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:

The intricate dance of post-translational modifications in the rhythm of life

Abstract

Endogenous biological rhythms with approximately 24-h periodicity are generated by the circadian clock, in which clock genes coordinate with one another and form a transcriptional–translational negative feedback loop. The precision of the circadian clock is further regulated by multiple post-translational modifications (PTMs), including phosphorylation, ubiquitination, acetylation and SUMOylation. Here, we review current understanding of the regulatory mechanisms of the core clock proteins by PTMs in the mammalian circadian clock.

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: A basic model of the circadian molecular clock.
Figure 2: PER stability is controlled by cross-talk of multiple PTMs.
Figure 3: CRY stability is controlled by FBXL3 and multiple competing mechanisms.
Figure 4: Temporal regulation of CLOCK–BMAL1 activity.

Similar content being viewed by others

References

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

    Article  CAS  PubMed  Google Scholar 

  2. Bass, J. & Takahashi, J.S. Circadian integration of metabolism and energetics. Science 330, 1349–1354 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Gallego, M. & Virshup, D.M. Post-translational modifications regulate the ticking of the circadian clock. Nat. Rev. Mol. Cell Biol. 8, 139–148 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Reischl, S. & Kramer, A. Kinases and phosphatases in the mammalian circadian clock. FEBS Lett. 585, 1393–1399 (2011).

    Article  CAS  PubMed  Google Scholar 

  5. Stojkovic, K., Wing, S.S. & Cermakian, N. A central role for ubiquitination within a circadian clock protein modification code. Front. Mol. Neurosci. 7, 69 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Mehra, A., Baker, C.L., Loros, J.J. & Dunlap, J.C. Post-translational modifications in circadian rhythms. Trends Biochem. Sci. 34, 483–490 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Toh, K.L. et al. An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science 291, 1040–1043 (2001). A mutation at the phosphorylation site of human PER2 causes decreased transcription of PER2 protein with decreased stability, this leading to FASP.

    Article  CAS  PubMed  Google Scholar 

  8. Xu, Y. et al. Modeling of a human circadian mutation yields insights into clock regulation by PER2. Cell 128, 59–70 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Seo, J. & Lee, K.-J. Post-translational modifications and their biological functions: proteomic analysis and systematic approaches. J. Biochem. Mol. Biol. 37, 35–44 (2004).

    CAS  PubMed  Google Scholar 

  10. Venne, A.S., Kollipara, L. & Zahedi, R.P. The next level of complexity: crosstalk of posttranslational modifications. Proteomics 14, 513–524 (2014).

    Article  CAS  PubMed  Google Scholar 

  11. Kaasik, K. et al. Glucose sensor O-GlcNAcylation coordinates with phosphorylation to regulate circadian clock. Cell Metab. 17, 291–302 (2013). O -GlcNAc modification competes with phosphorylation at FASP sites in PER2, thereby regulating PER2 stability and repressor activity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lee, C., Etchegaray, J.P., Cagampang, F.R., Loudon, A.S. & Reppert, S.M. Posttranslational mechanisms regulate the mammalian circadian clock. Cell 107, 855–867 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Camacho, F. et al. Human casein kinase Iδ phosphorylation of human circadian clock proteins period 1 and 2. FEBS Lett. 489, 159–165 (2001).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  15. Eide, E.J. et al. Control of mammalian circadian rhythm by CKIɛ-regulated proteasome-mediated PER2 degradation. Mol. Cell. Biol. 25, 2795–2807 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Akashi, M., Tsuchiya, Y., Yoshino, T. & Nishida, E. Control of intracellular dynamics of mammalian period proteins by casein kinase I ɛ (CKIɛ) and CKIδ in cultured cells. Mol. Cell. Biol. 22, 1693–1703 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Miyazaki, K. et al. Phosphorylation of clock protein PER1 regulates its circadian degradation in normal human fibroblasts. Biochem. J. 380, 95–103 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Isojima, Y. et al. CKIɛ/δ-dependent phosphorylation is a temperature-insensitive, period-determining process in the mammalian circadian clock. Proc. Natl. Acad. Sci. USA 106, 15744–15749 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chen, Z. et al. Identification of diverse modulators of central and peripheral circadian clocks by high-throughput chemical screening. Proc. Natl. Acad. Sci. USA 109, 101–106 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. Tsuchiya, Y. et al. Involvement of the protein kinase CK2 in the regulation of mammalian circadian rhythms. Sci. Signal. 2, ra26 (2009).

