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FLASH GENE
Symbol CLOCK contributors: mct - updated : 19-12-2016
HGNC name clock homolog (mouse)
HGNC id 2082
EXPRESSION
Type widely
constitutive of
   expressed in (based on citations)
organ(s)
SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
Cardiovascularvessel   moderately
Endocrineparathyroid   moderately
Hearing/Equilibriumear   highly
Nervousbraindiencephalonhypothalamussuprachiasmatic nuclei 
 braindiencephalonhypothalamussupraoptic nuclei 
 brainhindbraincerebellum  
Reproductivemale systemtestis  highly
Respiratoryrespiratory tracttrachea  moderately
tissue
SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
Epithelialsecretoryglandularexocrine 
Muscularsmooth  highly
cell lineage
cell lines
fluid/secretion
at STAGE
PROTEIN
PHYSICAL PROPERTIES basic
STRUCTURE
motifs/domains
  • basic helix-loop-helix (bHLH)
  • two PAS (PER - ARNT - SIM) domain
  • a motif C terminal to PAS putatively contributing to the PAS fold (PAC domain)
  • conjugated sumoylated
    mono polymer heteromer , dimer
    HOMOLOGY
    interspecies homolog to murine Clock (96.67 pc)
    homolog to rattus Clock (95.60 pc)
    intraspecies paralog to NPAS2
    Homologene
    FAMILY
  • basic helix-loop-helix (bHLH) family
  • PER-ARNT-SIM (PAS) family of transcription factors
  • CATEGORY enzyme , regulatory , transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm
    intracellular,nucleus,chromatin/chromosome
    basic FUNCTION
  • regulator of circadian rhythms and in restting a peripheral vascular clock (acting in connection with ARNTL as a transcriptional activator in the circadian pacemaker)
  • activating the transcription from the e-box element
  • required with BMAL1 for both circadian transcription and chromatin modification
  • acting as a histone acetyltransferase
  • CLOCK/ARNTL regulates CCRN4L (nocturnin) transcription through binding to the E-box of nocturnin promoter
  • plays important roles in regulating the circadian rhythms in photoreceptor cells
  • overlapping role of CLOCK and NPAS2 transcription factors in liver circadian oscillators
  • CLOCK/ARNTL regulates human nocturnin transcription through binding to the E-box of nocturnin promoter
  • with ARNTL, are involved in the neuronal differentiation of adult neural stem/progenitor cells which may extend our understanding of various neurological/psychological disorders linked to adult neurogenesis and circadian rhythm
  • possible involvement of CLOCK in susceptibility to n attention-deficit hyperactivity disorder (ADHD)
  • drives the transcriptional activation of GYS2 via two tandemly located E-boxes
  • regulates the circadian rhythms of hepatic glycogen synthesis through transcriptional activation of GYS2
  • CLOCK and ARNTL are critical modulators of molecular, cellular, and functional parameters of skeletal muscle
  • CLOCK is a modulator of the key regulator of immune response, transcription factor NFKB1
  • CLOCK increases NFKB1–mediated transcriptional activation of responsive promoters independent of its circadian partner ARNTL
  • ARNTL and CLOCK contribute to chromatoid body (CB) assembly and physiology
  • CLOCK, MTTP, and NOCT are involved in the circadian regulation of intestinal lipid absorption
  • CLOCK and ARNTL drives rhythmic gene expression and regulate biological functions under circadian control
  • CLOCK-dependent direct transactivation through multiple E-boxes and indirect regulations polyphonically orchestrate dynamic circadian outputs
  • plays a key role in maintaining circadian rhythms and activation of downstream elements
  • plays an important role in fertility and the CLOCK knockdown leads to reduction in reproduction and increased miscarriage risk
  • CELLULAR PROCESS nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS circadian
    PATHWAY
    metabolism
    signaling signal transduction
  • CLOCK/TGFB1 signaling is a novel therapeutic target of PTGS2 inhibition
  • a component
  • heterodimerizing with ARNTL and ARNTL2 (BMAL1 and BAML2 respectively)
