Circadian Clock (Homo sapiens)

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1-41226-293417, 1812, 27, 38-43338, 35-3728, 3023, 243119-2244, 4524, 2532cytosolendoplasmic reticulum lumennucleoplasmextracellular regionUbiquitinated Phosphorylated CRY ProteinsFBXL3:CRY ComplexCryptochrome-2Phosphorylated CRY ProteinsCLOCK or NPAS2Period circadian protein homolog 2NR1D1_HUMANPhosphorylated BMAL1:CLOCK/NPAS2 Heterodimer Bound to DNABMAL1:CLOCK/NPAS2 HeterodimerCasein kinase I delta or Casein kinase I epsilonCRY ProteinsCryptochrome-1DNA Containing an E-box ElementSCF-beta-TrCP1 complexPhosphorylated PER ProteinsAVPBMAL1:CLOCK/NPAS2:CRY:PER ComplexD site-binding proteinNuclear receptor ROR-alphapro-factor VII, uncarboxylatedubiquitinBeta-TrCPBMAL2:CLOCK HeterodimerBMAL1Class E basic helix-loop-helix protein 41plasminogen activator inhibitor 1CRY:PER:Kinase Ternary Complex, unphosphorylatedUbiquitinated Phosphorylated PER ProteinsCRY:PER:Kinase Ternary Complex, phosphorylatedCRY:PER:Kinase Ternary Complex, phosphorylatedNocturninubiquitinBMAL1:CLOCK/NPAS2:CRY ComplexClass E basic helix-loop-helix protein 40Glucocorticoid receptor:Dexamethasone ComplexBeta-TrCP1:PER complexFBXL3Peroxisome proliferator-activated receptor alphaPeriod circadian protein homolog 11215, 16149-1186, 7513


At the center of the mammalian circadian clock is a negative transcription/translation-based feedback loop: The BMAL1:CLOCK/NPAS2 heterodimer transactivates CRY and PER genes by binding E-box elements in their promoters; the CRY and PER proteins then inhibit transactivation by BMAL1:CLOCK/NPAS2. BMAL1:CLOCK/NPAS2 activates transcription of CRY, PER, and several other genes in the morning. Levels of PER and CRY proteins rise during the day and inhibit expression of CRY, PER, and other BMAL1:CLOCK/NPAS2-activated genes in the afternoon and evening. During the night CRY and PER proteins are targeted for degradation by phosphorylation and polyubiquitination, allowing the cycle to commence again in the morning.
Transcription of the BMAL1 (ARNTL) gene is controlled by ROR-alpha and REV-ERBA, both of which are targets of BMAL1:CLOCK/NPAS2 in mice and both of which compete for the same element (RORE) in the BMAL1 promoter. ROR-alpha activates transcription of BMAL1; REV-ERBA represses transcription of BMAL1. This mutual control forms a secondary, reinforcing loop of the circadian clock. REV-ERBA shows strong circadian rhythmicity and confers circadian expression on BMAL1.
BMAL1 can form heterodimers with either CLOCK or NPAS2, which act redundantly but show different tissue specificity. The BMAL1:CLOCK and BMAL1:NPAS2 heterodimers activate a set of genes that possess E-box elements (consensus CACGTG) in their promoters. This confers circadian expression on the genes. The PER genes (PER1, PER2, PER3) and CRY genes (CRY1, CRY2) are among those activated by BMAL1:CLOCK and BMAL1:NPAS2. PER and CRY mRNA accumulates during the morning and the proteins accumulate during the afternoon. PER and CRY proteins form complexes in the cytosol and these are bound by either CSNK1D or CSNK1E kinases which phosphorylate PER and CRY. The phosphorylated PER:CRY:kinase complex is translocated into the nucleus due to the nuclear localization signal of PER and CRY. Within the nucleus the PER:CRY complexes bind BMAL1:CLOCK and BMAL1:NPAS2, inhibiting their transactivation activity and their phosphorylation. This reduces expression of the target genes of BMAL1:CLOCK and BMAL1:NPAS2 during the afternoon and evening.
PER:CRY complexes also traffic out of the nucleus into the cytosol due to the nuclear export signal of PER. During the night PER:CRY complexes are polyubiquitinated and degraded, allowing the cycle to begin again. Phosphorylated PER is bound by Beta-TrCP1, a cytosolic F-box type component of some SCF E3 ubiquitin ligases. CRY is bound by FBXL3, a nucleoplasmic F-box type component of some SCF E3 ubiquitin ligases. Phosphorylation of CRY1 by Adenosine monophosphate-activated kinase (AMPK) enhances degradation of CRY1. PER and CRY are subsequently polyubiquitinated and proteolyzed by the 26S proteasome.
The circadian clock is cell-autonomous and some, but not all cells of the body exhibit circadian rhythms in metabolism, cell division, and gene transcription. The suprachiasmatic nucleus (SCN) in the hypothalamus is the major clock in the body and receives its major input from light (via retinal neurons) and a minor input from nutrient intake. The SCN and other brain tissues determine waking and feeding cycles and influence the clocks in other tissues by hormone secretion and nervous stimulation. Independently of the SCN, other tissues such as liver receive inputs from signals from the brain and from nutrients.

