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Clock (Circadian Locomotor Output Cycles Kaput) is a gene encoding a basic helix-loop-helix-PAS transcription factor (CLOCK) that affects both the persistence and period of circadian rhythms. CLOCK functions as an essential activator of downstream elements in the pathway critical to the generation of circadian rhythms.[1]

Discovery and functionEdit

The Clock gene was first identified in 1994 by Dr. 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.[2] The Clock mutants discovered through the screen displayed an abnormally long period of daily activity. This trait proved to be heritable, and mice bred to be homozygous for the mutation eventually lost all circadian rhythmicity after several days in constant darkness.[3] This showed that intact Clock genes are necessary for normal mammalian circadian function.

CLOCK protein has been found to play a central role as a transcription factor in the circadian pacemaker. In Drosophila, newly synthesized CLOCK (CLK) is hypophosphorylated in the cytoplasm before entering the nucleus. Once in the nuclei, CLK is localized in nulear 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.[4] 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.[1][5] CLK is hyperphosphorylated when double-time (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.[5] Hypophosphorylated CLK then accumulates, binds to the E-boxes of per and tim and activates their transcription once again.[5] This cycle of post-translational phosphorylation suggest that temporal phosphorylation of CLK helps in the timing mechanism of the circadian clock.[4]

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.[6]

CLOCK exhibits histone acetyl transferase (HAT) activity, which is enhanced by dimerization with BMAL1.[7] Dr. Paolo Sassone-Corsi and colleagues demonstrated in vitro that CLOCK mediated HAT activity is necessary to rescue circadian rhythms in Clock mutants.[7]

Mutants of ClockEdit

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.[8]

DrosophilaEdit

In Drosophila, a mutant form of Clock (Jrk) resulting from a premature stop codon that eliminates the activation domain of the CLOCK protein, causes dominant effects: half of the heterozygous flies with this mutant gene have an altered period while the other half become arrhythmic. Homozygous flies are all arrhythmic. Furthermore, these mutant flies express low levels of PER and TIM proteins, indicating that Clock functions as a positive element in the circadian loop.[9]

MiceEdit

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.[3] In both heterozygotes and homozygotes, this mutation also produces lengthened periods and arrhythmicity at the single-cell level.[10]

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.[11] Neuronal PAS domain containing protein 2 (NPAS2, a CLOCK analog) can substitute for CLOCK in these Clock-null mice.[12]

Clock’s role in other feedback loopsEdit

The CLOCK-BMAL dimer is involved in regulation of other genes and feedback loops. An enzyme SIRT1 has also binds to the CLOCK-BMAL complex and acts to suppress its activity, perhaps by deacetylation of Bmal1 and surrounding histones.[13] However, SIRT1’s role is still controversial and it may also have a role in deacetylating PER protein, targeting it for degradation.[14]

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 loops 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 deacetylate BMAL1, suppressing it. 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.[15]

Other functions of ClockEdit

In humans, a polymorphism in Clock, rs6832769, may be related to the personality trait agreeableness.[16] Another single nucleotide polymorphism (SNP) in Clock, 3111C, has been associated with diurnal preference.[17] This SNP is also associated with increased insomnia,[18] difficulty losing weight,[19] and recurrence of major depressive episodes in patients with bipolar disorder.[20]

In mice, Clock has been implicated in sleep disorders, metabolism, pregnancy, and mood disorders. Clock mutant mice sleep less than normal mice each day.[21] The mice also display altered levels of plasma glucose and rhythms in food intake.[22] These mutants develop metabolic syndrome symptoms over time.[23] Furthermore, Clock mutants demonstrate disrupted estrous cycles and increased rates of full-term pregnancy failure.[24] Mutant Clock has also been linked to bipolar disorder-like symptoms in mice, including mania and euphoria.[25] Clock mutant mice also exhibit increased excitability of dopamine neurons in reward centers of the brain.[26] These results have led Dr. 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.[27][28]

