Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Time zones: a comparative genetics of circadian clocks

Abstract

The circadian clock is a widespread cellular mechanism that underlies diverse rhythmic functions in organisms from bacteria and fungi, to plants and animals. Intense genetic analysis during recent years has uncovered many of the components and molecular mechanisms comprising these clocks. Although autoregulatory genetic networks are a consistent feature in the design of all clocks, the weight of evidence favours their independent evolutionary origins in different kingdoms.

Key Points

  • Approximately 24-h rhythms govern a wide range of physiological and behavioural processes in organisms from bacteria to humans. Underlying these rhythmic activities is a cellular mechanism called the circadian clock.

  • Genetic analysis of the circadian clock has led to the identification of genes and proteins that constitute the core cellular mechanism in Drosophila, mammals, Neurospora, cyanobacteria and possibly Arabidopsis.

  • In Drosophila, several transcription factors operate in a genetic network incorporating autoregulatory feedback loops. Oscillations are achieved by delaying various steps in the network. For example, accumulation of one of the transcription factors — Period — is retarded in the cytoplasm by phosphorylation and degradation.

  • In mammals, homologues of the Drosophila genes also operate in the circadian cellular clock, although the function of some of the components is not conserved and has been co-opted by other proteins. For example, cryptochromes are part of the core mechanism in mammals, whereas the Drosophila homologue is involved in light regulation of the clock.

  • In the fungus Neurospora, three genes lie at the core of the circadian clock — white collar-1, white collar-2 and frequency. The proteins they encode are unrelated to the genes involved in the metazoan clocks apart from the PAS domain, which is found in various proteins, only some of which are involved in clock function.

  • The PAS domain has also been found in two components of the Arabidopsis circadian clock, and two Myb-related transcription factors that form an autoregulatory transcriptional network are probably components of a core mechanism that must include additional, unidentified factors. Redundancy is also a dominant feature of the Arabidopsis clock.

  • In cyanobacteria, most genes are subject to circadian regulation, which indicates that the clock might form a fundamental part of the physiology of this organism. The kai genes are essential components of the clock, although they are unlike any other clock genes, and their precise function in this clock is unknown.

  • Comparative analyses indicate that the circadian clock has evolved independently in bacteria, fungi, plants and animals. Instead it is proposed that the PAS domain and some closely neighbouring sequences might be a feature that is common to several circadian rhythm components because it allows the sensing of environmental and metabolic information, both recently described as important aspects of circadian regulation.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The Drosophila circadian clock.
Figure 2: Regulatory interactions in the mammalian clock.
Figure 3: Elements of the Neurospora clock.
Figure 4: Regulatory interactions in the Arabidopsis clock.
Figure 5: Possible regulation in the Synechococcus clock.

Similar content being viewed by others

References

  1. Czeisler, C. A. et al. Stability, precision, and near-24-hour period of the human circadian pacemaker. Science 284, 2177–2181 (1999).

    Article  CAS  PubMed  Google Scholar 

  2. Toh, K. L. et al. An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science 291, 1040–1043 (2001).First human mutation that affects circadian rhythmicity is associated with an alteration of PER2 . The altered PER2 protein is hypophosphorylated by casein kinase 1ɛ in vitro.

    Article  CAS  PubMed  Google Scholar 

  3. Chovnik, A. (ed.) Biological Clocks. Cold Spring Harbor Symposia of Quantitative Biology Vol. 25 (Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 1960).

    Google Scholar 

  4. Weiner, J. Time, Love, Memory (Alfred Knopf, New York, 1999).

    Google Scholar 

  5. Konopka, R. J. & Benzer, S. Clock mutants of Drosophila melanogaster. Proc. Natl Acad. Sci. USA 68, 2112–2116 (1971).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Feldman, J. F. & Wasar, N. in Biochronometry (ed. M. Menaker) 652–656 (National Academy of Science, Washington DC, 1971).

    Google Scholar 

  7. Bruce, V. G. Mutants of the biological clock in Chlamydomonas reinhardi. Genetics 70, 537–548 (1972).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Bargiello, T. A. & Young, M. W. Molecular genetics of a biological clock in Drosophila. Proc. Natl Acad. Sci. USA 81, 2142–2146 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Reddy, P., Zehring, W. A., Wheeler, D. A., Pirrotta, V., Hadfield, C., Hall, J. C. & Rosbash, M. Molecular analysis of the period locus in Drosophila melanogaster and identification of a transcript involved in biological rhythms. Cell 38, 701–710 (1984).

    Article  CAS  PubMed  Google Scholar 

  10. McClung, C. R., Fox, B. A. & Dunlap, J. C. The Neurospora clock gene frequency shares a sequence element with the Drosophila clock gene period. Nature 339, 558–562 (1989).

