Skip to main content

Thank you for visiting 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.

Peroxiredoxins are conserved markers of circadian rhythms

A Corrigendum to this article was published on 08 August 2012


Cellular life emerged 3.7 billion years ago. With scant exception, terrestrial organisms have evolved under predictable daily cycles owing to the Earth’s rotation. The advantage conferred on organisms that anticipate such environmental cycles has driven the evolution of endogenous circadian rhythms that tune internal physiology to external conditions. The molecular phylogeny of mechanisms driving these rhythms has been difficult to dissect because identified clock genes and proteins are not conserved across the domains of life: Bacteria, Archaea and Eukaryota. Here we show that oxidation–reduction cycles of peroxiredoxin proteins constitute a universal marker for circadian rhythms in all domains of life, by characterizing their oscillations in a variety of model organisms. Furthermore, we explore the interconnectivity between these metabolic cycles and transcription–translation feedback loops of the clockwork in each system. Our results suggest an intimate co-evolution of cellular timekeeping with redox homeostatic mechanisms after the Great Oxidation Event 2.5 billion years ago.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: The peroxiredoxin active site is highly conserved in all domains of life.
Figure 2: Peroxiredoxin oxidation cycles are conserved in eukaryotic models of the circadian clock.
Figure 3: Peroxiredoxin oxidation cycles are conserved in prokaryotic models of the circadian clock.
Figure 4: Peroxiredoxin oxidation cycles in circadian clock mutants.
Figure 5: Relationships between peroxiredoxins and the cyanobacterial Kai-based oscillator.
Figure 6: Phylogenetic origins of circadian oscillatory systems.

Accession codes

Primary accessions


Protein Data Bank


  1. 1

    Dunlap, J. C. Molecular bases for circadian clocks. Cell 96, 271–290 (1999)

    CAS  Article  Google Scholar 

  2. 2

    Woelfle, M. A., Ouyang, Y., Phanvijhitsiri, K. & Johnson, C. H. The adaptive value of circadian clocks; an experimental assessment in cyanobacteria. Curr. Biol. 14, 1481–1486 (2004)

    CAS  Article  Google Scholar 

  3. 3

    Dodd, A. N. et al. Plant circadian clocks increase photosynthesis, growth, survival, and competitive advantage. Science 309, 630–633 (2005)

    ADS  CAS  Article  Google Scholar 

  4. 4

    Barger, L. K., Lockley, S. W., Rajaratnam, S. M. & Landrigan, C. P. Neurobehavioral, health, and safety consequences associated with shift work in safety-sensitive professions. Curr. Neurol. Neurosci. Rep. 9, 155–164 (2009)

    Article  Google Scholar 

  5. 5

    Wijnen, H. & Young, M. W. Interplay of circadian clocks and metabolic rhythms. Annu. Rev. Genet. 40, 409–448 (2006)

    CAS  Article  Google Scholar 

  6. 6

    Allada, R., Emery, P., Takahashi, J. S. & Rosbash, M. Stopping time: the genetics of fly and mouse circadian clocks. Annu. Rev. Neurosci. 24, 1091–1119 (2001)

    CAS  Article  Google Scholar 

  7. 7

    Rosbash, M. The implications of multiple circadian clock origins. PLoS Biol. 7, e62 (2009)

    Article  Google Scholar 

  8. 8

    Zheng, X. & Sehgal, A. Probing the relative importance of molecular oscillations in the circadian clock. Genetics 178, 1147–1155 (2008)

    CAS  Article  Google Scholar 

  9. 9

    O’Neill, J. S. et al. Circadian rhythms persist without transcription in a eukaryote. Nature 469, 554–558 (2011)

    ADS  Article  Google Scholar 

  10. 10

    O’Neill, J. S. & Reddy, A. B. Circadian clocks in human red blood cells. Nature 469, 498–503 (2011)

    ADS  Article  Google Scholar 

  11. 11

    Hall, A., Karplus, P. A. & Poole, L. B. Typical 2-Cys peroxiredoxins–structures, mechanisms and functions. FEBS J. 276, 2469–2477 (2009)

