Molecular Bases for Circadian Clocks

Dunlap, Jay C

doi:10.1016/s0092-8674(00)80566-8

Cited by 2,900Circadian rhythm and melatoninPlant Molecular Biology ResearchLight effects on plants

Molecular Bases for Circadian Clocks

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Dunlap, Jay C·1999·Cell

DOI 10.1016/s0092-8674(00)80566-8

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Abstract

Life is a cyclical chemical process that is regulated in four dimensions. We distinguish parts of the cycle: development describes the changes from single cell to adult, and aging the changes from adult to death. Birth to death, a cycle, and there are cycles within cycles—circannual rhythms, menstrual cycles, semilunar cycles, and daily 24 hr or circadian cycles. Twice a year we get a reminder of the importance of our internal circadian biological clocks. Daylight savings: in October we fall back just an hour, and yet we wake up an hour early on Monday anyway and think meals are late—but only for a day, until our clocks are reset. The reminder is about the way we process environmental information and time, namely that we use external time cues (light and temperature changes that track the day without) to set an internal clock that guides the day within. This internal clock is the lens through which we survey acute external factors; it takes the lead in determining what we perceive as time. It used to be that research in chronobiology moved along at a gentlemanly pace. It was a field in that it shared a common set of problems, a common vocabulary, and a series of common assumptions: only eukaryotes had real clocks and they probably evolved just once, since the basic properties of the rhythms were generally the same. Any cell in fungi, plants, or protists could be a clock cell, but only neurons kept time in organisms that had them. Input to the clock was readily separable from how the clock itself worked. But within the past few years progress in understanding how clocks work in this assemblage of organisms has been increasing exponentially, coming to a crescendo during the final half of 1998 in an eruption of data that has largely disproven the assumptions and permanently changed the face of the field. The dust is still settling, but what we now see, albeit in broad outline, is probably the outline of how a large part of biological timing works at the molecular level. It's been quite a ride. How'd we get this far? One ought naturally to be able to consult reviews, but there have been so many concerning the molecular analysis of rhythms that clearly what is needed here is a review of the survey of the reviews. This brings to mind a short story by H. L. Mencken in which peace of mind was brought to the literary populace in the early 1900s only through the synthesis and condensation of all of the pertinent literary critiques each week into reviews of reviews and ultimately into a grand review word (the first week being something like MIFLHMP) that readers could read, be satisfied that they were up to date, and enjoy their evenings being at home, content (90Mencken, H.L. (1919). The criticism of criticism of criticism. In Prejudices—First Series, H.L. Mencken, ed. (New York: Knopf), pp. 308–316.Google Scholar). For such a telegraphically quick review of the molecular basis of the currently understood transcription/translation feedback loop (we'll get to this) circadian oscillators, the review word for the late 80s and early 90s would have been PERFRQT, reflecting the Drosophila period gene and the Neurospora frequency gene (the fruits of the first decades of genetic and molecular genetic analysis of clocks) and the fact that the Drosophila timeless gene, tim, was still in the process of arriving. This era was spent convincing ourselves that such genes really were the key to understanding how clocks work. Flies and fungi were PERFRQT systems for working out basic tools, paradigms, and approaches—gene products whose expression levels themselves oscillate, the importance of negative feedback, criteria to begin to distinguish which oscillatory gene products might contribute to the action of an internal timer as distinct from being output (reviewed in 32Dunlap J.C Genetic and molecular analysis of circadian rhythms.Annu. Rev. Genetics. 1996; 30: 579-601Crossref PubMed Scopus (167) Google Scholar), and a universal appreciation of the importance of genetics. If overall this left us with a less than PERFRQT understanding of timing in general, at least many found optimism in the sense that we were, finally, asking the right questions. This naturally segued into an interlude where light resetting was explained by two different mechanisms, through transcriptional induction of oscillator components in Neurospora (26Crosthwaite S.C Loros J.J Dunlap J.C Light-Induced resetting of a circadian clock is mediated by a rapid increase in frequency transcript.Cell. 1995; 81: 1003-1012Abstract Full Text PDF PubMed Scopus (242) Google Scholar) or protein turnover in Drosophila (reviewed in 166Young M The molecular control of circadian behavioral rhythms and their entrainment in Drosophila.Annu. Rev. Biochem. 1998; 67: 135-152Crossref PubMed Scopus (137) Google Scholar). But by mid 1997 the word was PASWCCLK (the first clock components with known biochemical functions [transcriptional activators], the first mammalian clock gene, and th