    Article  CAS  PubMed  Google Scholar 

  11. Young, M. W. Life's 24-hour clock: molecular control of circadian rhythms in animal cells. Trends Biochem. Sci. 25, 601–606 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Martinek, S., Inonog, S., Manoukian, A. S. & Young, M. W. A role for the segment polarity gene shaggy/GSK-3 in the Drosophila circadian clock. Cell 105, 769–779 (2001).GSK-3, a kinase central to developmental signalling in the Wnt pathway, phosphorylates Timeless (TIM). TIM phosphorylation determines when PER/TIM complexes move to nuclei.

    Article  CAS  PubMed  Google Scholar 

  13. Shimomura, K. et al. Genome-wide epistatic interaction analysis reveals complex genetic determinants of circadian behavior in mice. Genome Res. 11, 959–980 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Allada, R., Emery, P., Takahashi, J. S. & Rosbash, M. STOPPING TIME: the genetics of fly and mouse circadian clocks. Annu. Rev. Neurosci. 24, 1091–1109 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Scully, A. L. & Kay, S. A. Time flies for Drosophila. Cell 100, 297–300 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. Kloss, B., Rothenfluh, A., Young, M. W. & Saez, L. Phosphorylation of period is influenced by cycling physical associations of double-time, period, and timeless in the Drosophila clock. Neuron 30, 699–706 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Rothenfluh, A., Young, M. W. & Saez, L. A TIMELESS-independent function for PERIOD proteins in the Drosophila clock. Neuron 26, 505–514 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Ceriani, M. F. et al. Light-dependent sequestration of TIMELESS by CRYPTOCHROME. Science 285, 553–556 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Emery, P., Stanewsky, R., Hall, J. C. & Rosbash, M. A unique circadian-rhythm photoreceptor. Nature 404, 456–457 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Naidoo, N., Song, W., Hunter-Ensor, M. & Sehgal, A. A role for the proteasome in the light response of the timeless clock protein. Science 285, 1737–1741 (1999).

    Article  CAS  PubMed  Google Scholar 

  21. Helfrich-Forster, C., Winter, C., Hofbauer, A., Hall, J. C. & Stanewsky, R. The circadian clock of fruit flies is blind after elimination of all known photoreceptors. Neuron 30, 249–261 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Curtin, K. D., Huang, Z. J. & Rosbash, M. Temporally regulated nuclear entry of the Drosophila period protein contributes to the circadian clock. Neuron 14, 365–372 (1995).

    Article  CAS  PubMed  Google Scholar 

  23. Zeng, H., Qian, Z., Myers, M. P. & Rosbash, M. A light-entrainment mechanism for the Drosophila circadian clock. Nature 380, 129–135 (1996).

    Article  CAS  PubMed  Google Scholar 

  24. Price, J. L. et al. double-time is a novel Drosophila clock gene that regulates PERIOD protein accumulation. Cell 94, 83–95 (1998).

    Article  CAS  PubMed  Google Scholar 

  25. Peifer, M. & Polakis, P. Wnt signaling in oncogenesis and embryogenesis—a look outside the nucleus. Science 287, 1606–1609 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Allada, R., White, N. E., So, W. V., Hall, J. C. & Rosbash, M. A mutant Drosophila homolog of mammalian Clock disrupts circadian rhythms and transcription of period and timeless. Cell 93, 791–804 (1998).Describes the isolation of the Drosophila orthologue of mammalian Clock and an arrhythmic mutation of the gene that suppresses per and tim transcription.

    Article  CAS  PubMed  Google Scholar 

  27. Darlington, T. K. et al. Closing the circadian loop: CLOCK-induced transcription of its own inhibitors per and tim. Science 280, 1599–1603 (1998).Establishes that in Drosophila Clock and Cycle positively regulate transcription of per and tim , and that nuclear PER and TIM proteins suppress CLK/CYC activity.

    Article  CAS  PubMed  Google Scholar 

  28. Bae, K., Lee, C., Sidote, D., Chuang, K. Y. & Edery, I. Circadian regulation of a Drosophila homolog of the mammalian Clock gene: PER and TIM function as positive regulators. Mol. Cell. Biol. 18, 6142–6151 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lee, C., Bae, K. & Edery, I. The Drosophila CLOCK protein undergoes daily rhythms in abundance, phosphorylation, and interactions with the PER–TIM complex. Neuron 21, 857–867 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Glossop, N. R., Lyons, L. C. & Hardin, P. E. Interlocked feedback loops within the Drosophila circadian oscillator. Science 286, 766–768 (1999).

    Article  CAS  PubMed  Google Scholar 

  31. Blau, J. & Young, M. W. Cycling vrille expression is required for a functional Drosophila clock. Cell 99, 661–671 (1999).Identification and cloning of clock gene vri . VRI forms a second autoregulatory loop in the clock and also controls some output pathways.

