CLOCK

Last updated
CLOCK
Circadian CLOCK protein.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CLOCK , KAT13D, bHLHe8, clock circadian regulator
External IDs OMIM: 601851 MGI: 99698 HomoloGene: 3603 GeneCards: CLOCK
Orthologs
SpeciesHumanMouse
Entrez

9575

12753

Ensembl

ENSG00000134852

ENSMUSG00000029238

UniProt

O15516

O08785

RefSeq (mRNA)

NM_001267843
NM_004898

NM_007715
NM_001289826
NM_001305222

RefSeq (protein)

NP_001254772
NP_004889

NP_001276755
NP_001292151
NP_031741

Location (UCSC) Chr 4: 55.43 – 55.55 Mb Chr 5: 76.36 – 76.45 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

CLOCK (from circadian locomotor output cycles kaput) is a gene encoding a basic helix-loop-helix-PAS transcription factor that is known to affect both the persistence and period of circadian rhythms.

Contents

Research shows that the CLOCK gene plays a major role as an activator of downstream elements in the pathway critical to the generation of circadian rhythms. [5] [6]

Discovery

The CLOCK gene was first identified in 1997 by Joseph Takahashi and his colleagues. Takahashi used forward mutagenesis screening of mice treated with N-ethyl-N-nitrosourea to create and identify mutations in key genes that broadly affect circadian activity. [7] The CLOCK mutants discovered through the screen displayed an abnormally long period of daily activity. This trait proved to be heritable. Mice bred to be heterozygous showed longer periods of 24.4 hours compared to the control 23.3 hour period. Mice homozygous for the mutation showed 27.3 hour periods, but eventually lost all circadian rhythmicity after several days in constant darkness. [8] That showed that "intact CLOCK genes" are necessary for normal mammalian circadian function [ how? ].

Function

CLOCK protein has been found to play a central role as a transcription factor in the circadian pacemaker. [9] In Drosophila , newly synthesized CLOCK (CLK) is hypophosphorylated in the cytoplasm before entering the nucleus. Once in the nuclei, CLK is localized in nuclear foci and is later redistributed homogeneously. CYCLE (CYC) (also known as dBMAL for the BMAL1 ortholog in mammals) dimerizes with CLK via their respective PAS domains. This dimer then recruits co-activator CREB-binding protein (CBP) and is further phosphorylated. [10] Once phosphorylated, this CLK-CYC complex binds to the E-box elements of the promoters of period (per) and timeless (tim) via its bHLH domain, causing the stimulation of gene expression of per and tim. A large molar excess of period (PER) and timeless (TIM) proteins causes formation of the PER-TIM heterodimer which prevents the CLK-CYC heterodimer from binding to the E-boxes of per and tim, essentially blocking per and tim transcription. [6] [11] CLK is hyperphosphorylated when doubletime (DBT) kinase interacts with the CLK-CYC complex in a PER reliant manner, destabilizing both CLK and PER, leading to the degradation of both proteins. [11] Hypophosphorylated CLK then accumulates, binds to the E-boxes of per and tim and activates their transcription once again. [11] This cycle of post-translational phosphorylation suggest that temporal phosphorylation of CLK helps in the timing mechanism of the circadian clock. [10]

A similar model is found in mice, in which BMAL1 dimerizes with CLOCK to activate per and cryptochrome (cry) transcription. PER and CRY proteins form a heterodimer which acts on the CLOCK-BMAL heterodimer to repress the transcription of per and cry. [12] The heterodimer CLOCK:BMAL1 functions similarly to other transcriptional activator complexes; CLOCK:BMAL1 interacts with the E-box regulatory elements. PER and CRY proteins accumulate and dimerize during subjective night, and translocate into the nucleus to interact with the CLOCK:BMAL1 complex, directly inhibiting their own expression. This research has been conducted and validated through crystallographic analysis. [13]

CLOCK exhibits histone acetyl transferase (HAT) activity, which is enhanced by dimerization with BMAL1. [14] Dr. Paolo Sassone-Corsi and colleagues demonstrated in vitro that CLOCK mediated HAT activity is necessary to rescue circadian rhythms in Clock mutants. [14]

Role in other feedback loops

The CLOCK-BMAL dimer is involved in regulation of other genes and feedback loops. An enzyme SIRT1 also binds to the CLOCK-BMAL complex and acts to suppress its activity, perhaps by deacetylation of Bmal1 and surrounding histones. [15] However, SIRT1's role is still controversial and it may also have a role in deacetylating PER protein, targeting it for degradation. [16]