    Article  PubMed  Google Scholar 

  21. Hirota, T. et al. High-throughput chemical screen identifies a novel potent modulator of cellular circadian rhythms and reveals CKIα as a clock regulatory kinase. PLoS Biol. 8, e1000559 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kloss, B. et al. The Drosophila clock gene double-time encodes a protein closely related to human casein kinase Iɛ. Cell 94, 97–107 (1998).

    Article  CAS  PubMed  Google Scholar 

  23. 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 

  24. Lowrey, P.L. et al. Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. Science 288, 483–492 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gallego, M., Eide, E.J., Woolf, M.F., Virshup, D.M. & Forger, D.B. An opposite role for tau in circadian rhythms revealed by mathematical modeling. Proc. Natl. Acad. Sci. USA 103, 10618–10623 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Meng, Q.-J. et al. Setting clock speed in mammals: the CK1ɛ tau mutation in mice accelerates circadian pacemakers by selectively destabilizing PERIOD proteins. Neuron 58, 78–88 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Etchegaray, J.P. et al. Casein kinase 1 delta regulates the pace of the mammalian circadian clock. Mol. Cell. Biol. 29, 3853–3866 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Shirogane, T., Jin, J., Ang, X.L. & Harper, J.W. SCFβ-TRCP controls clock-dependent transcription via casein kinase 1-dependent degradation of the mammalian period-1 (Per1) protein. J. Biol. Chem. 280, 26863–26872 (2005).

    Article  CAS  PubMed  Google Scholar 

  29. Reischl, S. et al. β-TrCP1-mediated degradation of PERIOD2 is essential for circadian dynamics. J. Biol. Rhythms 22, 375–386 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Ohsaki, K. et al. The role of β-TrCP1 and β-TrCP2 in circadian rhythm generation by mediating degradation of clock protein PER2. J. Biochem. 144, 609–618 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Militi, S. et al. Early doors (Edo) mutant mouse reveals the importance of period 2 (PER2) PAS domain structure for circadian pacemaking. Proc. Natl. Acad. Sci. USA 113, 2756–2761 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Xu, Y. et al. Functional consequences of a CKIδ mutation causing familial advanced sleep phase syndrome. Nature 434, 640–644 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Zhang, L. et al. A PERIOD3 variant causes a circadian phenotype and is associated with a seasonal mood trait. Proc. Natl. Acad. Sci. USA 113, E1536–E1544 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Hirano, A. et al. A Cryptochrome 2 mutation yields advanced sleep phase in humans. eLife 5, e16695 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Jones, C.R. et al. Familial advanced sleep-phase syndrome: a short-period circadian rhythm variant in humans. Nat. Med. 5, 1062–1065 (1999).

    Article  CAS  PubMed  Google Scholar 

  36. Brennan, K.C. et al. Casein kinase iδ mutations in familial migraine and advanced sleep phase. Sci. Transl. Med. 5, 183ra56, 1–11 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Liu, Z. et al. PER1 phosphorylation specifies feeding rhythm in mice. Cell Rep. 7, 1509–1520 (2014).

    Article  CAS  PubMed  Google Scholar 

  38. Vanselow, K. et al. Differential effects of PER2 phosphorylation: molecular basis for the human familial advanced sleep phase syndrome (FASPS). Genes Dev. 20, 2660–2672 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Shanware, N.P. et al. Casein kinase 1-dependent phosphorylation of familial advanced sleep phase syndrome-associated residues controls PERIOD 2 stability. J. Biol. Chem. 286, 12766–12774 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zhou, M., Kim, J.K., Eng, G.W.L., Forger, D.B. & Virshup, D.M.A. A Period2 phosphoswitch regulates and temperature compensates circadian period. Mol. Cell 60, 77–88 (2015).Switching of PER2 phosphorylation at FASP sites (for stabilization) and the β-TrCP phosphodegron (for degradation) is dependent on temperature and thus plays an important role in temperature compensation.