    Article  CAS  PubMed  Google Scholar 

  32. Mitsui, S., Yamaguchi, S., Matsuo, T., Ishida, Y. & Okamura, H. Antagonistic role of E4BP4 and PAR proteins in the circadian oscillatory mechanism. Genes Dev. 15, 995–1006 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Reppert, S. M. & Weaver, D. R. Molecular analysis of mammalian circadian rhythms. Annu. Rev. Physiol. 63, 647–676 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. Ripperger, J. A. & Schibler, U. Circadian regulation of gene expression in animals. Curr. Opin. Cell Biol. 13, 357–362 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Cermakian, N. & Sassone-Corsi, P. Multilevel regulation of the circadian clock. Nature Rev. Mol. Cell Biol. 1, 59–67 (2000).

    Article  CAS  Google Scholar 

  36. Vielhaber, E., Eide, E., Rivers, A., Gao, Z. H. & Virshup, D. M. Nuclear entry of the circadian regulator mPER1 is controlled by mammalian casein kinase I epsilon. Mol. Cell. Biol. 20, 4888–4899 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Keesler, G. A. et al. Phosphorylation and destabilization of human period I clock protein by human casein kinase I ɛ. NeuroReport 11, 951–955 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Takano, A., Shimizu, K., Kani, S., Buijs, R. M., Okada, M. & Nagai, K. Cloning and characterization of rat casein kinase 1ɛ. FEBS Lett. 477, 106–112 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Ralph, M. R. & Menaker, M. A mutation of the circadian system in golden hamsters. Science 241, 1225–1227 (1988).

    Article  CAS  PubMed  Google Scholar 

  40. Lowrey, P. L. et al. Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. Science 288, 483–492 (2000).Cloning of the hamster Tau gene shows that it encodes casein kinase 1ɛ, and that the tau mutation alters phosphorylation and binding to PER in vitro.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. King, D. P. et al. Positional cloning of the mouse circadian clock gene. Cell 89, 641–653 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Jin, X. et al. A molecular mechanism regulating rhythmic output from the suprachiasmatic circadian clock. Cell 96, 57–68 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Bunger, M. K. et al. Mop3 is an essential component of the master circadian pacemaker in mammals. Cell 103, 1009–1017 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sangoram, A. M. et al. Mammalian circadian autoregulatory loop: a timeless ortholog and mPer1 interact and negatively regulate CLOCK–BMAL1-induced transcription. Neuron 21, 1101–1113 (1998).

    Article  CAS  PubMed  Google Scholar 

  45. Bae, K. et al. Differential functions of mPer1, mPer2, and mPer3 in the SCN circadian clock. Neuron 30, 525–536 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Zheng, B. et al. Nonredundant roles of the mPer1 and mPer2 genes in the mammalian circadian clock. Cell 105, 683–694 (2001).

    Article  CAS  PubMed  Google Scholar 

  47. Shearman, L. P. et al. Interacting molecular loops in the mammalian circadian clock. Science 288, 1013–1019 (2000).Describes the role of PER2 as a positive regulator of Bmal1 expression, and CRY as a negative regulator of Per and Cry expression in mouse tissues.

    Article  CAS  PubMed  Google Scholar 

  48. Okamura, H. et al. Photic induction of mPer1 and mPer2 in cry-deficient mice lacking a biological clock. Science 286, 2531–2534 (1999).

    Article  CAS  PubMed  Google Scholar 

  49. Van der Horst, G. T. et al. Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms. Nature 398, 627–630 (1999).First demonstration that, in mammals, cryptochromes are required for the function of the clock.

    Article  CAS  PubMed  Google Scholar 

  50. Vitaterna, M. H. et al. Differential regulation of mammalian period genes and circadian rhythmicity by cryptochromes 1 and 2. Proc. Natl Acad. Sci. USA 96, 12114–12119 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kume, K. et al. mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop. Cell 98, 193–205 (1999).Shows that cryptochromes are transcriptional regulators of Per and Cry.

    Article  CAS  PubMed  Google Scholar 

  52. Selby, C. P., Thompson, C., Schmitz, T. M., Van Gelder, R. N. & Sancar, A. Functional redundancy of cryptochromes and classical photoreceptors for nonvisual ocular photoreception in mice. Proc. Natl Acad. Sci. USA 97, 14697–14702 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Krishnan, B. et al. A new role for cryptochrome in a Drosophila circadian oscillator. Nature 411, 313–317 (2001).

    Article  CAS  PubMed  Google Scholar 

  54. Balsalobre, A., Damiola, F. & Schibler, U. A serum shock induces circadian gene expression in mammalian tissue culture cells. Cell 93, 929–937 (1998).Rat fibroblasts in culture for over two decades can show circadian rhythms of expression for some clock genes.