The CLOCK-BMAL dimer acts as a positive limb of a feedback loop. The binding of CLOCK-BMAL to an E-box promoter element activates transcription of clock genes such as per1, 2, and 3 and tim in mice. It has been shown in mice that CLOCK-BMAL also activates the Nicotinamide phosphoribosyltransferase gene (also called Nampt), part of a separate feedback loop. This feedback loop creates a metabolic oscillator. The CLOCK-BMAL dimer activates transcription of the Nampt gene, which codes for the NAMPT protein. NAMPT is part of a series of enzymatic reactions that covert niacin (also called nicotinamide) to NAD. SIRT1, which requires NAD for its enzymatic activity, then uses increased NAD levels to suppress BMAL1 through deacetylation. This suppression results in less transcription of the NAMPT, less NAMPT protein, less NAD made, and therefore less SIRT1 and less suppression of the CLOCK-BMAL dimer. This dimer can again positively activate the Nampt gene transcription and the cycle continues, creating another oscillatory loop involving CLOCK-BMAL as positive elements. The key role that Clock plays in metabolic and circadian loops highlights the close relationship between metabolism and circadian clocks. [17]

Evolution

Phylogeny

The first circadian rhythms were most likely generated by light-driven cell division cycles in ancestral prokaryotic species. [18] This proto-rhythm later evolved into a self-sustaining clock via gene duplication and functional divergence of clock genes. The kaiA/B/C gene clusters remain the oldest of the clock genes as they are present in cyanobacteria, with kaiC most likely the ancestor of kaiA and kaiB. [18] The function of these ancestral clock genes was most likely related to chromosome function before evolving a timing mechanism. [18] The kaiA and kaiB genes arose after cyanobacteria separated from other prokaryotes. [19] Harsh climate conditions in the early history of the Earth’s formation, such as UV irradiation, may have led to the diversification of clock genes in prokaryotes in response to drastic changes in climate. [19]

Cryptochromes, light-sensitive proteins regulated by Cry genes, are most likely descendents of kaiC resulting from a genome duplication predating the Cambrian explosion and are responsible for negative regulation of circadian clocks. Other distinct clock gene lineages arose early in vertebrate evolution, with gene BMAL1 paralogous to CLOCK. Their common ancestor, however, most likely predated the insect-vertebrate split roughly 500 mya. [18] WC1, an analog of CLOCK/BMAL1 found in fungal genomes, is a proposed candidate common ancestor predating the fungi-animal split. [18] A BLAST search conducted in a 2004 review of clock gene evolution suggested the Clock gene may have arisen from a duplication in the BMAL1 gene, though this hypothesis remains speculative. [18] Another theory alternatively proposes the NPAS2 gene as the paralog of CLOCK that performs a similar role in the circadian rhythm pathway but in different tissues. [20]

Variant allele forms

Allelic variations within the Clock1a gene in particular are hypothesized to have effects on seasonal timing according to a 2014 study conducted in a population of cyprinid fishes. [21] Polymorphisms in the gene mainly affect the length of the PolyQ domain region, providing an example of divergent evolution where species sharing an ecological niche will partition resources in seasonally variable environments. [21] The length of the PolyQ domain is associated with changes in transcription level of CLOCK. On average, longer allele lengths were correlated with recently derived species and earlier-spawning species, most likely due to seasonal changes in water temperature. [21] The researchers hypothesize that the length of the domain may serve to compensate for changes in temperature by altering the rate of CLOCK transcription. All other amino acids remained identical across native species, indicating that functional constraint may be another factor influencing CLOCK gene evolution in addition to gene duplication and diversification. [20] [21]

Role in mammalian evolution

One 2017 study investigating the role of CLOCK expression in neurons determined its function in regulating transcriptional networks that could provide insight into human brain evolution. [22] The researchers synthesized differentiated human neurons in vitro and then performed gene knockdown to test the effect of CLOCK on neuronal cell signaling. When CLOCK activity was disrupted, increased neuronal migration of tissue in the neocortex was observed, suggesting a molecular mechanism for cortical expansion unique to human brain development. [22] However, the precise role of CLOCK in metabolic regulation of cortical neurons remains to be determined. Another study looking at the relationship between CLOCK polymorphisms in the 3’ flanking region and morning/evening preference in adults found a correlation between subjects with the 3111C allele and preference for evening hours based on answers provided in a scored questionnaire. [23] This region is well conserved between mice and humans and polymorphisms have been shown to affect mRNA stability, indicating allelic variants could disrupt normal circadian patterns in mammals leading to conditions such as insomnia or other sleep disorders. [23]