    Article  PubMed  CAS  Google Scholar 

  41. 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 ɛ. Mol. Cell. Biol. 20, 4888–4899 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Vielhaber, E.L., Duricka, D., Ullman, K.S. & Virshup, D.M. Nuclear export of mammalian PERIOD proteins. J. Biol. Chem. 276, 45921–45927 (2001).

    Article  CAS  PubMed  Google Scholar 

  43. Takano, A. et al. Cloning and characterization of rat casein kinase 1ɛ. FEBS Lett. 477, 106–112 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Takano, A., Isojima, Y. & Nagai, K. Identification of mPer1 phosphorylation sites responsible for the nuclear entry. J. Biol. Chem. 279, 32578–32585 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Jakubcakova, V. et al. Light entrainment of the mammalian circadian clock by a PRKCA-dependent posttranslational mechanism. Neuron 54, 831–843 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Mehta, N. et al. GRK2 fine-tunes circadian clock speed and entrainment via transcriptional and post-translational control of PERIOD proteins. Cell Rep. 12, 1272–1288 (2015).

    Article  CAS  PubMed  Google Scholar 

  47. Sakakida, Y. et al. Importin α/β mediates nuclear transport of a mammalian circadian clock component, mCRY2, together with mPER2, through a bipartite nuclear localization signal. J. Biol. Chem. 280, 13272–13278 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Chaves, I. et al. Functional evolution of the photolyase/cryptochrome protein family: importance of the C terminus of mammalian CRY1 for circadian core oscillator performance. Mol. Cell. Biol. 26, 1743–1753 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Miyazaki, K., Mesaki, M. & Ishida, N. Nuclear entry mechanism of rat PER2 (rPER2): role of rPER2 in nuclear localization of CRY protein. Mol. Cell. Biol. 21, 6651–6659 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Yagita, K. et al. Dimerization and nuclear entry of mPER proteins in mammalian cells. Genes Dev. 14, 1353–1363 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lee, H.-M. et al. The period of the circadian oscillator is primarily determined by the balance between casein kinase 1 and protein phosphatase 1. Proc. Natl. Acad. Sci. USA 108, 16451–16456 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Gallego, M., Kang, H. & Virshup, D.M. Protein phosphatase 1 regulates the stability of the circadian protein PER2. Biochem. J. 399, 169–175 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Schmutz, I. et al. Protein phosphatase 1 (PP1) is a post-translational regulator of the mammalian circadian clock. PLoS One 6, e21325 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Partch, C.L. & Sancar, A. Cryptochromes and circadian photoreception in animals. Methods Enzymol. 393, 726–745 (2005).

    Article  CAS  PubMed  Google Scholar 

  55. Scoma, H.D. et al. The de-ubiquitinylating enzyme, USP2, is associated with the circadian clockwork and regulates its sensitivity to light. PLoS One 6, e25382 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Tong, X., Buelow, K., Guha, A., Rausch, R. & Yin, L. USP2a protein deubiquitinates and stabilizes the circadian protein CRY1 in response to inflammatory signals. J. Biol. Chem. 287, 25280–25291 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Yang, Y. et al. Regulation of behavioral circadian rhythms and clock protein PER1 by the deubiquitinating enzyme USP2. Biol. Open 1, 789–801 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Asher, G. et al. SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell 134, 317–328 (2008).

    Article  CAS  PubMed  Google Scholar 

  59. Nakahata, Y. et al. The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell 134, 329–340 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 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).

    Article  CAS  PubMed  Google Scholar 

  61. Godinho, S.I.H. et al. The after-hours mutant reveals a role for Fbxl3 in determining mammalian circadian period. Science 316, 897–900 (2007). ENU mutagenesis screening identifies an Fbxl3 point mutation that causes an extremely long circadian period, thus indicating that Fbxl3 is a circadian gene.