    CAS  Article  Google Scholar 

  12. 12

    Wood, Z. A., Poole, L. B. & Karplus, P. A. Peroxiredoxin evolution and the regulation of hydrogen peroxide signaling. Science 300, 650–653 (2003)

    ADS  CAS  Article  Google Scholar 

  13. 13

    Barranco-Medina, S., Lazaro, J. J. & Dietz, K. J. The oligomeric conformation of peroxiredoxins links redox state to function. FEBS Lett. 583, 1809–1816 (2009)

    CAS  Article  Google Scholar 

  14. 14

    Woo, H. A. et al. Reversible oxidation of the active site cysteine of peroxiredoxins to cysteine sulfinic acid. Immunoblot detection with antibodies specific for the hyperoxidized cysteine-containing sequence. J. Biol. Chem. 278, 47361–47364 (2003)

    CAS  Article  Google Scholar 

  15. 15

    Lopez-Molina, L., Conquet, F., Dubois-Dauphin, M. & Schibler, U. The DBP gene is expressed according to a circadian rhythm in the suprachiasmatic nucleus and influences circadian behavior. EMBO J. 16, 6762–6771 (1997)

    CAS  Article  Google Scholar 

  16. 16

    Johnson, C. H., Mori, T. & Xu, Y. A cyanobacterial circadian clockwork. Curr. Biol. 18, R816–R825 (2008)

    CAS  Article  Google Scholar 

  17. 17

    Nakajima, M. et al. Reconstitution of circadian oscillation of cyanobacterial KaiC phosphorylation in vitro . Science 308, 414–415 (2005)

    ADS  CAS  Article  Google Scholar 

  18. 18

    Dvornyk, V., Vinogradova, O. & Nevo, E. Origin and evolution of circadian clock genes in prokaryotes. Proc. Natl Acad. Sci. USA 100, 2495–2500 (2003)

    ADS  CAS  Article  Google Scholar 

  19. 19

    Whitehead, K., Pan, M., Masumura, K., Bonneau, R. & Baliga, N. S. Diurnally entrained anticipatory behavior in archaea. PLoS ONE 4, e5485 (2009)

    ADS  Article  Google Scholar 

  20. 20

    Lakin-Thomas, P. L. Transcriptional feedback oscillators: maybe, maybe not. J. Biol. Rhythms 21, 83–92 (2006)

    CAS  Article  Google Scholar 

  21. 21

    Reddy, A. B. & O’Neill, J. S. Healthy clocks, healthy body, healthy mind. Trends Cell Biol. 20, 36–44 (2009)

    Article  Google Scholar 

  22. 22

    Young, M. W. & Kay, S. A. Time zones: a comparative genetics of circadian clocks. Nature Rev. Genet. 2, 702–715 (2001)

    CAS  Article  Google Scholar 

  23. 23

    Young, M. W. The molecular control of circadian behavioral rhythms and their entrainment in Drosophila . Annu. Rev. Biochem. 67, 135–152 (1998)

    CAS  Article  Google Scholar 

  24. 24

    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)

    CAS  Article  Google Scholar 

  25. 25

    Hardin, P. E. The circadian timekeeping system of Drosophila . Curr. Biol. 15, R714–R722 (2005)

    CAS  Article  Google Scholar 

  26. 26

    Dunlap, J. C. & Loros, J. J. How fungi keep time: circadian system in Neurospora and other fungi. Curr. Opin. Microbiol. 9, 579–587 (2006)

    CAS  Article  Google Scholar 

  27. 27

    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)

    ADS  CAS  Article  Google Scholar 

  28. 28

    Granshaw, T., Tsukamoto, M. & Brody, S. Circadian rhythms in Neurospora crassa: farnesol or geraniol allow expression of rhythmicity in the otherwise arrhythmic strains frq10, wc-1, and wc-2 . J. Biol. Rhythms 18, 287–296 (2003)

    CAS  Article  Google Scholar 

  29. 29

    Lakin-Thomas, P. L. & Brody, S. Circadian rhythms in microorganisms: new complexities. Annu. Rev. Microbiol. 58, 489–519 (2004)

