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CLOCK

From Wikipedia, the free encyclopedia
For other uses, seeClock (disambiguation).

CLOCK
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesCLOCK,KAT13D, bHLHe8, clock circadian regulator
External IDsOMIM:601851;MGI:99698;HomoloGene:3603;GeneCards:CLOCK;OMA:CLOCK - orthologs
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 MbChr 5: 76.36 – 76.45 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

CLOCK(backronymforcircadian locomotor output cycles kaput) is ageneencoding abasic helix-loop-helix-PAStranscription factorthat is known to affect both the persistence andperiodofcircadian rhythms.

Research shows that theCLOCKgene plays a major role as anactivatorof downstream elements in the pathway critical to the generation ofcircadian rhythms.[5][6]

Discovery

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TheCLOCKgene was first identified in 1997 byJoseph Takahashiand his colleagues. Takahashi used forward mutagenesis screening of mice treated withN-ethyl-N-nitrosoureato create and identifymutationsin key genes that broadly affect circadian activity.[7]TheCLOCKmutants discovered through the screen displayed an abnormally long period of daily activity. This trait proved to beheritable.Mice bred to beheterozygousshowed longer periods of 24.4 hours compared to the control 23.3 hour period. Micehomozygousfor the mutation showed 27.3 hour periods, but eventually lost all circadian rhythmicity after several days in constant darkness.[8]That showed that "intactCLOCKgenes "are necessary for normal mammalian circadian function, as these mutations were semidominant.[8]

Function

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CLOCK protein has been found to play a central role as a transcription factor in the circadian pacemaker.[9]InDrosophila,newly synthesized CLOCK (CLK) is hypophosphorylated in thecytoplasmbefore 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 theBMAL1orthologin mammals) dimerizes with CLK via their respectivePAS domains.This dimer then recruits co-activatorCREB-binding protein(CBP) and is further phosphorylated.[10]Once phosphorylated, this CLK-CYC complex binds to theE-boxelements of the promoters ofperiod(per) andtimeless(tim) via its bHLH domain, causing the stimulation of gene expression ofperandtim.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 ofperandtim,essentially blockingperandtimtranscription.[6][11]CLK ishyperphosphorylatedwhendoubletime(DBT)kinaseinteracts 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 ofperandtimand 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 activateperandcryptochrome(cry) transcription. PER and CRY proteins form a heterodimer which acts on the CLOCK-BMAL heterodimer to repress the transcription ofperandcry.[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 exhibitshistone acetyl transferase(HAT) activity, which is enhanced bydimerizationwith BMAL1.[14]Dr. Paolo Sassone-Corsi and colleagues demonstratedin vitrothat CLOCK mediated HAT activity is necessary to rescue circadian rhythms in Clock mutants.[14]

Role in other feedback loops

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The CLOCK-BMAL dimer is involved in regulation of other genes and feedback loops. An enzymeSIRT1also binds to the CLOCK-BMAL complex and acts to suppress its activity, perhaps bydeacetylationofBmal1and surroundinghistones.[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 asper1, 2, and 3 andtimin mice. It has been shown in mice that CLOCK-BMAL also activates theNicotinamide phosphoribosyltransferasegene (also calledNampt), part of a separate feedback loop. This feedback loop creates a metabolic oscillator. The CLOCK-BMAL dimer activates transcription of theNamptgene, which codes for the NAMPT protein. NAMPT is part of a series of enzymatic reactions that covertniacin(also callednicotinamide) toNAD.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 theNamptgene transcription and the cycle continues, creating another oscillatory loop involving CLOCK-BMAL as positive elements. The key role thatClockplays in metabolic and circadian loops highlights the close relationship between metabolism and circadian clocks.[17]

Evolution

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Phylogeny

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The firstcircadian rhythmswere most likely generated by light-driven cell division cycles in ancestralprokaryoticspecies.[18]This proto-rhythm later evolved into a self-sustaining clock viagene duplicationand functional divergence of clock genes. ThekaiA/B/Cgene clusters remain the oldest of the clock genes as they are present incyanobacteria,withkaiC most likely the ancestor ofkaiA andkaiB.[18]The function of these ancestral clock genes was most likely related to chromosome function before evolving a timing mechanism.[18]ThekaiA andkaiB 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 byCrygenes,are most likely descendents ofkaiCresulting from a genome duplication predating theCambrian explosionand are responsible for negative regulation of circadian clocks. Other distinct clock gene lineages arose early in vertebrate evolution, with gene BMAL1paralogousto CLOCK. Their common ancestor, however, most likely predated theinsect-vertebrate splitroughly 500 mya.[18]WC1, an analog of CLOCK/BMAL1 found in fungal genomes, is a proposed candidate common ancestor predating thefungi-animal split.[18]A BLAST search conducted in a 2004 review of clock gene evolution suggested theClockgene 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