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The circadian rhythmicity of cortisol is regulated via ACTH as dictated by the hypothalamic suprachiasmatic nucleus.
“The circadian rhythmicity of cortisol is regulated via ACTH (18) as dictated by the hypothalamic suprachiasmatic nucleus (19).”
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In mammals, a master circadian clock resides in the suprachiasmatic nuclei (SCN) of the hypothalamus.
“In mammals, a master circadian clock resides in the suprachiasmatic nuclei (SCN) of the hypothalamus.”
From Nonredundant roles of the mPer1 and mPer2 genes in the mammalian circadian clock. (2001) · cites this paper as Dunlap, 1999
In vitro studies have shown that the expression of mPers is driven by the CLOCK/BMAL1 transcription complex.
“In vitro studies have shown that the expression of mPers is driven by the CLOCK/BMAL1 transcription complex, and it was hypothesized that mPERs, together with mCRYs, serve to regulate the CLOCK/BMAL1 transcription complex negatively (Dunlap, 1999; Gekakis et al., 1998; Griffin et al., 1999; Kume et al., 1999)”
From Nonredundant roles of the mPer1 and mPer2 genes in the mammalian circadian clock. (2001) · cites this paper as Dunlap, 1999

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Protein kinase CK2 interacts with and phosphorylates the Arabidopsis circadian clock-associated 1 protein
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Circadian clock locus frequency: protein encoded by a single open reading frame defines period length and temperature compensation.
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The Mouse Clock Mutation Behaves as an Antimorph and Maps Within the W19H Deletion, Distal of Kit
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Circadian rhythms in drosophila can be driven by period expression in a restricted group of central brain cells
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Light and temperature cooperate to regulate the circadian locomotor rhythm of wild type and period mutants of Drosophila melanogaster
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Glyceraldehyde-3-phosphate Dehydrogenase Is Regulated on a Daily Basis by the Circadian Clock
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Eukaryotic circadian systems: cycles in common
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A Period-Extender Gene, pex , That Extends the Period of the Circadian Clock in the Cyanobacterium Synechococcus sp. Strain PCC 7942
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Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus
Damiola, F., Le Minh, N., Preitner, N., Kornmann, B., Fleury-Olela, F., & Schibler, U. (2000) · Genes & Development · doi:10.1101/gad.183500 · Cited by 2,394 · see citing works
Resetting of circadian time in peripheral tissues by glucocorticoid signaling
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Mop3 is an essential component of the master circadian pacemaker in mammals.
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mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop
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An h Per2 Phosphorylation Site Mutation in Familial Advanced Sleep Phase Syndrome
Toh, K. L., Jones, C. R., He, Y., Eide, E. J., Hinz, W. A., Virshup, D. M., Ptáček, L. J., & Fu, Y.-H. (2001) · Science · doi:10.1126/science.1057499 · Cited by 1,460 · see citing works
Molecular analysis of mammalian circadian rhythms
Reppert, S. M., & Weaver, D. R. (2001) · Annual Review of Physiology · doi:10.1146/annurev.physiol.63.1.647 · Cited by 1,444 · see citing works
Interacting molecular loops in the mammalian circadian clock
Shearman, L. P., Sriram, S., Weaver, D. R., Maywood, E. S., Chaves, I., Zheng, B., Kume, K., Lee, C. C., van der, G. T. J., Horst, et al. (2000) · Science · doi:10.1126/science.288.5468.1013 · Cited by 1,367 · see citing works
Design principles of biochemical oscillators
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Rest in Drosophila is a sleep-like state
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“The circadian rhythmicity of cortisol is regulated via ACTH (18) as dictated by the hypothalamic suprachiasmatic nucleus (19).”
Background
Evolutionary conservations, changes of circadian rhythms and their effect on circadian disturbances and therapeutic approaches
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“…driving the expression of interlocking negative regulatory PER (Per), CRY (Cry), and REV-ERBα (Nr1d1) proteins and driving clock-controlled genes as output (Antoch et al., 1997; King et al., 1997; Tei et al., 1997; Gekakis et al., 1998; Hogenesch et al., 1998; Dunlap, 1999; Ko and Takahashi, 2006).”
Self-citation

Authors: Dunlap, J. C.
Affiliations: Dartmouth College (US)
Corresponding author: Dunlap, Jay C
ORCID: Dunlap, Jay C
Venue: Cell
Publisher: Elsevier BV
Published: 1999-01
Volume: 96
Issue: 2
Pages: 271-290
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/s0092-8674(00)80566-8
OpenAlex: W1979385177
Cited by: 2,900
References: 166
Citations by year: 2026: 56 · 2025: 82 · 2024: 70 · 2023: 76 · 2022: 98 · 2021: 97 · 2020: 89 · 2019: 81 · 2018: 91 · 2017: 102 · 2016: 71 · 2015: 89 · 2014: 96 · 2013: 66 · 2012: 83
FWCI: 19.62
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor, 1196 d)
Locations: Cell (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
Funders: National Institutes of Health (1k05mh001186-01)
National Institute of Mental Health (MH01186, MH 44651, R01MH044651)
National Institute of General Medical Sciences (GM34985)
Topics: Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
Life Sciences › Agricultural and Biological Sciences › Plant Science › Plant Molecular Biology Research
Life Sciences › Agricultural and Biological Sciences › Plant Science › Light effects on plants
Keywords: circadian clock, clock genes, circadian rhythm, chronobiology
MeSH terms: Cyanobacteria, Animals, Biological Clocks, Circadian Rhythm, Drosophila, Feedback, Humans, Intracellular Fluid, Neurospora, Phylogeny, Plants, Evolution, Molecular

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Molecular Bases for Circadian Clocks

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