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  1. Camacho F, Cilio M, Guo Y, Virshup DM, Patel K, Khorkova O, Styren S, Morse B, Yao Z, Keesler GA.; ''Human casein kinase Idelta phosphorylation of human circadian clock proteins period 1 and 2.''; PubMed Europe PMC
  2. Xu Y, Padiath QS, Shapiro RE, Jones CR, Wu SC, Saigoh N, Saigoh K, Ptácek LJ, Fu YH.; ''Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome.''; PubMed Europe PMC
  3. Tamaru T, Hirayama J, Isojima Y, Nagai K, Norioka S, Takamatsu K, Sassone-Corsi P.; ''CK2alpha phosphorylates BMAL1 to regulate the mammalian clock.''; PubMed Europe PMC
  4. Knutti D, Kaul A, Kralli A.; ''A tissue-specific coactivator of steroid receptors, identified in a functional genetic screen.''; PubMed Europe PMC
  5. Wu N, Yin L, Hanniman EA, Joshi S, Lazar MA.; ''Negative feedback maintenance of heme homeostasis by its receptor, Rev-erbalpha.''; PubMed Europe PMC
  6. Larrouy D, Vidal H, Andreelli F, Laville M, Langin D.; ''Cloning and mRNA tissue distribution of human PPARgamma coactivator-1.''; PubMed Europe PMC
  7. Crumbley C, Burris TP.; ''Direct regulation of CLOCK expression by REV-ERB.''; PubMed Europe PMC
  8. Eide EJ, Vielhaber EL, Hinz WA, Virshup DM.; ''The circadian regulatory proteins BMAL1 and cryptochromes are substrates of casein kinase Iepsilon.''; PubMed Europe PMC
  9. Poliandri AH, Gamsby JJ, Christian M, Spinella MJ, Loros JJ, Dunlap JC, Parker MG.; ''Modulation of clock gene expression by the transcriptional coregulator receptor interacting protein 140 (RIP140).''; PubMed Europe PMC
  10. Giguère V, Tini M, Flock G, Ong E, Evans RM, Otulakowski G.; ''Isoform-specific amino-terminal domains dictate DNA-binding properties of ROR alpha, a novel family of orphan hormone nuclear receptors.''; PubMed Europe PMC
  11. Adelmant G, Bègue A, Stéhelin D, Laudet V.; ''A functional Rev-erb alpha responsive element located in the human Rev-erb alpha promoter mediates a repressing activity.''; PubMed Europe PMC
  12. Dardente H, Fortier EE, Martineau V, Cermakian N.; ''Cryptochromes impair phosphorylation of transcriptional activators in the clock: a general mechanism for circadian repression.''; PubMed Europe PMC
  13. Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM.; ''A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis.''; PubMed Europe PMC
  14. Zhou YD, Barnard M, Tian H, Li X, Ring HZ, Francke U, Shelton J, Richardson J, Russell DW, McKnight SL.; ''Molecular characterization of two mammalian bHLH-PAS domain proteins selectively expressed in the central nervous system.''; PubMed Europe PMC
  15. Gekakis N, Staknis D, Nguyen HB, Davis FC, Wilsbacher LD, King DP, Takahashi JS, Weitz CJ.; ''Role of the CLOCK protein in the mammalian circadian mechanism.''; PubMed Europe PMC
  16. Hogenesch JB, Gu YZ, Jain S, Bradfield CA.; ''The basic-helix-loop-helix-PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors.''; PubMed Europe PMC
  17. Toh KL, Jones CR, He Y, Eide EJ, Hinz WA, Virshup DM, Ptácek LJ, Fu YH.; ''An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome.''; PubMed Europe PMC
  18. Motzkus D, Loumi S, Cadenas C, Vinson C, Forssmann WG, Maronde E.; ''Activation of human period-1 by PKA or CLOCK/BMAL1 is conferred by separate signal transduction pathways.''; PubMed Europe PMC
  19. Muñoz E, Baler R.; ''The circadian E-box: when perfect is not good enough.''; PubMed Europe PMC
  20. Rutter J, Reick M, Wu LC, McKnight SL.; ''Regulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors.''; PubMed Europe PMC
  21. Busino L, Bassermann F, Maiolica A, Lee C, Nolan PM, Godinho SI, Draetta GF, Pagano M.; ''SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins.''; PubMed Europe PMC