In 2010, a Yale University team led by Dr. Yong Zhu found that variations in the epigenetics of the Clock gene may lead to an increased risk of breast cancer.[29] 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.[30]

The CLOCK gene may also be a target for somatic mutations in microsatellite unstable colorectal cancers. In a study done in 2010 by researchers in the University of Helsinki, 53% of putative novel microsatellite instability target genes responsible for colorectal cancer contained CLOCK mutations.[31]

See alsoEdit

ReferencesEdit

  1. 1.0 1.1 Dunlap JC (January 1999). Molecular bases for circadian clocks. Cell 96 (2): 271–90.
  2. King DP, Zhao Y, Sangoram AM, Wilsbacher LD, Tanaka M, Antoch MP, Steeves TD, Vitaterna MH, Kornhauser JM, Lowrey PL, Turek FW, Takahashi JS (April 1997). Positional Cloning of the Mouse Circadian Clock Gene. Cell 89 (4): 641–653.
  3. 3.0 3.1 Vitaterna MH, King DP, Chang AM, Kornhauser JM, Lowrey PL, McDonald JD, Dove WF, Pinto LH, Turek FW, Takahashi JS (April 1994). Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior. Science 264 (5159): 719–25.
  4. 4.0 4.1 Hung, HC, Maurer, C, Zorn, D, Chang, WL, Weber, F (2009-08-28). Sequential and compartment-specific phosphorylation controls the life cycle of the circadian CLOCK protein.. The Journal of Biological Chemistry 284 (35): 23734–42.
  5. 5.0 5.1 5.2 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 Dev. 20 (6): 723–33.
  6. Gekakis N, Staknis D, Nguyen HB, Davis FC, Wilsbacher LD, King DP, Takahashi JS, Weitz CJ (June 1998). Role of the CLOCK protein in the mammalian circadian mechanism. Science 280 (5369): 1564–9.
  7. 7.0 7.1 Doi M, Hirayama J, Sassone-Corsi P (2006). Circadian regulator CLOCK is a histone acetyltransferase. Cell 125 (3): 497–508.
  8. Panda S, Antoch MP, Miller BH, Su AI, Schook AB, Straume M, Schultz PG, Kay SA, Takahashi JS, Hogenesch JB (May 2002). Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 109 (3): 307–20.
  9. 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.
  10. Herzog ED, Takahashi JS, Block GD (December 1998). Clock controls circadian period in isolated suprachiasmatic nucleus neurons. Nat. Neurosci. 1 (8): 708–13.
  11. 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): 465–77.
  12. DeBruyne JP, Weaver DR, Reppert SM (May 2007). CLOCK and NPAS2 have overlapping roles in the suprachiasmatic circadian clock. Nat. Neurosci. 10 (5): 543–5.
  13. Nakahata Y, Kaluzova M, Grimaldi B, Sahar S, Hirayama J, Chen D, Guarente LP, Sassone-Corsi P (July 2008). The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell 134 (2): 329–40.
  14. Asher G, Gatfield D, Stratmann M, Reinke H, Dibner C, Kreppel F, Mostoslavsky R, Alt FW, Schibler U (July 2008). SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell 134 (2): 317–28.
  15. Ramsey KM, Yoshino J, Brace CS, Abrassart D, Kobayashi Y, Marcheva B, Hong HK, Chong JL, Buhr ED, Lee C, Takahashi JS, Imai S, Bass J (May 2009). Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis. Science 324 (5927): 651–4.
  16. Terracciano A, Sanna S, Uda M, Deiana B, Usala G, Busonero F, Maschio A, Scally M, Patriciu N, Chen WM, Distel MA, Slagboom EP, Boomsma DI, Villafuerte S, Sliwerska E, Burmeister M, Amin N, Janssens AC, van Duijn CM, Schlessinger D, Abecasis GR, Costa PT (June 2010). Genome-wide association scan for five major dimensions of personality. Mol. Psychiatry 15 (6): 647–56.
