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[[File:Circadian Feedback Loop.jpg|thumb|Circadian Feedback Loop in ''[[Neurospora]]'', ''[[Drosophila]]'', and Mammals. Clock and BMAL1 homologues bind to the E-box to form PER and TIM homologues, which self-regulate production.]]
[[File:Circadian Feedback Loop.jpg|thumb|Circadian Feedback Loop in ''[[Neurospora]]'', ''[[Drosophila]]'', and Mammals. Clock and BMAL1 homologues bind to the E-box to form PER and TIM homologues, which self-regulate production.]]


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 nuclear foci and is later redistributed homogeneously. CYCLE (CYC) (also known as dBMAL for the [[BMAL1]] [[Ortholog#Orthology|ortholog]] in mammals) dimerizes with CLK via their respective [[PAS domain]]s. This dimer then recruits co-activator [[CREB-binding protein]] (CBP) and is further phosphorylated.<ref name="Hung_2009">{{cite journal | author = Hung HC, Maurer C, Zorn D, Chang WL, Weber F | title = Sequential and compartment-specific phosphorylation controls the life cycle of the circadian CLOCK protein | journal = J. Biol. Chem. | volume = 284 | issue = 35 | pages = 23734–42 | year = 2009 | pmid = 19564332 | pmc = 2749147 | doi = 10.1074/jbc.M109.025064 }}</ref> Once phosphorylated, this CLK-CYC complex binds to the [[E-box]] elements of the promoters of [[Period (gene)|period]] (per) and [[Timeless (gene)|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.<ref name="Dunlap_1999"/><ref name="Yu_2006">{{cite journal | author = Yu W, Zheng H, Houl JH, Dauwalder B, Hardin PE | title = PER-dependent rhythms in CLK phosphorylation and E-box binding regulate circadian transcription | journal = Genes Dev. | volume = 20 | issue = 6 | pages = 723–33 |date=March 2006 | pmid = 16543224 | pmc = 1434787 | doi = 10.1101/gad.1404406 }}</ref> CLK is [[hyperphosphorylated]] when [[doubletime (gene)|doubletime]] (DBT) [[Protein kinase|kinase]] interacts with the CLK-CYC complex in a PER reliant manner, destabilizing both CLK and PER, leading to the degradation of both proteins.<ref name="Yu_2006"/>
CLOCK protein has been found to play a central role as a transcription factor in the circadian pacemaker.<ref name="Hardin_2000">{{cite journal | author = Hardin P | title = From biological clock to biological rhythms | journal = Genome Biol. | volume = 1 | issue = 4 | pages = 1023.1-1023.5 | year = 2000 | pmid = 138871 | pmc = 138871 | doi = 10.1186/gb-2000-1-4-reviews1023 }}</ref> 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#Orthology|ortholog]] in mammals) dimerizes with CLK via their respective [[PAS domain]]s. This dimer then recruits co-activator [[CREB-binding protein]] (CBP) and is further phosphorylated.<ref name="Hung_2009">{{cite journal | author = Hung HC, Maurer C, Zorn D, Chang WL, Weber F | title = Sequential and compartment-specific phosphorylation controls the life cycle of the circadian CLOCK protein | journal = J. Biol. Chem. | volume = 284 | issue = 35 | pages = 23734–42 | year = 2009 | pmid = 19564332 | pmc = 2749147 | doi = 10.1074/jbc.M109.025064 }}</ref> Once phosphorylated, this CLK-CYC complex binds to the [[E-box]] elements of the promoters of [[Period (gene)|period]] (per) and [[Timeless (gene)|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.<ref name="Dunlap_1999"/><ref name="Yu_2006">{{cite journal | author = Yu W, Zheng H, Houl JH, Dauwalder B, Hardin PE | title = PER-dependent rhythms in CLK phosphorylation and E-box binding regulate circadian transcription | journal = Genes Dev. | volume = 20 | issue = 6 | pages = 723–33 |date=March 2006 | pmid = 16543224 | pmc = 1434787 | doi = 10.1101/gad.1404406 }}</ref> CLK is [[hyperphosphorylated]] when [[doubletime (gene)|doubletime]] (DBT) [[Protein kinase|kinase]] interacts with the CLK-CYC complex in a PER reliant manner, destabilizing both CLK and PER, leading to the degradation of both proteins.<ref name="Yu_2006"/>
Hypophosphorylated CLK then accumulates, binds to the E-boxes of ''per'' and ''tim'' and activates their transcription once again.<ref name="Yu_2006"/> This cycle of post-translational phosphorylation suggest that temporal phosphorylation of CLK helps in the timing mechanism of the circadian clock.<ref name="Hung_2009"/>
Hypophosphorylated CLK then accumulates, binds to the E-boxes of ''per'' and ''tim'' and activates their transcription once again.<ref name="Yu_2006"/> This cycle of post-translational phosphorylation suggest that temporal phosphorylation of CLK helps in the timing mechanism of the circadian clock.<ref name="Hung_2009"/>


