY2

MOP9

pdf

c-fos

fos-B

NFGI-A

CREB

PKA

CBP

bHLH–PAS domain

PKG

ARNT

p300

SRC-1

Rsk-2

H3

CKIɛ

vrille

avp

dbp

CREM

ENCYCLOPEDIA OF LIFE SCIENCES

Circadian rhythms

Glossary

E-BOX ELEMENT

Promoter element recognized by transcription factors of the basic helix–loop–helix class.

PHASE SHIFT

A shift in the endogenous circadian rhythms that occurs when an organism is placed in different lighting regimes (or other external stimuli).

SUBJECTIVE NIGHT AND DAY

Correspond to the endogenous night–day circadian cycle of an organism, independent of the astronomical day and night.

HISTONE ACETYL-TRANSFERASES AND DEACETYLASES

Enzymes that modify histones by adding and removing acetyl groups, a chemical modification thought to remodel chromatin structure.

UBIQUITIN LIGASE

An enzyme that couples the small protein ubiquitin to lysine residues on a target protein, marking that protein for destruction by the proteasome.

PHOTOLYASE

A DNA repair enzyme that splits pyrimidine dimers (lesions caused by UV irradiation) into monomers.

OPSINS

Hydrophobic glycoproteins found in the visual pigments of vertebrates.

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Cermakian, N., Sassone-Corsi, P. Multilevel regulation of the circadian clock. Nat Rev Mol Cell Biol 1, 59–67 (2000). https://doi.org/10.1038/35036078

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