Mutants

Clock mutant organisms can either possess a null mutation or an antimorphic allele at the Clock locus that codes for an antagonist to the wild-type protein. The presence of an antimorphic protein downregulates the transcriptional products normally upregulated by Clock. [24]

Drosophila

In Drosophila, a mutant form of Clock (Jrk) was identified by Allada, Hall, and Rosbash in 1998. The team used forward genetics to identify non-circadian rhythms in mutant flies. Jrk results from a premature stop codon that eliminates the activation domain of the CLOCK protein. This mutation causes dominant effects: half of the heterozygous flies with this mutant gene have a lengthened period of 24.8 hours, while the other half become arrhythmic. Homozygous flies lose their circadian rhythm. Furthermore, the same researchers demonstrated that these mutant flies express low levels of PER and TIM proteins, indicating that Clock functions as a positive element in the circadian loop. While the mutation affects the circadian clock of the fly, it does not cause any physiological or behavioral defects. [25] The similar sequence between Jrk and its mouse homolog suggests common circadian rhythm components were present in both Drosophila and mice ancestors. A recessive allele of Clock leads to behavioral arrhythmicity while maintaining detectable molecular and transcriptional oscillations. This suggests that Clk contributes to the amplitude of circadian rhythms. [26]

Mice

The mouse homolog to the Jrk mutant is the ClockΔ19 mutant that possesses a deletion in exon 19 of the Clock gene. This dominant-negative mutation results in a defective CLOCK-BMAL dimer, which causes mice to have a decreased ability to activate per transcription. In constant darkness, ClockΔ19 mice heterozygous for the Clock mutant allele exhibit lengthened circadian periods, while ClockΔ19/Δ19 mice homozygous for the allele become arrhythmic. [8] In both heterozygotes and homozygotes, this mutation also produces lengthened periods and arrhythmicity at the single-cell level. [27]

Clock -/- null mutant mice, in which Clock has been knocked out, display completely normal circadian rhythms. The discovery of a null Clock mutant with a wild-type phenotype directly challenged the widely accepted premise that Clock is necessary for normal circadian function. Furthermore, it suggested that the CLOCK-BMAL1 dimer need not exist to modulate other elements of the circadian pathway. [28] Neuronal PAS domain containing protein 2 (NPAS2, a CLOCK paralog [29] ) can substitute for CLOCK in these Clock-null mice. Mice with one NPAS2 allele showed shorter periods at first, but eventual arrhythmic behavior. [30]

Observed effects

In humans, a polymorphism in Clock, rs6832769, may be related to the personality trait agreeableness. [31] Another single nucleotide polymorphism (SNP) in Clock, 3111C, associated with diurnal preference, [23] is also associated with increased insomnia, [32] difficulty losing weight, [33] and recurrence of major depressive episodes in patients with bipolar disorder. [34]

In mice, Clock has been implicated in sleep disorders, metabolism, pregnancy, and mood disorders. Clock mutant mice sleep less than normal mice each day. [35] The mice also display altered levels of plasma glucose and rhythms in food intake. [36] These mutants develop metabolic syndrome symptoms over time. [37] Furthermore, Clock mutants demonstrate disrupted estrous cycles and increased rates of full-term pregnancy failure. [38] Mutant Clock has also been linked to bipolar disorder-like symptoms in mice, including mania and euphoria. [39] Clock mutant mice also exhibit increased excitability of dopamine neurons in reward centers of the brain. [40] These results have led Colleen McClung to propose using Clock mutant mice as a model for human mood and behavior disorders.

The CLOCK-BMAL dimer has also been shown to activate reverse-erb receptor alpha (Rev-ErbA alpha) and retinoic acid orphan receptor alpha (ROR-alpha). REV-ERBα and RORα regulate Bmal by binding to retinoic acid-related orphan receptor response elements (ROREs) in its promoter. [41] [42]

Variations in the epigenetics of the Clock gene may lead to an increased risk of breast cancer. [43] It was found that in women with breast cancer, there was significantly less methylation of the Clock promoter region. It was also noted that this effect was greater in women with estrogen and progesterone receptor-negative tumors. [44]

The CLOCK gene may also be a target for somatic mutations in microsatellite unstable colorectal cancers. In one study, 53% of microsatellite instability colorectal cancer cases contained somatic CLOCK mutations. [45] Nascent research in the expression of circadian genes in adipose tissue suggests that suppression of the CLOCK gene may causally correlate not only with obesity, but also with type 2 diabetes, [46] with quantitative physical responses to circadian food intake as potential inputs to the clock system. [47]

See also

Related Research Articles

The Casein kinase 1 family of protein kinases are serine/threonine-selective enzymes that function as regulators of signal transduction pathways in most eukaryotic cell types. CK1 isoforms are involved in Wnt signaling, circadian rhythms, nucleo-cytoplasmic shuttling of transcription factors, DNA repair, and DNA transcription.