Revision as of 03:10, 10 April 2015

For other uses, see Clock (disambiguation).

Template:PBB 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

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. 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.[3] This showed that intact Clock genes are necessary for normal mammalian circadian function.

Function

File:Circadian Feedback Loop.jpg
Circadian Feedback Loop in Neurospora, Drosophila, and Mammals. Clock and BMAL1 homologues bind to the E-box to form PER and TIM homologues, which self-regulate production.

CLOCK protein has been found to play a central role as a transcription factor in the circadian pacemaker.[4] 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.[5] 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][6] 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.[6] Hypophosphorylated CLK then accumulates, binds to the E-boxes of per and tim and activates their transcription once again.[6] This cycle of post-translational phosphorylation suggest that temporal phosphorylation of CLK helps in the timing mechanism of the circadian clock.[5]

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.[7]

CLOCK exhibits histone acetyl transferase (HAT) activity, which is enhanced by dimerization with BMAL1.[8] Dr. Paolo Sassone-Corsi and colleagues demonstrated in vitro that CLOCK mediated HAT activity is necessary to rescue circadian rhythms in Clock mutants.[8]

Clock’s role in other feedback loops

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.[9] However, SIRT1’s role is still controversial and it may also have a role in deacetylating PER protein, targeting it for degradation.[10]

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.[11]

Other functions of Clock

In humans, a polymorphism in Clock, rs6832769, may be related to the personality trait agreeableness.[12] Another single nucleotide polymorphism (SNP) in Clock, 3111C, has been associated with diurnal preference.[13] This SNP is also associated with increased insomnia,[14] difficulty losing weight,[15] and recurrence of major depressive episodes in patients with bipolar disorder.[16]

In mice, Clock has been implicated in sleep disorders, metabolism, pregnancy, and mood disorders. Clock mutant mice sleep less than normal mice each day.[17] The mice also display altered levels of plasma glucose and rhythms in food intake.[18] These mutants develop metabolic syndrome symptoms over time.[19] Furthermore, Clock mutants demonstrate disrupted estrous cycles and increased rates of full-term pregnancy failure.[20] Mutant Clock has also been linked to bipolar disorder-like symptoms in mice, including mania and euphoria.[21] Clock mutant mice also exhibit increased excitability of dopamine neurons in reward centers of the brain.[22] 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.[23][24]

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.[25] 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.[26]

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.[27]


Mutants of Clock

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.[28]

File:1-s2.0-S0092867400814403-gr2.jpg
PER and TIM production of Drosophila Jrk mutants

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, 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.[29] Further research by Allada revealed the recessive allele of Clock that leads to behavioral arrhythmicity while maintaining detectable molecular and transcriptional oscillations. This suggests that Clk contributes to the amplitude of circadian rhythms.[30]