    CAS  Article  Google Scholar 

  30. 30

    Corellou, F. et al. Clocks in the green lineage: comparative functional analysis of the circadian architecture of the picoeukaryote ostreococcus. Plant Cell 21, 3436–3449 (2009)

    CAS  Article  Google Scholar 

  31. 31

    Mas, P., Alabadi, D., Yanovsky, M. J., Oyama, T. & Kay, S. A. Dual role of TOC1 in the control of circadian and photomorphogenic responses in Arabidopsis . Plant Cell 15, 223–236 (2003)

    CAS  Article  Google Scholar 

  32. 32

    Ditty, J. L., Canales, S. R., Anderson, B. E., Williams, S. B. & Golden, S. S. Stability of the Synechococcus elongatus PCC 7942 circadian clock under directed anti-phase expression of the kai genes. Microbiology 151, 2605–2613 (2005)

    CAS  Article  Google Scholar 

  33. 33

    Pulido, P. et al. Functional analysis of the pathways for 2-Cys peroxiredoxin reduction in Arabidopsis thaliana chloroplasts. J. Exp. Bot. 61, 4043–4054 (2010)

    CAS  Article  Google Scholar 

  34. 34

    Yoshida, Y., Iigusa, H., Wang, N. & Hasunuma, K. Cross-talk between the cellular redox state and the circadian system in Neurospora . PLoS ONE 6, e28227 (2011)

    ADS  CAS  Article  Google Scholar 

  35. 35

    Wang, M. et al. A universal molecular clock of protein folds and its power in tracing the early history of aerobic metabolism and planet oxygenation. Mol. Biol. Evol. 28, 567–582 (2011)

    CAS  Article  Google Scholar 

  36. 36

    Nathan, C. & Ding, A. SnapShot: reactive oxygen intermediates (ROI). Cell 140, 951–951.e2 (2010)

    Article  Google Scholar 

  37. 37

    Zelko, I. N., Mariani, T. J. & Folz, R. J. Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression. Free Radic. Biol. Med. 33, 337–349 (2002)

    CAS  Article  Google Scholar 

  38. 38

    Mulholland, P. J., Houser, J. N. & Maloney, K. O. Stream diurnal dissolved oxygen profiles as indicators of in-stream metabolism and disturbance effects: Fort Benning as a case study. Ecol. Indic. 5, 243–252 (2005)

    CAS  Article  Google Scholar 

  39. 39

    Venkiteswaran, J. J., Wassenaar, L. I. & Schiff, S. L. Dynamics of dissolved oxygen isotopic ratios: a transient model to quantify primary production, community respiration, and air-water exchange in aquatic ecosystems. Oecologia 153, 385–398 (2007)

    ADS  Article  Google Scholar 

  40. 40

    Bamforth, S. S. Diurnal changes in shallow aquatic habitats. Limnol. Oceanogr. 7, 348–353 (1962)

    ADS  Article  Google Scholar 

  41. 41

    Ochoa, D. & Pazos, F. Studying the co-evolution of protein families with the Mirrortree web server. Bioinformatics 26, 1370–1371 (2010)

    CAS  Article  Google Scholar 

  42. 42

    Peixoto, A. A., Campesan, S., Costa, R. & Kyriacou, C. P. Molecular evolution of a repetitive region within the per gene of Drosophila . Mol. Biol. Evol. 10, 127–139 (1993)

    CAS  PubMed  Google Scholar 

  43. 43

    McIntosh, B. E., Hogenesch, J. B. & Bradfield, C. A. Mammalian Per-Arnt-Sim proteins in environmental adaptation. Annu. Rev. Physiol. 72, 625–645 (2010)

    CAS  Article  Google Scholar 

  44. 44

    Rutter, J., Reick, M. & McKnight, S. L. Metabolism and the control of circadian rhythms. Annu. Rev. Biochem. 71, 307–331 (2002)

    CAS  Article  Google Scholar 

  45. 45

    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)

    CAS  Article  Google Scholar 

  46. 46

    Shima, S., Thauer, R. K. & Ermler, U. Hyperthermophilic and salt-dependent formyltransferase from Methanopyrus kandleri . Biochem. Soc. Trans. 32, 269–272 (2004)