  17. Katzenberg D, Young T, Finn L, Lin L, King DP, Takahashi JS, Mignot E (1998). A CLOCK polymorphism associated with human diurnal preference. Sleep 21 (6): 569–76.
  18. Serretti A, Benedetti F, Mandelli L, Lorenzi C, Pirovano A, Colombo C, Smeraldi E (2003). Genetic dissection of psychopathological symptoms: insomnia in mood disorders and CLOCK gene polymorphism. Am J Med Genet B Neuropsychiatr Genet. 121B (1): 35–8.
  19. Garaulet M, Corbalán MD, Madrid JA, Morales E, Baraza JC, Lee YC, Ordovas JM. (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): 516–23.
  20. Benedetti F, Serretti A, Colombo C, Barbini B, Lorenzi C, Campori E, Smeraldi E (2003). Influence of CLOCK gene polymorphism on circadian mood fluctuation and illness recurrence in bipolar depression. Am J Med Genet B Neuropsychiatr Genet. 123B (1): 23–6.
  21. 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. J. Neurosci. 20 (21): 8138–43.
  22. Rudic RD, McNamara P, Curtis AM, Boston RC, Panda S, Hogenesch JB, Fitzgerald GA (November 2004). BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis. PLoS Biol. 2 (11): e377.
  23. Turek FW, Joshu C, Kohsaka A, Lin E, Ivanova G, McDearmon E, Laposky A, Losee-Olson S, Easton A, Jensen DR, Eckel RH, Takahashi JS, Bass J (May 2005). Obesity and metabolic syndrome in circadian Clock mutant mice. Science 308 (5724): 1043–5.
  24. Miller BH, Olson SL, Turek FW, Levine JE, Horton TH, Takahashi JS (August 2004). Circadian clock mutation disrupts estrous cyclicity and maintenance of pregnancy. Curr. Biol. 14 (15): 1367–73.
  25. McClung CA (May 2007). Circadian genes, rhythms and the biology of mood disorders. Pharmacol. Ther. 114 (2): 222–32.
  26. McClung CA, Sidiropoulou K, Vitaterna M, Takahashi JS, White FJ, Cooper DC, Nestler EJ (2005). Regulation of dopaminergic transmission and cocaine reward by the Clock gene. Proc Natl Acad Sci USA 102 (26): 9377–81.
  27. 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): 251–60.
  28. Guillaumond F, Dardente H, Giguère V, Cermakian N (October 2005). Differential control of Bmal1 circadian transcription by REV-ERB and ROR nuclear receptors. J. Biol. Rhythms 20 (5): 391–403.
  29. Dodson, Helen Women With Variants in "CLOCK" Gene Have Higher Risk of Breast Cancer. Yale Office of Public Affairs and Communications. URL accessed on 21 April 2011.
  30. Hoffman AE, Yi CH, Zheng T, Stevens RG, Leaderer D, Zhang Y, Holford TR, Hansen J, Paulson J, Zhu Y (February 2010). CLOCK in breast tumorigenesis: genetic, epigenetic, and transcriptional profiling analyses. Cancer Res. 70 (4): 1459–68.
  31. Alhopuro, P, Björklund, M, Sammalkorpi, H, Turunen, M, Tuupanen, S, Biström, M, Niittymäki, I, Lehtonen, HJ, Kivioja, T, Launonen, V, Saharinen, J, Nousiainen, K, Hautaniemi, S, Nuorva, K, Mecklin, JP, Järvinen, H, Orntoft, T, Arango, D, Lehtonen, R, Karhu, A, Taipale, J, Aaltonen, LA (2010 Jul). Mutations in the circadian gene CLOCK in colorectal cancer. Molecular cancer research : MCR 8 (7): 952–60.

Further readingEdit

  • Wager-Smith K, Kay SA (September 2000). Circadian rhythm genetics: from flies to mice to humans. Nat. Genet. 26 (1): 23–7.


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