  • essential component of the major circadian transactivation complex that dimerizes with ARNTL to drive rhythmic expression from E-box–containing promoters
  • ARNTL in a complex with CLOCK or NPAS2 regulates cerebral redox homeostasis and connects impaired clock gene function to neurodegeneration
  • INTERACTION
    DNA binding to E-box element (5'-CACGTG-3')
    RNA
    small molecule
    protein
  • RARA and RXRA
  • ARNTL, ARNT, ARNT2
  • interacting with KAT5, and both are required for cisplatin resistance
  • melatonin interacts with CLOCK to affect the mammalian circadian system
  • interaction with ID2 (could potentially regulate aspects of both clock input and output through a time-of-day specific interaction with CLOCK and ARNTL1)
  • bind in a rhythmic manner to the core enhancer of the MYOD1 promoter
  • molecular link between two essential determinants of the circadian and immune mechanisms, the transcription factors CLOCK and NFKB1, respectively
  • ARNTL and CLOCK may act as Kamikaze activators, in that they are rapidly degraded once bound to DBP chromatin
  • CLOCK is a substrate of SUMO and sumoylation of CLOCK upregulates the transcriptional activity of ESR1
  • THRAP3 promotes the binding of CLOCK-ARNTL to DNA and links it to the basic transcriptional machinery
  • CLOCK is a positive regulator of ICAM1, and promotes the adhesion of mononuclear cells to endothelial cells
  • in mammalian circadian clockwork, the CLOCK-ARNTL complex binds to DNA enhancers of target genes and drives circadian oscillation of transcription
  • PER1 represses the activity of the circadian transcription factors ARNTL and CLOCK, either independently or together with CRYPTOCHROME (CRY)
  • FTO modulates circadian rhythms and inhibits the CLOCK-ARNTL-induced transcription
  • lack of NR1D1 increased ARNTL, NPAS2, CLOCK, and FABP7 expression, confirming the direct regulation of these genes by NR1D1 also in the brain
  • NPAS2 can compensate for loss of CLOCK in peripheral cells as well as in suprachiasmatic nucleus (SCN)
  • cell & other
    REGULATION
    induced by reduced forms of NAD and NADP when dimerizing with BMAL1 for DNA binding
    inhibited by oxidized forms of NAD and NADP when dimerizing with BMAL1 for DNA binding
    repressed by phosphorylation that contributes to the suppression of CLOCK-ARNTL-mediated transactivation through dual regulation: inhibition of CLOCK activity and promotion of its degradation
    Other regulation by a complex phospho-regulatory site that controls the activity and degradation of CLOCK, a core transcription factor that is essential for circadian behavior
    RAI1 regulates the transcription of circadian locomotor output cycles kaput (CLOCK), a key component of the mammalian circadian oscillator that transcriptionally regulates many critical circadian genes
    sumoylation of CLOCK upregulates the transcriptional activity of ESR1, stimulated cell growth and increased the proportion of S phase cells in the cell cycle
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional       loss of function
    of the clock component CLOCK of beta cells leads to hypoinsulinaemia and diabetes
    Susceptibility
  • to sleep dysregulation in major depression disorder and bipolar disorder
  • to a more severe lifetime body weight loss in eating disorder
  • to adult attention-deficit hyperactivity disorder
  • to variation of energy intake and sleep pattern
  • Variant & Polymorphism other
  • 3111T/C predispose eating disorders patients to a more severe lifetime body weight loss
  • polymorphisms increasing the risk of adult attention-deficit hyperactivity disorder
  • association of genetic variation at CLOCK with total energy intake, which was particularly relevant for SNP rs3749474
  • Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • cell structure and function of skeletal muscle is impaired in Clock delta 19 and Bmal1&
  • 8722;/&
    8722; mice
  • Clock-deficient mice showed increased synthesis of collagen, increased oxidative stress, and greater transforming growth factor-beta (TGFB1) expression