    Article  CAS  PubMed  Google Scholar 

  55. Yagita, K., Tamanini, F., van Der Horst, G. T. & Okamura, H. Molecular mechanisms of the biological clock in cultured fibroblasts. Science 292, 278–281 (2001).

    Article  CAS  PubMed  Google Scholar 

  56. Damiola, F. et al. Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes Dev. 14, 2950–2961 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Stokkan, K. A., Yamazaki, S., Tei, H., Sakaki, Y. & Menaker, M. Entrainment of the circadian clock in the liver by feeding. Science 291, 490–493 (2001).References 56 and 57 show that peripheral clocks can be entrained by non-photic stimuli, such as feeding.

    Article  CAS  PubMed  Google Scholar 

  58. Kornmann, B., Preitner, N., Rifat, D., Fleury-Olela, F. & Schibler, U. Analysis of circadian liver gene expression by ADDER, a highly sensitive method for the display of differentially expressed mRNAs. Nucleic Acids Res. 29, E51–1 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Whitmore, D., Foulkes, N. S. & Sassone-Corsi, P. Light acts directly on organs and cells in culture to set the vertebrate circadian clock. Nature 404, 87–91 (2000).Photoreceptive clocks are discovered in the internal organs of zebrafish.

    Article  CAS  PubMed  Google Scholar 

  60. Aronson, B. D., Johnson, K. A., Loros, J. J. & Dunlap, J. C. Negative feedback defining a circadian clock: autoregulation of the clock gene frequency. Science 263, 1578–1584 (1994).

    Article  CAS  PubMed  Google Scholar 

  61. Gu, Y. Z., Hogenesch, J. B. & Bradfield, C. A. The PAS superfamily: sensors of environmental and developmental signals. Annu. Rev. Pharmacol. Toxicol. 40, 519–561 (2000).

    Article  CAS  PubMed  Google Scholar 

  62. Lee, K., Loros, J. J. & Dunlap, J. C. Interconnected feedback loops in the Neurospora circadian system. Science 289, 107–110 (2000).

    Article  CAS  PubMed  Google Scholar 

  63. Somers, D. E., Schultz, T. F., Milnamow, M. & Kay, S. A. ZEITLUPE encodes a novel clock-associated PAS protein from Arabidopsis. Cell 101, 319–329 (2000).

    Article  CAS  PubMed  Google Scholar 

  64. Crosthwaite, S. K., Dunlap, J. C. & Loros, J. J. Neurospora wc-1 and wc-2: transcription, photoresponses and the origins of circadian rhythmicity. Science 276, 763–769 (1997).

    Article  CAS  PubMed  Google Scholar 

  65. Ballario, P. & Macino, G. White collar proteins: PASsing the light signal in Neurospora crassa. Trends Microbiol. 5, 458–462 (1997).

    Article  CAS  PubMed  Google Scholar 

  66. Talora, C., Franchi, L., Linden, H., Ballario, P. & Macino, G. Role of a white collar-1–white collar-2 complex in blue-light signal transduction. EMBO J. 18, 4961–4968 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Collett, M., Dunlap, J. C. & Loros, J. J. Circadian clock-specific roles for the light response protein WHITE COLLAR-2. Mol. Cell. Biol. 21, 2619–2628 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Cheng, P., Yang, Y., Heintzen, C. & Liu, Y. Coiled-coil domain-mediated FRQ–FRQ interaction is essential for its circadian clock function in Neurospora. EMBO J. 20, 101–108 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Denault, D. L., Loros, J. J. & Dunlap, J. C. WC-2 mediates WC-1–FRQ interaction within the PAS protein-linked circadian feedback loop of Neurospora crassa. EMBO J. 20, 109–117 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Merrow, M. et al. Circadian regulation of the light input pathway in Neurospora crassa. EMBO J. 20, 307–315 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Loros, J. J. & Dunlap, J. C. Genetic and molecular analysis of circadian rhythms in Neurospora. Annu. Rev. Physiol. 63, 757–794 (2001).

    Article  CAS  PubMed  Google Scholar 

  72. Christie, J. M., Salomon, M., Nozue, K., Wada, M. & Briggs, W. R. LOV (light, oxygen, or voltage) domains of the blue-light photoreceptor phototropin (nph1): binding sites for the chromophore flavin mononucleotide. Proc. Natl Acad. Sci. USA 96, 8779–8783 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Heintzen, C., Loros, J. J. & Dunlap, J. C. The PAS protein VIVID defines a clock-associated feedback loop that represses light input, modulates gating, and regulates clock resetting. Cell 104, 453–464 (2001).Shows that VIVID regulates the circadian phase of light resetting of the Neurospora clock.

    Article  CAS  PubMed  Google Scholar 

  74. Schrode, L. B. et al. vvd is required for light adaptation of conidiation-specific genes of Neurospora crassa, but not circadian conidiation. Fungal Genet. Biol. 32, 169–181 (2001).