    Article  CAS  PubMed  Google Scholar 

  62. Siepka, S.M. et al. Circadian mutant Overtime reveals F-box protein FBXL3 regulation of Cryptochrome and Period gene expression. Cell 129, 1011–1023 (2007). ENU mutagenesis screening shows that Fbxl3 is a circadian gene by identifying a novel variant, as in ref. 59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Busino, L. et al. SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins. Science 316, 900–904 (2007). FBXL3 is shown to be responsible for CRY ubiquitination and proteasomal degradation, and to strongly affect the circadian clock.

    Article  CAS  PubMed  Google Scholar 

  64. Yoo, S.-H. et al. Competing E3 ubiquitin ligases govern circadian periodicity by degradation of CRY in nucleus and cytoplasm. Cell 152, 1091–1105 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Hirano, A. et al. FBXL21 regulates oscillation of the circadian clock through ubiquitination and stabilization of cryptochromes. Cell 152, 1106–1118 (2013).

    Article  CAS  PubMed  Google Scholar 

  66. Dardente, H., Mendoza, J., Fustin, J.-M., Challet, E. & Hazlerigg, D.G. Implication of the F-Box Protein FBXL21 in circadian pacemaker function in mammals. PLoS One 3, e3530 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Tong, X. et al. CUL4-DDB1-CDT2 E3 ligase regulates the molecular clock activity by promoting ubiquitination-dependent degradation of the mammalian CRY1. PLoS One 10, e0139725 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Fang, L. et al. Circadian clock gene CRY2 degradation is involved in chemoresistance of colorectal cancer. Mol. Cancer Ther. 14, 1476–1487 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Lamia, K.A. et al. AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science 326, 437–440 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Kurabayashi, N., Hirota, T., Sakai, M., Sanada, K. & Fukada, Y. DYRK1A and glycogen synthase kinase 3β, a dual-kinase mechanism directing proteasomal degradation of CRY2 for circadian timekeeping. Mol. Cell. Biol. 30, 1757–1768 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Harada, Y., Sakai, M., Kurabayashi, N., Hirota, T. & Fukada, Y. Ser-557-phosphorylated mCRY2 is degraded upon synergistic phosphorylation by glycogen synthase kinase-3β. J. Biol. Chem. 280, 31714–31721 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Hirano, A. et al. In vivo role of phosphorylation of cryptochrome 2 in the mouse circadian clock. Mol. Cell. Biol. 34, 4464–4473 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Gao, P. et al. Phosphorylation of the cryptochrome 1 C-terminal tail regulates circadian period length. J. Biol. Chem. 288, 35277–35286 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Papp, S.J. et al. DNA damage shifts circadian clock time via Hausp-dependent Cry1 stabilization. eLife 4 (2015).

  75. Hirano, A. et al. USP7 and TDP-43: pleiotropic regulation of cryptochrome protein stability paces the oscillation of the mammalian circadian clock. PLoS One 11, e0154263 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Xing, W. et al. SCF(FBXL3) ubiquitin ligase targets cryptochromes at their cofactor pocket. Nature 496, 64–68 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Hirota, T. et al. Identification of small molecule activators of cryptochrome. Science 337, 1094–1097 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Yagita, K. et al. Nucleocytoplasmic shuttling and mCRY-dependent inhibition of ubiquitylation of the mPER2 clock protein. EMBO J. 21, 1301–1314 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Czarna, A. et al. Structures of Drosophila cryptochrome and mouse cryptochrome1 provide insight into circadian function. Cell 153, 1394–1405 (2013).

    Article  CAS  PubMed  Google Scholar 

  80. Schmalen, I. et al. Interaction of circadian clock proteins CRY1 and PER2 is modulated by zinc binding and disulfide bond formation. Cell 157, 1203–1215 (2014).

    Article  CAS  PubMed  Google Scholar 

  81. Yoshitane, H. et al. Roles of CLOCK phosphorylation in suppression of E-box-dependent transcription. Mol. Cell. Biol. 29, 3675–3686 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Stratmann, M., Suter, D.M., Molina, N., Naef, F. & Schibler, U. Circadian Dbp transcription relies on highly dynamic BMAL1-CLOCK interaction with E boxes and requires the proteasome. Mol. Cell 48, 277–287 (2012). Visualization of the dynamics of binding of BMAL1 and CLOCK to the E-box of the Dbp promoter in vitro reveals that proteasome-mediated degradation of BMAL1–CLOCK increases the dynamics and transactivation of E-box mediated transcription.