  22. Matsumura R, Matsubara C, Node K, Takumi T, Akashi M.; ''Nuclear receptor-mediated cell-autonomous oscillatory expression of the circadian transcription factor, neuronal PAS domain protein 2 (NPAS2).''; PubMed Europe PMC
  23. Griffin EA, Staknis D, Weitz CJ.; ''Light-independent role of CRY1 and CRY2 in the mammalian circadian clock.''; PubMed Europe PMC
  24. Lee C, Etchegaray JP, Cagampang FR, Loudon AS, Reppert SM.; ''Posttranslational mechanisms regulate the mammalian circadian clock.''; PubMed Europe PMC
  25. Ueda HR, Hayashi S, Chen W, Sano M, Machida M, Shigeyoshi Y, Iino M, Hashimoto S.; ''System-level identification of transcriptional circuits underlying mammalian circadian clocks.''; PubMed Europe PMC
  26. Miyajima N, Horiuchi R, Shibuya Y, Fukushige S, Matsubara K, Toyoshima K, Yamamoto T.; ''Two erbA homologs encoding proteins with different T3 binding capacities are transcribed from opposite DNA strands of the same genetic locus.''; PubMed Europe PMC
  27. Thompson CL, Bowes Rickman C, Shaw SJ, Ebright JN, Kelly U, Sancar A, Rickman DW.; ''Expression of the blue-light receptor cryptochrome in the human retina.''; PubMed Europe PMC
  28. Hogenesch JB, Chan WK, Jackiw VH, Brown RC, Gu YZ, Pray-Grant M, Perdew GH, Bradfield CA.; ''Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway.''; PubMed Europe PMC
  29. Phelan CA, Gampe RT, Lambert MH, Parks DJ, Montana V, Bynum J, Broderick TM, Hu X, Williams SP, Nolte RT, Lazar MA.; ''Structure of Rev-erbalpha bound to N-CoR reveals a unique mechanism of nuclear receptor-co-repressor interaction.''; PubMed Europe PMC
  30. Takahashi JS, Hong HK, Ko CH, McDearmon EL.; ''The genetics of mammalian circadian order and disorder: implications for physiology and disease.''; PubMed Europe PMC
  31. Raspè E, Mautino G, Duval C, Fontaine C, Duez H, Barbier O, Monte D, Fruchart J, Fruchart JC, Staels B.; ''Transcriptional regulation of human Rev-erbalpha gene expression by the orphan nuclear receptor retinoic acid-related orphan receptor alpha.''; PubMed Europe PMC
  32. Ikeda M, Nomura M.; ''cDNA cloning and tissue-specific expression of a novel basic helix-loop-helix/PAS protein (BMAL1) and identification of alternatively spliced variants with alternative translation initiation site usage.''; PubMed Europe PMC
  33. Ko CH, Takahashi JS.; ''Molecular components of the mammalian circadian clock.''; PubMed Europe PMC
  34. Yin L, Lazar MA.; ''The orphan nuclear receptor Rev-erbalpha recruits the N-CoR/histone deacetylase 3 corepressor to regulate the circadian Bmal1 gene.''; PubMed Europe PMC
  35. Crumbley C, Wang Y, Kojetin DJ, Burris TP.; ''Characterization of the core mammalian clock component, NPAS2, as a REV-ERBalpha/RORalpha target gene.''; PubMed Europe PMC
  36. Miyazaki K, Nagase T, Mesaki M, Narukawa J, Ohara O, Ishida N.; ''Phosphorylation of clock protein PER1 regulates its circadian degradation in normal human fibroblasts.''; PubMed Europe PMC
  37. Xu Y, Toh KL, Jones CR, Shin JY, Fu YH, Ptácek LJ.; ''Modeling of a human circadian mutation yields insights into clock regulation by PER2.''; PubMed Europe PMC
  38. Raghuram S, Stayrook KR, Huang P, Rogers PM, Nosie AK, McClure DB, Burris LL, Khorasanizadeh S, Burris TP, Rastinejad F.; ''Identification of heme as the ligand for the orphan nuclear receptors REV-ERBalpha and REV-ERBbeta.''; PubMed Europe PMC
  39. Shearman LP, Zylka MJ, Weaver DR, Kolakowski LF, Reppert SM.; ''Two period homologs: circadian expression and photic regulation in the suprachiasmatic nuclei.''; PubMed Europe PMC
  40. Yin L, Wu N, Curtin JC, Qatanani M, Szwergold NR, Reid RA, Waitt GM, Parks DJ, Pearce KH, Wisely GB, Lazar MA.; ''Rev-erbalpha, a heme sensor that coordinates metabolic and circadian pathways.''; PubMed Europe PMC