Timeless (tim) is a gene in multiple species but is most notable for its role in Drosophila for encoding TIM, an essential protein that regulates circadian rhythm. Timeless mRNA and protein oscillate rhythmically with time as part of a transcription-translation negative feedback loop involving the period (per) gene and its protein.

Period (per) is a gene located on the X chromosome of Drosophila melanogaster. Oscillations in levels of both per transcript and its corresponding protein PER have a period of approximately 24 hours and together play a central role in the molecular mechanism of the Drosophila biological clock driving circadian rhythms in eclosion and locomotor activity. Mutations in the per gene can shorten (perS), lengthen (perL), and even abolish (per0) the period of the circadian rhythm.

<span class="mw-page-title-main">NPAS2</span> Protein-coding gene in the species Homo sapiens

Neuronal PAS domain protein 2 (NPAS2) also known as member of PAS protein 4 (MOP4) is a transcription factor protein that in humans is encoded by the NPAS2 gene. NPAS2 is paralogous to CLOCK, and both are key proteins involved in the maintenance of circadian rhythms in mammals. In the brain, NPAS2 functions as a generator and maintainer of mammalian circadian rhythms. More specifically, NPAS2 is an activator of transcription and translation of core clock and clock-controlled genes through its role in a negative feedback loop in the suprachiasmatic nucleus (SCN), the brain region responsible for the control of circadian rhythms.

<span class="mw-page-title-main">ARNTL2</span> Protein-coding gene in humans

Aryl hydrocarbon receptor nuclear translocator-like 2, also known as Arntl2, Mop9, Bmal2, or Clif, is a gene.

<span class="mw-page-title-main">Period circadian protein homolog 1</span> Protein-coding gene in the species Homo sapiens

Period circadian protein homolog 1 is a protein in humans that is encoded by the PER1 gene.

<span class="mw-page-title-main">Basic helix-loop-helix ARNT-like protein 1</span> Human protein and coding gene

Basic helix-loop-helix ARNT-like protein 1 or aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL), or brain and muscle ARNT-like 1 is a protein that in humans is encoded by the BMAL1 gene on chromosome 11, region p15.3. It's also known as MOP3, and, less commonly, bHLHe5, BMAL, BMAL1C, JAP3, PASD3, and TIC.

<span class="mw-page-title-main">PAS domain</span> Protein domain

A Per-Arnt-Sim (PAS) domain is a protein domain found in all kingdoms of life. Generally, the PAS domain acts as a molecular sensor, whereby small molecules and other proteins associate via binding of the PAS domain. Due to this sensing capability, the PAS domain has been shown as the key structural motif involved in protein-protein interactions of the circadian clock, and it is also a common motif found in signaling proteins, where it functions as a signaling sensor.

In molecular biology, an oscillating gene is a gene that is expressed in a rhythmic pattern or in periodic cycles. Oscillating genes are usually circadian and can be identified by periodic changes in the state of an organism. Circadian rhythms, controlled by oscillating genes, have a period of approximately 24 hours. For example, plant leaves opening and closing at different times of the day or the sleep-wake schedule of animals can all include circadian rhythms. Other periods are also possible, such as 29.5 days resulting from circalunar rhythms or 12.4 hours resulting from circatidal rhythms. Oscillating genes include both core clock component genes and output genes. A core clock component gene is a gene necessary for to the pacemaker. However, an output oscillating gene, such as the AVP gene, is rhythmic but not necessary to the pacemaker.

Joseph S. Takahashi is a Japanese American neurobiologist and geneticist. Takahashi is a professor at University of Texas Southwestern Medical Center as well as an investigator at the Howard Hughes Medical Institute. Takahashi's research group discovered the genetic basis for the mammalian circadian clock in 1994 and identified the Clock gene in 1997. Takahashi was elected to the National Academy of Sciences in 2003.

<i>Cycle</i> (gene)

Cycle (cyc) is a gene in Drosophila melanogaster that encodes the CYCLE protein (CYC). The Cycle gene (cyc) is expressed in a variety of cell types in a circadian manner. It is involved in controlling both the sleep-wake cycle and circadian regulation of gene expression by promoting transcription in a negative feedback mechanism. The cyc gene is located on the left arm of chromosome 3 and codes for a transcription factor containing a basic helix-loop-helix (bHLH) domain and a PAS domain. The 2.17 kb cyc gene is divided into 5 coding exons totaling 1,625 base pairs which code for 413 aminos acid residues. Currently 19 alleles are known for cyc. Orthologs performing the same function in other species include ARNTL and ARNTL2.