    Article  CAS  PubMed  Google Scholar 

  83. Reid, G. et al. Cyclic, proteasome-mediated turnover of unliganded and liganded ERα on responsive promoters is an integral feature of estrogen signaling. Mol. Cell 11, 695–707 (2003).

    Article  CAS  PubMed  Google Scholar 

  84. 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 

  85. 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 

  86. Gekakis, N. et al. Role of the CLOCK protein in the mammalian circadian mechanism. Science 280, 1564–1569 (1998).

    Article  CAS  PubMed  Google Scholar 

  87. Spengler, M.L., Kuropatwinski, K.K., Schumer, M. & Antoch, M.P. A serine cluster mediates BMAL1-dependent CLOCK phosphorylation and degradation. Cell Cycle 8, 4138–4146 (2009).

    Article  CAS  PubMed  Google Scholar 

  88. Sahar, S., Zocchi, L., Kinoshita, C., Borrelli, E. & Sassone-Corsi, P. Regulation of BMAL1 protein stability and circadian function by GSK3β-mediated phosphorylation. PLoS One 5, e8561 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Kwak, Y. et al. Cyclin-dependent kinase 5 (Cdk5) regulates the function of CLOCK protein by direct phosphorylation. J. Biol. Chem. 288, 36878–36889 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Zhang, L. et al. PKCγ participates in food entrainment by regulating BMAL1. Proc. Natl. Acad. Sci. USA 109, 20679–20684 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Lee, J. et al. Dual modification of BMAL1 by SUMO2/3 and ubiquitin promotes circadian activation of the CLOCK/BMAL1 complex. Mol. Cell. Biol. 28, 6056–6065 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Cardone, L. et al. Circadian clock control by SUMOylation of BMAL1. Science 309, 1390–1394 (2005).

    Article  CAS  PubMed  Google Scholar 

  93. Li, S. et al. CLOCK is a substrate of SUMO and sumoylation of CLOCK upregulates the transcriptional activity of estrogen receptor-α. Oncogene 32, 4883–4891 (2013).

    Article  CAS  PubMed  Google Scholar 

  94. Li, M.-D. et al. O-GlcNAc signaling entrains the circadian clock by inhibiting BMAL1/CLOCK ubiquitination. Cell Metab. 17, 303–310 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Gossan, N.C. et al. The E3 ubiquitin ligase UBE3A is an integral component of the molecular circadian clock through regulating the BMAL1 transcription factor. Nucleic Acids Res. 42, 5765–5775 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Doi, M., Hirayama, J. & Sassone-Corsi, P. Circadian regulator CLOCK is a histone acetyltransferase. Cell 125, 497–508 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. Hirayama, J. et al. CLOCK-mediated acetylation of BMAL1 controls circadian function. Nature 450, 1086–1090 (2007).

    Article  CAS  PubMed  Google Scholar 

  98. Tamaru, T. et al. CRY drives cyclic CK2-mediated BMAL1 phosphorylation to control the mammalian circadian clock. PLoS Biol. 13, e1002293 (2015). Sequential modification of BMAL1 is found to be mediated by CKII and CRY, and to be critical for activation and inactivation of the BMAL1–CLOCK heterodimer.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Tamaru, T. et al. CK2α phosphorylates BMAL1 to regulate the mammalian clock. Nat. Struct. Mol. Biol. 16, 446–448 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Padmanabhan, K., Robles, M.S., Westerling, T. & Weitz, C.J. Feedback regulation of transcriptional termination by the mammalian circadian clock PERIOD complex. Science 337, 599–602 (2012).

    Article  CAS  PubMed  Google Scholar 

  101. Matsumura, R. et al. The mammalian circadian clock protein period counteracts cryptochrome in phosphorylation dynamics of circadian locomotor output cycles kaput (CLOCK). J. Biol. Chem. 289, 32064–32072 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Dardente, H., Fortier, E.E., Martineau, V. & Cermakian, N. Cryptochromes impair phosphorylation of transcriptional activators in the clock: a general mechanism for circadian repression. Biochem. J. 402, 525–536 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Partch, C.L., Shields, K.F., Thompson, C.L., Selby, C.P. & Sancar, A. Posttranslational regulation of the mammalian circadian clock by cryptochrome and protein phosphatase 5. Proc. Natl. Acad. Sci. USA 103, 10467–10472 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Eide, E.J., Vielhaber, E.L., Hinz, W.A. & Virshup, D.M. The circadian regulatory proteins BMAL1 and cryptochromes are substrates of casein kinase Iɛ. J. Biol. Chem. 277, 17248–17254 (2002).