    CAS  Article  Google Scholar 

  47. 47

    Declercq, J. P. et al. Crystal structure of human peroxiredoxin 5, a novel type of mammalian peroxiredoxin at 1.5 Å resolution. J. Mol. Biol. 311, 751–759 (2001)

    CAS  Article  Google Scholar 

  48. 48

    Schröder, E. et al. Crystal structure of decameric 2-Cys peroxiredoxin from human erythrocytes at 1.7 Å resolution. Structure 8, 605–615 (2000)

    Article  Google Scholar 

  49. 49

    Xu, Y., Mori, T. & Johnson, C. H. Cyanobacterial circadian clockwork: roles of KaiA, KaiB and the kaiBC promoter in regulating KaiC. EMBO J. 22, 2117–2126 (2003)

    CAS  Article  Google Scholar 

  50. 50

    Pazos, F. & Valencia, A. Similarity of phylogenetic trees as indicator of protein-protein interaction. Protein Eng. 14, 609–614 (2001)

    CAS  Article  Google Scholar 

  51. 51

    Gould, P. D. et al. Delayed fluorescence as a universal tool for the measurement of circadian rhythms in higher plants. Plant J. 58, 893–901 (2009)

    CAS  Article  Google Scholar 

  52. 52

    Rosato, E. & Kyriacou, C. P. Analysis of locomotor activity rhythms in Drosophila. Nature Protocols 1, 559–568 (2006)

    Article  Google Scholar 

  53. 53

    Reddy, A. B. et al. Circadian orchestration of the hepatic proteome. Curr. Biol. 16, 1107–1115 (2006)

    CAS  Article  Google Scholar 

  54. 54

    Whitehead, K., Pan, M., Masumura, K., Bonneau, R. & Baliga, N. S. Diurnally entrained anticipatory behavior in archaea. PLoS ONE 4, e5485 (2009)

    ADS  Article  Google Scholar 

  55. 55

    Mori, T., Binder, B. & Johnson, C. H. Circadian gating of cell division in cyanobacteria growing with average doubling times of less than 24 hours. Proc. Natl Acad. Sci. USA 93, 10183–10188 (1996)

    ADS  CAS  Article  Google Scholar 

  56. 56

    Yoo, S. H. et al. PERIOD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. Proc. Natl Acad. Sci. USA 101, 5339–5346 (2004)

    ADS  CAS  Article  Google Scholar 

  57. 57

    House, S. B., Thomas, A., Kusano, K. & Gainer, H. Stationary organotypic cultures of oxytocin and vasopressin magnocellular neurons from rat and mouse hypothalamus. J. Neuroendocrinol. 10, 849–861 (1998)

    CAS  Article  Google Scholar 

  58. 58

    Hastings, M. H., Reddy, A. B., McMahon, D. G. & Maywood, E. S. Analysis of circadian mechanisms in the suprachiasmatic nucleus by transgenesis and biolistic transfection. Methods Enzymol. 393, 579–592 (2005)

    CAS  Article  Google Scholar 

  59. 59

    Maywood, E. S. et al. Synchronization and maintenance of timekeeping in suprachiasmatic circadian clock cells by neuropeptidergic signaling. Curr. Biol. 16, 599–605 (2006)

    CAS  Article  Google Scholar 

  60. 60

    Davis, R. H. Neurospora: Contributions of a Model Organism (Oxford Univ. Press, 2000)

    Google Scholar 

  61. 61

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

    ADS  CAS  Article  Google Scholar 

  62. 62

    Olmedo, M. et al. A role in the regulation of transcription by light for RCO-1 and RCM-1, the Neurospora homologs of the yeast Tup1–Ssn6 repressor. Fungal Genet. Biol. 47, 939–952 (2010)

    CAS  Article  Google Scholar 

  63. 63

    Woo, H. A. & Rhee, S. G. in Methods in Redox Signaling (ed. Das, D. ) Ch. 4 19–23 (Mary Ann Liebert, 2010)