Doubletime (DBT), also known as discs overgrown (DCO), is a gene that encodes the double-time protein in fruit flies. Michael Young and his team at Rockefeller University Rockefeller University first identified and characterized the gene in 1998.

<span class="mw-page-title-main">Michael Rosbash</span> American geneticist and chronobiologist (born 1944)

Michael Morris Rosbash is an American geneticist and chronobiologist. Rosbash is a professor and researcher at Brandeis University and investigator at the Howard Hughes Medical Institute. Rosbash's research group cloned the Drosophila period gene in 1984 and proposed the Transcription Translation Negative Feedback Loop for circadian clocks in 1990. In 1998, they discovered the cycle gene, clock gene, and cryptochrome photoreceptor in Drosophila through the use of forward genetics, by first identifying the phenotype of a mutant and then determining the genetics behind the mutation. Rosbash was elected to the National Academy of Sciences in 2003. Along with Michael W. Young and Jeffrey C. Hall, he was awarded the 2017 Nobel Prize in Physiology or Medicine "for their discoveries of molecular mechanisms controlling the circadian rhythm".

Jeffrey L. Price is an American researcher and author in the fields of circadian rhythms and molecular biology. His chronobiology work with Drosophila melanogaster has led to the discoveries of the circadian genes timeless (tim) and doubletime (dbt), and the doubletime regulators spaghetti (SPAG) and bride of doubletime (BDBT).

Paul Hardin is an American scientist in the field of chronobiology and a pioneering researcher in the understanding of circadian clocks in flies and mammals. Hardin currently serves as a distinguished professor in the biology department at Texas A&M University. He is best known for his discovery of circadian oscillations in the mRNA of the clock gene Period (per), the importance of the E-Box in per activation, the interlocked feedback loops that control rhythms in activator gene transcription, and the circadian regulation of olfaction in Drosophila melanogaster. Born in a suburb of Chicago, Matteson, Illinois, Hardin currently resides in College Station, Texas, with his wife and three children.

Vrille (vri) is a bZIP transcription factor found on chromosome 2 in Drosophila melanogaster. Vrille mRNA and protein product (VRI) oscillate predictably on a 24-hour timescale and interact with other circadian clock genes to regulate circadian rhythms in Drosophila. It is also a regulator in embryogenesis; it is expressed in multiple cell types during multiple stages in development, coordinating embryonic dorsal/ventral polarity, wing-vein differentiation, and ensuring tracheal integrity. It is also active in the embryonic gut but the precise function there is unknown. Mutations in vri alter circadian period and cause circadian arrhythmicity and developmental defects in Drosophila.

<i>Drosophila</i> circadian rhythm

Drosophila circadian rhythm is a daily 24-hour cycle of rest and activity in the fruit flies of the genus Drosophila. The biological process was discovered and is best understood in the species Drosophila melanogaster. Other than normal sleep-wake activity, D. melanogaster has two unique daily behaviours, namely regular vibration during the process of hatching from the pupa, and during mating. Locomotor activity is maximum at dawn and dusk, while eclosion is at dawn.

Transcription-translation feedback loop (TTFL) is a cellular model for explaining circadian rhythms in behavior and physiology. Widely conserved across species, the TTFL is auto-regulatory, in which transcription of clock genes is regulated by their own protein products.

dClock (clk) is a gene located on the 3L chromosome of Drosophila melanogaster. Mapping and cloning of the gene indicates that it is the Drosophila homolog of the mouse gene CLOCK (mClock). The Jrk mutation disrupts the transcription cycling of per and tim and manifests dominant effects.