    Article  CAS  PubMed  Google Scholar 

  105. Koike, N. et al. Transcriptional architecture and chromatin landscape of the core circadian clock in mammals. Science 338, 349–354 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Katada, S. & Sassone-Corsi, P. The histone methyltransferase MLL1 permits the oscillation of circadian gene expression. Nat. Struct. Mol. Biol. 17, 1414–1421 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Duong, H.A. & Weitz, C.J. Temporal orchestration of repressive chromatin modifiers by circadian clock Period complexes. Nat. Struct. Mol. Biol. 21, 126–132 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. DiTacchio, L. et al. Histone lysine demethylase JARID1a activates CLOCK-BMAL1 and influences the circadian clock. Science 333, 1881–1885 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Kwon, I. et al. BMAL1 shuttling controls transactivation and degradation of the CLOCK/BMAL1 heterodimer. Mol. Cell. Biol. 26, 7318–7330 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Kondratov, R.V. et al. BMAL1-dependent circadian oscillation of nuclear CLOCK: posttranslational events induced by dimerization of transcriptional activators of the mammalian clock system. Genes Dev. 17, 1921–1932 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Yoshitane, H. et al. CLOCK-controlled polyphonic regulation of circadian rhythms through canonical and noncanonical E-boxes. Mol. Cell. Biol. 34, 1776–1787 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Ripperger, J.A. & Schibler, U. Rhythmic CLOCK-BMAL1 binding to multiple E-box motifs drives circadian Dbp transcription and chromatin transitions. Nat. Genet. 38, 369–374 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. Rey, G. et al. Genome-wide and phase-specific DNA-binding rhythms of BMAL1 control circadian output functions in mouse liver. PLoS Biol. 9, e1000595 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Huang, N. et al. Crystal structure of the heterodimeric CLOCK:BMAL1 transcriptional activator complex. Science 337, 189–194 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Robles, M.S., Boyault, C., Knutti, D., Padmanabhan, K. & Weitz, C.J. Identification of RACK1 and protein kinase Cα as integral components of the mammalian circadian clock. Science 327, 463–466 (2010).

    Article  CAS  PubMed  Google Scholar 

  116. Zhao, X. et al. Circadian amplitude regulation via FBXW7-targeted REV-ERBα degradation. Cell 165, 1644–1657 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Yin, L., Wang, J., Klein, P.S. & Lazar, M.A. Nuclear receptor Rev-erbα is a critical lithium-sensitive component of the circadian clock. Science 311, 1002–1005 (2006).

    Article  CAS  PubMed  Google Scholar 

  118. Yin, L., Joshi, S., Wu, N., Tong, X. & Lazar, M.A. E3 ligases Arf-bp1 and Pam mediate lithium-stimulated degradation of the circadian heme receptor Rev-erb alpha. Proc. Natl. Acad. Sci. USA 107, 11614–11619 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Shi, G. et al. Dual roles of FBXL3 in the mammalian circadian feedback loops are important for period determination and robustness of the clock. Proc. Natl. Acad. Sci. USA 110, 4750–4755 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was funded by NIH grants GM079180 and HL059596 to L.J.P. and Y-H.F. and by the William Bowes Neurogenetics Fund. L.J.P. is supported an investigator of the Howard Hughes Medical Institute. A.H. was supported by the Uehara memorial foundation (Japan). We thank S. Guangsen for critical comments on this manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Louis J Ptáček.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hirano, A., Fu, YH. & Ptáček, L. The intricate dance of post-translational modifications in the rhythm of life. Nat Struct Mol Biol 23, 1053–1060 (2016). https://doi.org/10.1038/nsmb.3326

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nsmb.3326

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