    Google Scholar 

  64. 64

    Ishiura, M. et al. Expression of a gene cluster kaiABC as a circadian feedback process in cyanobacteria. Science 281, 1519–1523 (1998)

    ADS  CAS  Article  Google Scholar 

  65. 65

    Qin, X. et al. Intermolecular associations determine the dynamics of the circadian KaiABC oscillator. Proc. Natl Acad. Sci. USA 107, 14805–14810 (2010)

    ADS  CAS  Article  Google Scholar 

  66. 66

    Xu, Y. et al. Intramolecular regulation of phosphorylation status of the circadian clock protein KaiC. PLoS ONE 4, e7509 (2009)

    ADS  Article  Google Scholar 

  67. 67

    Stork, T., Laxa, M., Dietz, M. S. & Dietz, K. J. Functional characterisation of the peroxiredoxin gene family members of Synechococcus elongatus PCC 7942. Arch. Microbiol. 191, 141–151 (2009)

    CAS  Article  Google Scholar 

  68. 68

    Xu, Y., Mori, T. & Johnson, C. H. Cyanobacterial circadian clockwork: roles of KaiA, KaiB and the kaiBC promoter in regulating KaiC. EMBO J. 22, 2117–2126 (2003)

    CAS  Article  Google Scholar 

  69. 69

    Ochoa, D. & Pazos, F. Studying the co-evolution of protein families with the Mirrortree web server. Bioinformatics 26, 1370–1371 (2010)

    CAS  Article  Google Scholar 

  70. 70

    Pazos, F. & Valencia, A. Similarity of phylogenetic trees as indicator of protein–protein interaction. Protein Eng. 14, 609–614 (2001)

    CAS  Article  Google Scholar 

  71. 71

    Oster, H., Damerow, S., Hut, R. A. & Eichele, G. Transcriptional profiling in the adrenal gland reveals circadian regulation of hormone biosynthesis genes and nucleosome assembly genes. J. Biol. Rhythms 21, 350–361 (2006)

    CAS  Article  Google Scholar 

Download references


This work was primarily supported by the Wellcome Trust (083643/Z/07/Z and 093734/Z/10/Z), the European Research Council (ERC Starting Grant No. 281348, MetaCLOCK), and EMBO Young Investigators Programme, as well as the Medical Research Council Centre for Obesity and Related metabolic Disorders (MRC CORD), and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. C.P.K. and M.H.H. acknowledge European Commission grant EUCLOCK (no. 018741) and Biotechnology and Biological Sciences Research Council (BBSRC) grant BB/C006941/1. SynthSys is funded by BBSRC and Engineering and Physical Sciences Research Council (EPSRC) award BB/D019621 to A.J.M. and others. N.S.B. was supported by ENIGMA, US Department of Energy, under contract no. DE-AC02-05CH11231, and by a grant from the National Institutes of Health (NIH; P50GM076547). C.H.J. was supported by the NIH (R01GM088595, R01GM067152 and R21HL102492). M.M. was supported by the Netherlands Organisation for Scientific Research (NWO; Dutch Science Foundation VICI award and Open Programma) and the University of Groningen (Rosalind Franklin Fellowship Program). We thank M. Jain, G. O’Neill and J. Chambers for discussion about the manuscript, and S. G. Rhee, F. Rouyer and R. Stanewsky for the gifts of antisera.

Author information




A.B.R. and J.S.O. conceived and designed the experiments, and wrote the manuscript. R.S.E., E.W.G., G.v.O., M.O., X.Q., Y.X., Y.Z., M.P., U.K.V., K.A.F. and E.S.M. performed experiments. M.H.H., N.S.B., C.H.J., M.M., A.J.M. and C.P.K. provided reagents. R.S.E., E.W.G., G.v.O., M.O. and Y.Z. contributed equally to this work.

Corresponding authors

Correspondence to John S. O’Neill or Akhilesh B. Reddy.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Tables 1-9, Supplementary Figures 1-10 and additional references. (PDF 1924 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Edgar, R., Green, E., Zhao, Y. et al. Peroxiredoxins are conserved markers of circadian rhythms. Nature 485, 459–464 (2012).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links