  41. Hastings MH, Maywood ES, O'Neill JS.; ''Cellular circadian pacemaking and the role of cytosolic rhythms.''; PubMed Europe PMC
  42. Green CB, Takahashi JS, Bass J.; ''The meter of metabolism.''; PubMed Europe PMC
  43. Tei H, Okamura H, Shigeyoshi Y, Fukuhara C, Ozawa R, Hirose M, Sakaki Y.; ''Circadian oscillation of a mammalian homologue of the Drosophila period gene.''; PubMed Europe PMC
  44. Akashi M, Tsuchiya Y, Yoshino T, Nishida E.; ''Control of intracellular dynamics of mammalian period proteins by casein kinase I epsilon (CKIepsilon) and CKIdelta in cultured cells.''; PubMed Europe PMC
  45. Sato TK, Yamada RG, Ukai H, Baggs JE, Miraglia LJ, Kobayashi TJ, Welsh DK, Kay SA, Ueda HR, Hogenesch JB.; ''Feedback repression is required for mammalian circadian clock function.''; PubMed Europe PMC
  46. van der Spek PJ, Kobayashi K, Bootsma D, Takao M, Eker AP, Yasui A.; ''Cloning, tissue expression, and mapping of a human photolyase homolog with similarity to plant blue-light receptors.''; PubMed Europe PMC
  47. Nakamura K, Inoue I, Takahashi S, Komoda T, Katayama S.; ''Cryptochrome and Period Proteins Are Regulated by the CLOCK/BMAL1 Gene: Crosstalk between the PPARs/RXRalpha-Regulated and CLOCK/BMAL1-Regulated Systems.''; PubMed Europe PMC
  48. Reick M, Garcia JA, Dudley C, McKnight SL.; ''NPAS2: an analog of clock operative in the mammalian forebrain.''; PubMed Europe PMC
  49. Yin L, Wu N, Lazar MA.; ''Nuclear receptor Rev-erbalpha: a heme receptor that coordinates circadian rhythm and metabolism.''; PubMed Europe PMC
  50. Isojima Y, Nakajima M, Ukai H, Fujishima H, Yamada RG, Masumoto KH, Kiuchi R, Ishida M, Ukai-Tadenuma M, Minami Y, Kito R, Nakao K, Kishimoto W, Yoo SH, Shimomura K, Takao T, Takano A, Kojima T, Nagai K, Sakaki Y, Takahashi JS, Ueda HR.; ''CKIepsilon/delta-dependent phosphorylation is a temperature-insensitive, period-determining process in the mammalian circadian clock.''; PubMed Europe PMC
  51. Latres E, Chiaur DS, Pagano M.; ''The human F box protein beta-Trcp associates with the Cul1/Skp1 complex and regulates the stability of beta-catenin.''; PubMed Europe PMC
  52. Kobayashi K, Kanno S, Smit B, van der Horst GT, Takao M, Yasui A.; ''Characterization of photolyase/blue-light receptor homologs in mouse and human cells.''; PubMed Europe PMC
  53. Keesler GA, Camacho F, Guo Y, Virshup D, Mondadori C, Yao Z.; ''Phosphorylation and destabilization of human period I clock protein by human casein kinase I epsilon.''; PubMed Europe PMC
  54. Pilegaard H, Saltin B, Neufer PD.; ''Exercise induces transient transcriptional activation of the PGC-1alpha gene in human skeletal muscle.''; PubMed Europe PMC
  55. Shirogane T, Jin J, Ang XL, Harper JW.; ''SCFbeta-TRCP controls clock-dependent transcription via casein kinase 1-dependent degradation of the mammalian period-1 (Per1) protein.''; PubMed Europe PMC
  56. Juge-Aubry C, Pernin A, Favez T, Burger AG, Wahli W, Meier CA, Desvergne B.; ''DNA binding properties of peroxisome proliferator-activated receptor subtypes on various natural peroxisome proliferator response elements. Importance of the 5'-flanking region.''; PubMed Europe PMC
  57. Steeves TD, King DP, Zhao Y, Sangoram AM, Du F, Bowcock AM, Moore RY, Takahashi JS.; ''Molecular cloning and characterization of the human CLOCK gene: expression in the suprachiasmatic nuclei.''; PubMed Europe PMC
  58. Wu Z, Huang X, Feng Y, Handschin C, Feng Y, Gullicksen PS, Bare O, Labow M, Spiegelman B, Stevenson SC.; ''Transducer of regulated CREB-binding proteins (TORCs) induce PGC-1alpha transcription and mitochondrial biogenesis in muscle cells.''; PubMed Europe PMC