    Article  CAS  Google Scholar 

  75. Strayer, C. et al. Cloning of the Arabidopsis clock gene TOC1, an autoregulatory response regulator homolog. Science 289, 768–771 (2000).

    Article  CAS  PubMed  Google Scholar 

  76. Millar, A. J. & Kay, S. A. Circadian control of cab gene transcription and mRNA accumulation in Arabidopsis. Plant Cell 3, 541–550 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Somers, D. E., Devlin, P. F. & Kay, S. A. Phytochromes and cryptochromes in the entrainment of the Arabidopsis circadian clock. Science 282, 1488–1490 (1998).First report of cryptochromes as circadian photoreceptors in any organism.

    Article  CAS  PubMed  Google Scholar 

  78. Bunning, E. The Physiological Clock; Circadian Rhythms and Biological Chronometry 3rd edn (Springer, New York, 1973).

    Google Scholar 

  79. Wang, Z. Y. & Tobin, E. M. Constitutive expression of the CIRCADIAN CLOCK ASSOCIATED 1 (CCA1) gene disrupts circadian rhythms and suppresses its own expression. Cell 93, 1207–1217 (1998).Discovery of a role for the transcription factor CCA1 in the Arabidopsis clock.

    Article  CAS  PubMed  Google Scholar 

  80. Schaffer, R. et al. The late elongated hypocotyl mutation of Arabidopsis disrupts circadian rhythms and the photoperiodic control of flowering. Cell 93, 1219–1229 (1998).LHY is suggested to be a clock component.

    Article  CAS  PubMed  Google Scholar 

  81. Alabadí, D. et al. Reciprocal regulation between TOC1 and LHY/CCA1 within the Arabidopsis circadian clock. Science 293, 880–883 (2001). Shows a negative-feedback loop in a plant clock.

    Article  PubMed  Google Scholar 

  82. Harmer, S. L. et al. Orchestrated transcription of key pathways in Arabidopsis by the circadian clock. Science 290, 2110–2113 (2000).A comprehensive study of clock-controlled transcription in a eukaryote. It establishes a cis -acting element that mediates clock control of transcription in plants.

    Article  CAS  PubMed  Google Scholar 

  83. Wang, Z. Y. et al. A Myb-related transcription factor is involved in the phytochrome regulation of an Arabidopsis Lhcb gene. Plant Cell 9, 491–507 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Green, R. M. & Tobin, E. M. Loss of the circadian clock-associated protein 1 in Arabidopsis results in altered clock-regulated gene expression. Proc. Natl Acad. Sci. USA 96, 4176–4179 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Matsushika, A., Makino, S., Kojima, M. & Mizuno, T. Circadian waves of expression of the APRR1/TOC1 family of pseudo-response regulators in Arabidopsis thaliana: insight into the plant circadian clock. Plant Cell Physiol. 41, 1002–1012 (2000).

    Article  CAS  PubMed  Google Scholar 

  86. Sugano, S., Andronis, C., Ong, M. S., Green, R. M. & Tobin, E. M. The protein kinase CK2 is involved in regulation of circadian rhythms in Arabidopsis. Proc. Natl Acad. Sci. USA 96, 12362–12366 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Hicks, K. A. et al. Conditional circadian dysfunction of the Arabidopsis early-flowering 3 mutant. Science 274, 790–792 (1996).

    Article  CAS  PubMed  Google Scholar 

  88. Hicks, K. A., Albertson, T. M. & Wagner, D. R. Early flowering3 encodes a novel protein that regulates circadian clock function and flowering in Arabidopsis. Plant Cell 13, 1281–1292 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Covington, M. F. et al. ELF3 modulates resetting of the circadian clock in Arabidopsis. Plant Cell 13, 1305–1316 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. McWatters, H. G., Bastow, R. M., Hall, A. & Millar, A. J. The ELF3 zeitnehmer regulates light signalling to the circadian clock. Nature 408, 716–720 (2000).

    Article  CAS  PubMed  Google Scholar 

  91. Devlin, P. F. & Kay, S. A. Circadian photoperception. Annu. Rev. Physiol. 63, 677–694 (2001).

    Article  CAS  PubMed  Google Scholar 

  92. Martinez-Garcia, J. F., Huq, E. & Quail, P. H. Direct targeting of light signals to a promoter element-bound transcription factor. Science 288, 859–863 (2000).

    Article  CAS  PubMed  Google Scholar 

  93. Mas, P., Devlin, P. F., Panda, S. & Kay, S. A. Functional interaction of phytochrome B and cryptochrome 2. Nature 408, 207–211 (2000).

