Time zones: a comparative genetics of circadian clocks

Abstract

The circadian clock is a widespread cellular mechanism that underlies diverse rhythmic functions in organisms from bacteria and fungi, to plants and animals. Intense genetic analysis during recent years has uncovered many of the components and molecular mechanisms comprising these clocks. Although autoregulatory genetic networks are a consistent feature in the design of all clocks, the weight of evidence favours their independent evolutionary origins in different kingdoms.

Key Points

  • Approximately 24-h rhythms govern a wide range of physiological and behavioural processes in organisms from bacteria to humans. Underlying these rhythmic activities is a cellular mechanism called the circadian clock.

  • Genetic analysis of the circadian clock has led to the identification of genes and proteins that constitute the core cellular mechanism in Drosophila, mammals, Neurospora, cyanobacteria and possibly Arabidopsis.

  • In Drosophila, several transcription factors operate in a genetic network incorporating autoregulatory feedback loops. Oscillations are achieved by delaying various steps in the network. For example, accumulation of one of the transcription factors — Period — is retarded in the cytoplasm by phosphorylation and degradation.

  • In mammals, homologues of the Drosophila genes also operate in the circadian cellular clock, although the function of some of the components is not conserved and has been co-opted by other proteins. For example, cryptochromes are part of the core mechanism in mammals, whereas the Drosophila homologue is involved in light regulation of the clock.

  • In the fungus Neurospora, three genes lie at the core of the circadian clock — white collar-1, white collar-2 and frequency. The proteins they encode are unrelated to the genes involved in the metazoan clocks apart from the PAS domain, which is found in various proteins, only some of which are involved in clock function.

  • The PAS domain has also been found in two components of the Arabidopsis circadian clock, and two Myb-related transcription factors that form an autoregulatory transcriptional network are probably components of a core mechanism that must include additional, unidentified factors. Redundancy is also a dominant feature of the Arabidopsis clock.

  • In cyanobacteria, most genes are subject to circadian regulation, which indicates that the clock might form a fundamental part of the physiology of this organism. The kai genes are essential components of the clock, although they are unlike any other clock genes, and their precise function in this clock is unknown.

  • Comparative analyses indicate that the circadian clock has evolved independently in bacteria, fungi, plants and animals. Instead it is proposed that the PAS domain and some closely neighbouring sequences might be a feature that is common to several circadian rhythm components because it allows the sensing of environmental and metabolic information, both recently described as important aspects of circadian regulation.

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Figure 1: The Drosophila circadian clock.
Figure 2: Regulatory interactions in the mammalian clock.
Figure 3: Elements of the Neurospora clock.
Figure 4: Regulatory interactions in the Arabidopsis clock.
Figure 5: Possible regulation in the Synechococcus clock.

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Acknowledgements

We thank members of our laboratories and J. Dunlap, S. Golden and S. Williams for helpful comments on the manuscript. We were offered many important insights and apologize for not resolving all complaints.

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DATABASE LINKS

Familial advanced sleep phase syndrome

PER2

frequency

Timeless

Clock

Cycle

Double-time

cryptochrome

shaggy

vrille

Armadillo

Dishevelled

CLOCK

ARNTL

Clock

Per

Arntl

Cry1

Cry2

CCA1

TOC1

CONSTANS

elf3

PHYA

PHYB

PHYD

PHYE

CRY1

ARNT

LINKS

ARNT1

Glossary

ENTRAIN

To establish the phase of a rhythm by providing an environmenal signal, such as a light or temperature cycle, or a biological signal, such as a hormone pulse.

CRYPTOCHROME

A novel photoreceptor, discovered in plants and subsequently found in animals, that is thought to have evolved from photolyase (light-activated DNA-repair protein). Cryptochromes bind flavin and pterin, and promote redox reactions upon absorbing light.

PAS MOTIF

These motifs (PER/ARNT/SIM) are often associated with proteins that function as environmental or developmental sensors. They also promote physical associations among various transcription factors.

CHROMOPHORE

A light-absorbing molecule, such as pterin or retinal. Often physically associated with a protein partner to form a photoreceptor/phototransducer.

MYB DOMAIN

A structurally conserved DNA-binding domain found in various transcription factors. In plants, MYB proteins are ubiquitous and known to function in many regulatory systems, including secondary metabolism, cell morphogenesis, the cell cycle, and circadian rhythms.

RESPONSE REGULATOR

Works in conjunction with a sensor kinase that might be activated by an environmental signal. Activation and autophosphorylation of the sensor kinase promotes phosphorylation of a specific response regulator. The latter is often a transcription factor with activity that is modulated by phosphorylation.

PHYTOCHROME

One of three classes of known plant photoreceptors. Composed of a protein moiety covalently associated with a tetrapyrrole chromophore. Synthesized in a red-light-absorbing form, nascent phytochromes are converted by red light to a far-red-absorbing isoform that might have altered stability and function. All phytochromes include carboxy-terminal PAS domains.

P-LOOP MOTIF

Phosphate-binding domain (P-loop) associated with many ATP- and GTP-binding proteins. These usually have a structure composed of a glycine-rich sequence, followed by certain conserved lysine and serine or threonine residues.

PHOTOACTIVE YELLOW PROTEIN

A soluble cytoplasmic protein with a p-hydroxycinnamyl chromophore that functions as the receptor for the phototactic response in certain halophilic bacteria.

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Young, M., Kay, S. Time zones: a comparative genetics of circadian clocks. Nat Rev Genet 2, 702–715 (2001). https://doi.org/10.1038/35088576

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