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External references


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NameTypeDatabase referenceComment
AVP ProteinP01185 (UniProt)
BMAL1 ProteinO00327 (UniProt)


ComplexREACT_25684 (Reactome)


ComplexREACT_26318 (Reactome)


ComplexREACT_26547 (Reactome) BMAL1 (ARNTL) contains both a nuclear localization signal and a nuclear export signal. The shuttling of BMAL1 between the nucleus and cytoplasm is important for transactivation by BMAL1:CLOCK/NPAS2 and degradation of BMAL1:CLOCK/NPAS2. BMAL1 initially forms a heterodimer with CLOCK or NPAS2 in the cytosol. The heterodimer is then phosphorylated and translocated into the nucleus.


ComplexREACT_26482 (Reactome)
Beta-TrCP ProteinQ9Y297 (UniProt)


ComplexREACT_27062 (Reactome)


ProteinREACT_26942 (Reactome)
CRY Proteins ProteinREACT_26101 (Reactome)

Ternary Complex, phosphorylated

ComplexREACT_25528 (Reactome)

Ternary Complex, phosphorylated

ComplexREACT_26285 (Reactome)

Ternary Complex, unphosphorylated

ComplexREACT_26725 (Reactome) As inferred from mouse, PER proteins can form homodimers and CRY proteins can form heterodimers with PER proteins. CRY and PER proteins may therefore form trimers (PER:PER:CRY).
Casein kinase I delta

or Casein kinase I epsilon

UnknownREACT_26408 (Reactome)
Class E basic helix-

loop-helix protein 40

ProteinO14503 (UniProt)
Class E basic helix-

loop-helix protein 41

ProteinQ9C0J9 (UniProt)


ProteinQ16526 (UniProt)


ProteinQ49AN0 (UniProt)
D site-binding


ProteinQ10586 (UniProt)
DNA Containing an

E-box Element

UnknownREACT_25457 (Reactome) The consensus sequence of the E-box is CACGTG.
FBXL3 ProteinQ9UKT7 (UniProt)


ComplexREACT_25657 (Reactome)

receptor: Dexamethasone Complex

ComplexREACT_26089 (Reactome)
NR1D1_HUMAN ProteinP20393 (UniProt)
Nocturnin ProteinQ9UK39 (UniProt)
Nuclear receptor


ProteinP35398 (UniProt)
Period circadian

protein homolog 1

ProteinO15534 (UniProt)
Period circadian

protein homolog 2

ProteinO15055 (UniProt)

proliferator-activated receptor alpha

ProteinQ07869 (UniProt)

BMAL1:CLOCK/NPAS2 Heterodimer Bound to DNA

ComplexREACT_25790 (Reactome)

PER Proteins

ProteinREACT_25419 (Reactome)
Phosphorylated CRY


ProteinREACT_26910 (Reactome)


ComplexREACT_6992 (Reactome)

Phosphorylated PER Proteins

ProteinREACT_25524 (Reactome)

Phosphorylated CRY Proteins

ProteinREACT_26499 (Reactome)
plasminogen activator

inhibitor 1

ProteinP05121 (UniProt)
pro-factor VII,


ProteinP08709 (UniProt)
ubiquitin ProteinREACT_3316 (Reactome)
ubiquitin ProteinREACT_3995 (Reactome)

Annotated Interactions

No annotated interactions

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