    Article  CAS  PubMed  Google Scholar 

  94. Liu, X. L., Covington, M. F., Fankhauser, C., Chory, J. & Wagner, D. R. ELF3 encodes a circadian clock-regulated nuclear protein that functions in an Arabidopsis PHYB signal transduction pathway. Plant Cell 13, 1293–1304 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Golden, S. S., Ishiura, M., Johnson, C. H. & Kondo, T. Cyanobacterial circadian rhythms. Annu. Rev. Plant Physiol. Plant Mol. Biol. 48, 327–354 (1997).

    Article  CAS  PubMed  Google Scholar 

  96. Kondo, T., Tsinoremas, N. F., Golden, S. S., Johnson, C. H., Kutsuna, S. & Ishiura, M. Circadian clock mutants of cyanobacteria. Science 266, 1233–1236 (1994).

    Article  CAS  PubMed  Google Scholar 

  97. Ishiura, M. et al. Expression of a gene cluster kaiABC as a circadian feedback process in cyanobacteria. Science 281, 1519–1523 (1998).First cloning of clock genes in cyanobacteria. The inter-dependent, cycling expression of the three kai genes is shown.

    Article  CAS  PubMed  Google Scholar 

  98. Xu, Y., Mori, T. & Johnson, C. H. Circadian clock-protein expression in cyanobacteria: rhythms and phase setting. EMBO J. 19, 3349–3357 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Iwasaki, H., Taniguchi, Y., Ishiura, M. & Kondo, T. Physical interactions among circadian clock proteins KaiA, KaiB and KaiC in cyanobacteria. EMBO J. 18, 1137–1145 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Xu, Y., Piston, D. W. & Johnson, C. H. A bioluminescence resonance energy transfer (BRET) system: application to interacting circadian clock proteins. Proc. Natl Acad. Sci. USA 96, 151–156 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Nishiwaki, T., Iwasaki, H., Ishiura, M. & Kondo, T. Nucleotide binding and autophosphorylation of the clock protein KaiC as a circadian timing process of cyanobacteria. Proc. Natl Acad. Sci. USA 97, 495–499 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Iwasaki, H. et al. A kaiC-interacting sensory histidine kinase, SasA, necessary to sustain robust circadian oscillation in cyanobacteria. Cell 101, 223–233 (2000).Shows interaction of KaiC and SasA, and effects on period and amplitude of the cyanobacteria clock.

    Article  CAS  PubMed  Google Scholar 

  103. Liu, Y. et al. Circadian orchestration of gene expression in bacteria. Genes Dev. 9, 1469–1478 (1995).

    Article  CAS  PubMed  Google Scholar 

  104. Ouyang, Y., Andersson, C. R., Kondo, T., Golden, S. S. & Johnson, C. H. Resonating circadian clocks enhance fitness in cyanobacteria. Proc. Natl Acad. Sci. USA 95, 8660–8664 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Gekakis, N. et al. Isolation of timeless by PER protein interaction: defective interaction between timeless protein and long-period mutant PERL. Science 270, 811–815 (1995).

    Article  CAS  PubMed  Google Scholar 

  106. Vosshall, L. B., Price, J. L., Sehgal, A., Saez, L. & Young, M. W. Block in nuclear localization of period protein by a second clock mutation, timeless. Science 263, 1606–1609 (1994).

    Article  CAS  PubMed  Google Scholar 

  107. McNamara, P. et al. Regulation of CLOCK and MOP4 by nuclear hormone receptors in the vasculature: a humoral mechanism to reset a peripheral clock. Cell 105, 877–889 (2001).Retinoids physically associate with CLOCK and MOP4, and affect their ability to bind DNA.

    Article  CAS  PubMed  Google Scholar 

  108. Rutter, J., Reick, M., Wu, L. C. & McKnight, S. L. Regulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors. Science 293, 510–514 (2001).A possible connection between redox state of a cell and function of NPAS2, a paralogue of CLOCK that is active in circadian clocks of the mammalian forebrain.

    Article  CAS  PubMed  Google Scholar 

  109. Lakin-Thomas, P. L. & Brody, S. Circadian rhythms in Neurospora crassa: lipid deficiencies restore robust rhythmicity to null frequency and white-collar mutants. Proc. Natl Acad. Sci. USA 97, 256–261 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Merrow, M., Brunner, M. & Roenneberg, T. Assignment of circadian function for the Neurospora clock gene frequency. Nature 399, 584–586 (1999).

    Article  CAS  PubMed  Google Scholar 

  111. Andretic, R., Chaney, S. & Hirsh, J. Requirement of circadian genes for cocaine sensitization in Drosophila. Science 285, 1066–1068 (1999).

    Article  CAS  PubMed  Google Scholar 

  112. Belvin, M. P., Zhou, H. & Yin, J. C. The Drosophila dCREB2 gene affects the circadian clock. Neuron 22, 777–787 (1999).

    Article  CAS  PubMed  Google Scholar 

  113. Sawyer, L. A. et al. Natural variation in a Drosophila clock gene and temperature compensation. Science 278, 2117–2120 (1997).