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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 ofdivergent evolutionwhere species sharing anecological nichewill 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 anddiversification.[20][21]

Role in mammalian evolution

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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 neuronsin vitroand then performedgene knockdownto test the effect of CLOCK on neuronal cell signaling. When CLOCK activity was disrupted, increased neuronal migration of tissue in theneocortexwas observed, suggesting a molecular mechanism forcortical expansionunique 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 the3’ flanking regionand 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 andpolymorphismshave been shown to affect mRNA stability, indicating allelic variants could disrupt normal circadian patterns in mammals leading to conditions such asinsomniaor other sleep disorders.[23]

Mutants

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Clockmutant organisms can either possess a null mutation or anantimorphicallele at theClocklocus that codes for an antagonist to the wild-type protein. The presence of an antimorphic protein downregulates the transcriptional products normally upregulated byClock.[24]

Drosophila

[edit]

InDrosophila,a mutant form ofClock(Jrk) was identified by Allada,Hall,andRosbashin 1998. The team usedforward geneticsto identify non-circadian rhythms in mutant flies.Jrkresults from a prematurestop codonthat 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 thatClockfunctions 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 betweenJrkand its mousehomologsuggests common circadian rhythm components were present in bothDrosophilaand mice ancestors. A recessive allele ofClockleads to behavioral arrhythmicity while maintaining detectable molecular and transcriptional oscillations. This suggests thatClkcontributes to the amplitude of circadian rhythms.[26]

Mice

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The mouse homolog to theJrkmutant is theClockΔ19mutant that possesses a deletion in exon 19 of theClockgene. This dominant-negative mutation results in a defective CLOCK-BMAL dimer, which causes mice to have a decreased ability to activatepertranscription. In constant darkness,ClockΔ19mice heterozygous for theClockmutant allele exhibit lengthened circadian periods, whileClockΔ19/Δ19mice 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 whichClockhas been knocked out, display completely normal circadian rhythms. The discovery of a nullClockmutant with a wild-type phenotype directly challenged the widely accepted premise thatClockis 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 CLOCKparalog[29]) can substitute for CLOCK in theseClock-null mice. Mice with one NPAS2alleleshowed shorter periods at first, but eventual arrhythmic behavior.[30]

Observed effects

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In humans, apolymorphisminClock,rs6832769, may be related to thepersonality traitagreeableness.[31]Anothersingle nucleotide polymorphism(SNP) inClock,3111C, associated withdiurnalpreference,[23]is also associated with increasedinsomnia,[32]difficulty losing weight,[33]and recurrence of major depressive episodes in patients withbipolar disorder.[34]

In mice,Clockhas been implicated insleep disorders,metabolism,pregnancy,andmood disorders.Clockmutant mice sleep less than normal mice each day.[35]The mice also display altered levels of plasmaglucoseand rhythms in food intake.[36]These mutants developmetabolic syndromesymptoms over time.[36]Furthermore,Clockmutants demonstrate disruptedestrous cyclesand increased rates of full-term pregnancy failure.[37]MutantClockhas also been linked to bipolar disorder-like symptoms in mice, includingmaniaandeuphoria.[38]Clockmutant mice also exhibit increased excitability ofdopamineneurons in reward centers of the brain.[39]These results have ledColleen McClungto propose usingClockmutant 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 regulateBmalby binding to retinoic acid-related orphan receptor response elements (ROREs) in its promoter.[40][41]

Variations in theepigeneticsof theClockgene may lead to an increased risk ofbreast cancer.[42]It was found that in women with breast cancer, there was significantly less methylation of theClockpromoter region. It was also noted that this effect was greater in women with estrogen and progesterone receptor-negative tumors.[43]

The CLOCK gene may also be a target for somatic mutations in microsatellite unstablecolorectal cancers.In one study, 53% of microsatellite instability colorectal cancer cases contained somatic CLOCK mutations.[44]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,[45]with quantitative physical responses to circadian food intake as potential inputs to the clock system.[46]

See also

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References

[edit]
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Further reading

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