Ravi Allada is an Indian-American chronobiologist studying the circadian and homeostatic regulation of sleep primarily in the fruit fly Drosophila. He is currently the Executive Director of the Michigan Neuroscience Institute (MNI), a collective which connects neuroscience investigators across the University of Michigan to probe the mysteries of the brain on a cellular, molecular, and behavioral level. Working with Michael Rosbash, he positionally cloned the Drosophila Clock gene. In his laboratory at Northwestern, he discovered a conserved mechanism for circadian control of sleep-wake cycle, as well as circuit mechanisms that manage levels of sleep.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000134852 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000029238 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Walton ZE, Altman BJ, Brooks RC, Dang CV (4 March 2018). "Circadian Clock's Cancer Connections". Annual Review of Cancer Biology. 2 (1): 133–153. doi: 10.1146/annurev-cancerbio-030617-050216 . ISSN   2472-3428. S2CID   91120424.
  6. 1 2 Dunlap JC (January 1999). "Molecular bases for circadian clocks". Cell. 96 (2): 271–290. doi: 10.1016/S0092-8674(00)80566-8 . PMID   9988221. S2CID   14991100.
  7. ↑ King DP, Zhao Y, Sangoram AM, Wilsbacher LD, Tanaka M, Antoch MP, et al. (May 1997). "Positional cloning of the mouse circadian clock gene". Cell. 89 (4): 641–653. doi:10.1016/S0092-8674(00)80245-7. PMC   3815553 . PMID   9160755.
  8. 1 2 Vitaterna MH, King DP, Chang AM, Kornhauser JM, Lowrey PL, McDonald JD, et al. (April 1994). "Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior". Science. 264 (5159): 719–725. Bibcode:1994Sci...264..719H. doi:10.1126/science.8171325. PMC   3839659 . PMID   8171325.
  9. ↑ Hardin PE (2000). "From biological clock to biological rhythms". Genome Biology. 1 (4): REVIEWS1023. doi: 10.1186/gb-2000-1-4-reviews1023 . PMC   138871 . PMID   11178250.
  10. 1 2 Hung HC, Maurer C, Zorn D, Chang WL, Weber F (August 2009). "Sequential and compartment-specific phosphorylation controls the life cycle of the circadian CLOCK protein". The Journal of Biological Chemistry. 284 (35): 23734–23742. doi: 10.1074/jbc.M109.025064 . PMC   2749147 . PMID   19564332.
  11. 1 2 3 Yu W, Zheng H, Houl JH, Dauwalder B, Hardin PE (March 2006). "PER-dependent rhythms in CLK phosphorylation and E-box binding regulate circadian transcription". Genes & Development. 20 (6): 723–733. doi:10.1101/gad.1404406. PMC   1434787 . PMID   16543224.
  12. ↑ Gekakis N, Staknis D, Nguyen HB, Davis FC, Wilsbacher LD, King DP, et al. (June 1998). "Role of the CLOCK protein in the mammalian circadian mechanism". Science. 280 (5369): 1564–1569. Bibcode:1998Sci...280.1564G. doi:10.1126/science.280.5369.1564. PMID   9616112.
  13. ↑ Huang N, Chelliah Y, Shan Y, Taylor CA, Yoo SH, Partch C, et al. (July 2012). "Crystal structure of the heterodimeric CLOCK:BMAL1 transcriptional activator complex". Science. 337 (6091): 189–194. Bibcode:2012Sci...337..189H. doi:10.1126/science.1222804. PMC   3694778 . PMID   22653727.
  14. 1 2 Doi M, Hirayama J, Sassone-Corsi P (May 2006). "Circadian regulator CLOCK is a histone acetyltransferase". Cell. 125 (3): 497–508. doi: 10.1016/j.cell.2006.03.033 . PMID   16678094. S2CID   5968161.
  15. ↑ Nakahata Y, Kaluzova M, Grimaldi B, Sahar S, Hirayama J, Chen D, et al. (July 2008). "The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control". Cell. 134 (2): 329–340. doi:10.1016/j.cell.2008.07.002. PMC   3526943 . PMID   18662547.
  16. ↑ Asher G, Gatfield D, Stratmann M, Reinke H, Dibner C, Kreppel F, et al. (July 2008). "SIRT1 regulates circadian clock gene expression through PER2 deacetylation". Cell. 134 (2): 317–328. doi: 10.1016/j.cell.2008.06.050 . PMID   18662546. S2CID   17267748.
  17. ↑ Ramsey KM, Yoshino J, Brace CS, Abrassart D, Kobayashi Y, Marcheva B, et al. (May 2009). "Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis". Science. 324 (5927): 651–654. Bibcode:2009Sci...324..651R. doi:10.1126/science.1171641. PMC   2738420 . PMID   19299583.