    Article  CAS  PubMed  Google Scholar 

  114. Jackson, F. R., Bargiello, T. A., Yun, S. H. & Young, M. W. Product of per locus of Drosophila shares homology with proteoglycans. Nature 320, 185–188 (1986).

    Article  CAS  PubMed  Google Scholar 

  115. Citri, Y. et al. A family of unusually spliced biologically active transcripts encoded by a Drosophila clock gene. Nature 326, 42–47 (1987).

    Article  CAS  PubMed  Google Scholar 

  116. Sehgal, A., Price, J. L., Man, B. & Young, M. W. Loss of circadian behavioral rhythms and per RNA oscillations in the Drosophila mutant timeless. Science 263, 1603–1606 (1994).

    Article  CAS  PubMed  Google Scholar 

  117. Myers, M. P., Wager-Smith, K., Wesley, C. S., Young, M. W. & Sehgal, A. Positional cloning and sequence analysis of the Drosophila clock gene, timeless. Science 270, 805–808 (1995).

    Article  CAS  PubMed  Google Scholar 

  118. Kloss, B. et al. The Drosophila clock gene double-time encodes a protein closely related to human casein kinase I ɛ. Cell 94, 97–107 (1998).Cloning of double -time. Description of casein kinase 1ɛ homologue and role in PER phosphorylation and stability. First enzyme as component of the molecular clock.

    Article  CAS  PubMed  Google Scholar 

  119. Rutila, J. E. et al. CYCLE is a second bHLH-PAS clock protein essential for circadian rhythmicity and transcription of Drosophila period and timeless. Cell 93, 805–814 (1998).Cloning of cycle and description of an arrhythmic mutation of this Drosophila clock gene.

    Article  CAS  PubMed  Google Scholar 

  120. Emery, P., So, W. V., Kaneko, M., Hall, J. C. & Rosbash, M. CRY, a Drosophila clock and light-regulated cryptochrome, is a major contributor to circadian rhythm resetting and photosensitivity. Cell 95, 669–679 (1998).

    Article  CAS  PubMed  Google Scholar 

  121. Stanewsky, R. et al. The cryb mutation identifies cryptochrome as a circadian photoreceptor in Drosophila. Cell 95, 681–692 (1998).Describes the characterization of a cryptochrome mutation in Drosophila and its effects on photoreceptivity of the clock.

    Article  CAS  PubMed  Google Scholar 

  122. Tei, H. et al. Circadian oscillation of a mammalian homologue of the Drosophila period gene. Nature 389, 512–516 (1997).

    Article  CAS  PubMed  Google Scholar 

  123. Sun, Z. S. et al. RIGUI, a putative mammalian ortholog of the Drosophila period gene. Cell 90, 1003–1011 (1997).

    Article  CAS  PubMed  Google Scholar 

  124. Shearman, L. P., Zylka, M. J., Weaver, D. R., Kolakowski, L. F. Jr & Reppert, S. M. Two period homologs: circadian expression and photic regulation in the suprachiasmatic nuclei. Neuron 19, 1261–1269 (1997).

    Article  CAS  PubMed  Google Scholar 

  125. Zylka, M. J. et al. Molecular analysis of mammalian timeless. Neuron 21, 1115–1122 (1998).

    Article  CAS  PubMed  Google Scholar 

  126. Takumi, T. et al. A light-independent oscillatory gene mPer3 in mouse SCN and OVLT. EMBO J. 17, 4753–4759 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Koike, N. et al. Identification of the mammalian homologues of the Drosophila timeless gene, Timeless1. FEBS Lett. 441, 427–431 (1998).

    Article  CAS  PubMed  Google Scholar 

  128. Takumi, T. et al. A mammalian ortholog of Drosophila timeless, highly expressed in SCN and retina, forms a complex with mPER1. Genes Cells 4, 67–75 (1999).

    Article  CAS  PubMed  Google Scholar 

  129. Tischkau, S. A. et al. Oscillation and light induction of timeless mRNA in the mammalian circadian clock. J. Neurosci. 19, 1–6 (1999).

    Article  Google Scholar 

  130. Vitaterna, M. H. et al. Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior. Science 264, 719–725 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Gekakis, N. et al. Role of the CLOCK protein in the mammalian circadian mechanism. Science 280, 1564–9 (1998).Establishes in mammals that CLOCK and BMAL1 positively regulate transcription of Per , and that nuclear PER proteins suppress CLOCK/BMAL1 activity.

    Article  CAS  PubMed  Google Scholar 

  132. Hogenesch, J. B., Gu, Y. Z., Jain, S. & Bradfield, C. A. The basic-helix–loop–helix–PAS orphan MOP3 forms transcriptionally active complexes with circadian and hypoxia factors. Proc. Natl Acad. Sci. USA 95, 5474–5479 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Honma, S. et al. Circadian oscillation of BMAL1, a partner of a mammalian clock gene Clock, in rat suprachiasmatic nucleus. Biochem. Biophys. Res. Commun. 250, 83–87 (1998).