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.[3] In both heterozygotes and homozygotes, this mutation also produces lengthened periods and arrhythmicity at the single-cell level.[31]

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.[32] Neuronal PAS domain containing protein 2 (NPAS2, a CLOCK paralog[33]) can substitute for CLOCK in these Clock-null mice.[34]


See also

References

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  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. doi:10.1016/S0092-8674(00)80245-7. PMID 9160755.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. ^ a b 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. doi:10.1126/science.8171325. PMID 8171325.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ Hardin P (2000). "From biological clock to biological rhythms". Genome Biol. 1 (4): 1023.1–1023.5. doi:10.1186/gb-2000-1-4-reviews1023. PMC 138871. PMID 138871.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  5. ^ a b Hung HC, Maurer C, Zorn D, Chang WL, Weber F (2009). "Sequential and compartment-specific phosphorylation controls the life cycle of the circadian CLOCK protein". J. Biol. Chem. 284 (35): 23734–42. doi:10.1074/jbc.M109.025064. PMC 2749147. PMID 19564332.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  6. ^ a b c 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. doi:10.1101/gad.1404406. PMC 1434787. PMID 16543224.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ 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. doi:10.1126/science.280.5369.1564. PMID 9616112.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  17. ^ 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. PMID 11050136.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ^ Fred W. Turek, Corinne Joshu, Akira Kohsaka, Emily Lin, Ganka Ivanova, Erin McDearmon, Aaron Laposky, Sue Losee-Olson, Amy Easton, Dalan R. Jensen, Robert H. Eckel, Joseph S. Takahashi1, Joseph Bass (April 2005). "Obesity and Metabolic Syndrome in Circadian Clock Mutant Mice". Science. 308 (5724): 1043–1045. doi:10.1126/science.1108750.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: numeric names: authors list (link)
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  25. ^ Dodson, Helen. "Women With Variants in "CLOCK" Gene Have Higher Risk of Breast Cancer". Yale Office of Public Affairs and Communications. Retrieved 21 April 2011.
  26. ^ Tammy M. Joska, Riasat Zaman and William J. Belden (September 2014). "Regulated DNA Methylation and the Circadian Clock: Implications in Cancer". Biology. 3 (3): 560–577. doi:10.3390/biology3030560.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  27. ^ 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). "Mutations in the circadian gene CLOCK in colorectal cancer". Mol. Cancer Res. 8 (7): 952–60. doi:10.1158/1541-7786.MCR-10-0086. PMID 20551151.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  29. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  30. ^ Allada R, Kadener S, Nandakumar N, Rosbash M (July 2003). "A recessive mutant of Drosophila Clock reveals a role in circadian rhythm amplitude". EMBO. 22 (13): 3367–3375. doi:10.1093/emboj/cdg318. PMID 165643.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  31. ^ Herzog ED, Takahashi JS, Block GD (December 1998). "Clock controls circadian period in isolated suprachiasmatic nucleus neurons". Nat. Neurosci. 1 (8): 708–13. doi:10.1038/3708. PMID 10196587.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  32. ^ 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. doi:10.1016/j.neuron.2006.03.041. PMID 16675400.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  33. ^ Debruyne, Jason P. (2008-12). "Oscillating perceptions: the ups and downs of the CLOCK protein in the mouse circadian system". Journal of genetics. 87 (5): 437–446. ISSN 0022-1333. PMC 2749070. PMID 19147932. Retrieved 2015-04-10. {{cite journal}}: Check date values in: |date= (help)
  34. ^ 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. doi:10.1038/nn1884. PMC 2782643. PMID 17417633.{{cite journal}}: CS1 maint: multiple names: authors list (link)

Further reading

  • Wager-Smith K, Kay SA (September 2000). "Circadian rhythm genetics: from flies to mice to humans". Nat. Genet. 26 (1): 23–7. doi:10.1038/79134. PMID 10973243.
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