  18. 1 2 3 4 5 6 Tauber E, Last KS, Olive PJ, Kyriacou CP (October 2004). "Clock gene evolution and functional divergence". Journal of Biological Rhythms. 19 (5): 445–458. doi: 10.1177/0748730404268775 . PMID   15534324. S2CID   30327894.
  19. 1 2 Dvornyk V, Vinogradova O, Nevo E (March 2003). "Origin and evolution of circadian clock genes in prokaryotes". Proceedings of the National Academy of Sciences of the United States of America. 100 (5): 2495–2500. Bibcode:2003PNAS..100.2495D. doi: 10.1073/pnas.0130099100 . PMC   151369 . PMID   12604787.
  20. 1 2 Layeghifard M, Rabani R, Pirhaji L, Yakhchali B (December 2008). "Evolutionary mechanisms underlying the functional divergence of duplicate genes involved in vertebrates' circadian rhythm pathway". Gene. 426 (1–2): 65–71. doi:10.1016/j.gene.2008.08.014. PMID   18804153.
  21. 1 2 3 4 Krabbenhoft TJ, Turner TF (2014-05-01). "Clock gene evolution: seasonal timing, phylogenetic signal, or functional constraint?". The Journal of Heredity. 105 (3): 407–415. doi:10.1093/jhered/esu008. PMC   3984439 . PMID   24558102.
  22. 1 2 Fontenot MR, Berto S, Liu Y, Werthmann G, Douglas C, Usui N, et al. (November 2017). "Novel transcriptional networks regulated by CLOCK in human neurons". Genes & Development. 31 (21): 2121–2135. doi:10.1101/gad.305813.117. PMC   5749161 . PMID   29196536.
  23. 1 2 3 Katzenberg D, Young T, Finn L, Lin L, King DP, Takahashi JS, Mignot E (September 1998). "A CLOCK polymorphism associated with human diurnal preference". Sleep. 21 (6): 569–576. doi: 10.1093/sleep/21.6.569 . PMID   9779516.
  24. ↑ Panda S, Antoch MP, Miller BH, Su AI, Schook AB, Straume M, et al. (May 2002). "Coordinated transcription of key pathways in the mouse by the circadian clock". Cell. 109 (3): 307–320. doi: 10.1016/S0092-8674(02)00722-5 . PMID   12015981. S2CID   17076121.
  25. ↑ Allada R, White NE, So WV, Hall JC, Rosbash M (May 1998). "A mutant Drosophila homolog of mammalian Clock disrupts circadian rhythms and transcription of period and timeless". Cell. 93 (5): 791–804. doi: 10.1016/S0092-8674(00)81440-3 . PMID   9630223. S2CID   1779880.
  26. ↑ Kraupp VO (January 1975). "[Pharmacodynamic examples on the effect enhancement or alteration of action through molecular dimerization]". Wiener Medizinische Wochenschrift. 125 (1–3): 23–29. doi:10.1093/emboj/cdg318. PMC   165643 . PMID   165643.
  27. ↑ Herzog ED, Takahashi JS, Block GD (December 1998). "Clock controls circadian period in isolated suprachiasmatic nucleus neurons". Nature Neuroscience. 1 (8): 708–713. doi:10.1038/3708. PMID   10196587. S2CID   19112613.
  28. ↑ Debruyne JP, Noton E, Lambert CM, Maywood ES, Weaver DR, Reppert SM (May 2006). "A clock shock: mouse CLOCK is not required for circadian oscillator function". Neuron. 50 (3): 465–477. doi: 10.1016/j.neuron.2006.03.041 . PMID   16675400. S2CID   19028601.
  29. ↑ Debruyne JP (December 2008). "Oscillating perceptions: the ups and downs of the CLOCK protein in the mouse circadian system". Journal of Genetics. 87 (5): 437–446. doi:10.1007/s12041-008-0066-7. PMC   2749070 . PMID   19147932.
  30. ↑ DeBruyne JP, Weaver DR, Reppert SM (May 2007). "CLOCK and NPAS2 have overlapping roles in the suprachiasmatic circadian clock". Nature Neuroscience. 10 (5): 543–545. doi:10.1038/nn1884. PMC   2782643 . PMID   17417633.
  31. ↑ Terracciano A, Sanna S, Uda M, Deiana B, Usala G, Busonero F, et al. (June 2010). "Genome-wide association scan for five major dimensions of personality". Molecular Psychiatry. 15 (6): 647–656. doi:10.1038/mp.2008.113. PMC   2874623 . PMID   18957941.
  32. ↑ Serretti A, Benedetti F, Mandelli L, Lorenzi C, Pirovano A, Colombo C, Smeraldi E (August 2003). "Genetic dissection of psychopathological symptoms: insomnia in mood disorders and CLOCK gene polymorphism". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics. 121B (1): 35–38. doi:10.1002/ajmg.b.20053. PMID   12898572. S2CID   84246654.
  33. ↑ Garaulet M, Corbalán MD, Madrid JA, Morales E, Baraza JC, Lee YC, Ordovas JM (March 2010). "CLOCK gene is implicated in weight reduction in obese patients participating in a dietary programme based on the Mediterranean diet". International Journal of Obesity. 34 (3): 516–523. doi:10.1038/ijo.2009.255. PMC   4426985 . PMID   20065968.
  34. ↑ Bunney BG, Li JZ, Walsh DM, Stein R, Vawter MP, Cartagena P, et al. (February 2015). "Circadian dysregulation of clock genes: clues to rapid treatments in major depressive disorder". Molecular Psychiatry. 20 (1): 48–55. doi:10.1038/mp.2014.138. PMC   4765913 . PMID   25349171.
  35. ↑ Naylor E, Bergmann BM, Krauski K, Zee PC, Takahashi JS, Vitaterna MH, Turek FW (November 2000). "The circadian clock mutation alters sleep homeostasis in the mouse". The Journal of Neuroscience. 20 (21): 8138–8143. doi: 10.1523/JNEUROSCI.20-21-08138.2000 . PMC   6772726 . PMID   11050136.
  36. ↑ Turek FW, Joshu C, Kohsaka A, Lin E, Ivanova G, McDearmon E, et al. (May 2005). "Obesity and metabolic syndrome in circadian Clock mutant mice". Science. 308 (5724): 1043–1045. Bibcode:2005Sci...308.1043T. doi:10.1126/science.1108750. PMC   3764501 . PMID   15845877.
  37. ↑ Turek FW, Joshu C, Kohsaka A, Lin E, Ivanova G, McDearmon E, et al. (May 2005). "Obesity and metabolic syndrome in circadian Clock mutant mice". Science. 308 (5724): 1043–1045. Bibcode:2005Sci...308.1043T. doi:10.1126/science.1108750. PMC   3764501 . PMID   15845877.
  38. ↑ Miller BH, Olson SL, Turek FW, Levine JE, Horton TH, Takahashi JS (August 2004). "Circadian clock mutation disrupts estrous cyclicity and maintenance of pregnancy". Current Biology. 14 (15): 1367–1373. Bibcode:2004CBio...14.1367M. doi:10.1016/j.cub.2004.07.055. PMC   3756147 . PMID   15296754.
  39. ↑ McClung CA (May 2007). "Circadian genes, rhythms and the biology of mood disorders". Pharmacology & Therapeutics. 114 (2): 222–232. doi:10.1016/j.pharmthera.2007.02.003. PMC   1925042 . PMID   17395264.
  40. ↑ McClung CA, Sidiropoulou K, Vitaterna M, Takahashi JS, White FJ, Cooper DC, Nestler EJ (June 2005). "Regulation of dopaminergic transmission and cocaine reward by the Clock gene". Proceedings of the National Academy of Sciences of the United States of America. 102 (26): 9377–9381. Bibcode:2005PNAS..102.9377M. doi: 10.1073/pnas.0503584102 . PMC   1166621 . PMID   15967985.
  41. ↑ Preitner N, Damiola F, Lopez-Molina L, Zakany J, Duboule D, Albrecht U, Schibler U (July 2002). "The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator". Cell. 110 (2): 251–260. doi: 10.1016/S0092-8674(02)00825-5 . PMID   12150932. S2CID   15224136.
  42. ↑ Guillaumond F, Dardente H, Giguère V, Cermakian N (October 2005). "Differential control of Bmal1 circadian transcription by REV-ERB and ROR nuclear receptors". Journal of Biological Rhythms. 20 (5): 391–403. CiteSeerX   10.1.1.882.4644 . doi:10.1177/0748730405277232. PMID   16267379. S2CID   33279857.
  43. ↑ Dodson H. "Women With Variants in "CLOCK" Gene Have Higher Risk of Breast Cancer". Yale Office of Public Affairs and Communications. Archived from the original on 2011-07-24. Retrieved 21 April 2011.
  44. ↑ Joska TM, Zaman R, Belden WJ (September 2014). "Regulated DNA methylation and the circadian clock: implications in cancer". Biology. 3 (3): 560–577. doi: 10.3390/biology3030560 . PMC   4192628 . PMID   25198253.
  45. ↑ Alhopuro P, Björklund M, Sammalkorpi H, Turunen M, Tuupanen S, Biström M, et al. (July 2010). "Mutations in the circadian gene CLOCK in colorectal cancer". Molecular Cancer Research. 8 (7): 952–960. doi: 10.1158/1541-7786.MCR-10-0086 . PMID   20551151.
  46. ↑ Yoshino J, Klein S (July 2013). "A novel link between circadian clocks and adipose tissue energy metabolism". Diabetes. 62 (7): 2175–2177. doi:10.2337/db13-0457. PMC   3712037 . PMID   23801717.
  47. ↑ Johnston JD (June 2014). "Physiological responses to food intake throughout the day". Nutrition Research Reviews. 27 (1): 107–118. doi:10.1017/S0954422414000055. PMC   4078443 . PMID   24666537.

Further reading

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.