    Article  CAS  PubMed  Google Scholar 

  134. Hsu, D. S. et al. Putative human blue-light photoreceptors hCRY1 and hCRY2 are flavoproteins. Biochemistry 35, 13871–13877 (1996).

    Article  CAS  PubMed  Google Scholar 

  135. Van der Spek, P. J. et al. Cloning, tissue expression, and mapping of a human photolyase homolog with similarity to plant blue-light receptors. Genomics 37, 177–182 (1996).

    Article  CAS  PubMed  Google Scholar 

  136. Thresher, R. J. et al. Role of mouse cryptochrome blue-light photoreceptor in circadian photoresponses. Science 282, 1490–1494 (1998).

    Article  CAS  PubMed  Google Scholar 

  137. Feldman, J. F. & Hoyle, M. N. Isolation of circadian clock mutants of Neurospora crassa. Genetics 75, 605–613 (1973).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Ballario, P. et al. White collar-1, a central regulator of blue light responses in Neurospora, is a zinc finger protein. EMBO J. 15, 1650–1657 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Linden, H. & Macino, G. White collar 2, a partner in blue-light signal transduction, controlling expression of light-regulated genes in Neurospora crassa. EMBO J. 16, 98–109 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Hall, M. D., Bennett, S. N. & Krissinger, W. A. Characterization of a newly isolated pigmentation mutant of Neurospora crassa. Georgia J. Sci. 51, 27 (1993).

    Google Scholar 

  141. Schmitz, O., Katayama M., Williams, S. B., Kondo, T. & Golden, S. S. CikA, a bacteriophytochrome that resets the cyanobacterial circadian clock. Science 289, 765–768 (2000). Demonstration of clock function of a two-component response regulator and potential photoreceptor.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank members of our laboratories and J. Dunlap, S. Golden and S. Williams for helpful comments on the manuscript. We were offered many important insights and apologize for not resolving all complaints.

Author information

Authors and Affiliations

Authors

Supplementary information

Related links

Related links

DATABASE LINKS

Familial advanced sleep phase syndrome

PER2

frequency

Timeless

Clock

Cycle

Double-time

cryptochrome

shaggy

vrille

Armadillo

Dishevelled

CLOCK

ARNTL

Clock

Per

Arntl

Cry1

Cry2

CCA1

TOC1

CONSTANS

elf3

PHYA

PHYB

PHYD

PHYE

CRY1

ARNT

LINKS

ARNT1

Glossary

ENTRAIN

To establish the phase of a rhythm by providing an environmenal signal, such as a light or temperature cycle, or a biological signal, such as a hormone pulse.

CRYPTOCHROME

A novel photoreceptor, discovered in plants and subsequently found in animals, that is thought to have evolved from photolyase (light-activated DNA-repair protein). Cryptochromes bind flavin and pterin, and promote redox reactions upon absorbing light.

PAS MOTIF

These motifs (PER/ARNT/SIM) are often associated with proteins that function as environmental or developmental sensors. They also promote physical associations among various transcription factors.

CHROMOPHORE

A light-absorbing molecule, such as pterin or retinal. Often physically associated with a protein partner to form a photoreceptor/phototransducer.

MYB DOMAIN

A structurally conserved DNA-binding domain found in various transcription factors. In plants, MYB proteins are ubiquitous and known to function in many regulatory systems, including secondary metabolism, cell morphogenesis, the cell cycle, and circadian rhythms.

RESPONSE REGULATOR

Works in conjunction with a sensor kinase that might be activated by an environmental signal. Activation and autophosphorylation of the sensor kinase promotes phosphorylation of a specific response regulator. The latter is often a transcription factor with activity that is modulated by phosphorylation.

PHYTOCHROME

One of three classes of known plant photoreceptors. Composed of a protein moiety covalently associated with a tetrapyrrole chromophore. Synthesized in a red-light-absorbing form, nascent phytochromes are converted by red light to a far-red-absorbing isoform that might have altered stability and function. All phytochromes include carboxy-terminal PAS domains.

P-LOOP MOTIF

Phosphate-binding domain (P-loop) associated with many ATP- and GTP-binding proteins. These usually have a structure composed of a glycine-rich sequence, followed by certain conserved lysine and serine or threonine residues.

PHOTOACTIVE YELLOW PROTEIN

A soluble cytoplasmic protein with a p-hydroxycinnamyl chromophore that functions as the receptor for the phototactic response in certain halophilic bacteria.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Young, M., Kay, S. Time zones: a comparative genetics of circadian clocks. Nat Rev Genet 2, 702–715 (2001). https://doi.org/10.1038/35088576

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/35088576

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing