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Molecular modulators of the circadian clock: lessons from flies and mice

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Abstract

Circadian timekeeping is a ubiquitous mechanism that enables organisms to maintain temporal coordination between internal biological processes and time of the local environment. The molecular basis of circadian rhythms lies in a set of transcription–translation feedback loops (TTFLs) that drives the rhythmic transcription of core clock genes, whose level and phase of expression serve as the marker of circadian time. However, it has become increasingly evident that additional regulatory mechanisms impinge upon the TTFLs to govern the properties and behavior of the circadian clock. Such mechanisms include changes in chromatin architecture, interactions with other transcription factor networks, post-transcriptional control by RNA modifications, alternative splicing and microRNAs, and post-translational regulation of subcellular trafficking and protein degradation. In this review, we will summarize the current knowledge of circadian clock regulation—from transcriptional to post-translational—drawing from literature pertaining to the Drosophila and murine circadian systems.

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References

  1. Abrahamson EE, Moore RY (2001) Suprachiasmatic nucleus in the mouse: retinal innervation, intrinsic organization and efferent projections. Brain Res 916:172–191. doi:10.1016/S0006-8993(01)02890-6

    Article  CAS  PubMed  Google Scholar 

  2. Maywood ES, Chesham JE, O’Brien JA, Hastings MH (2011) A diversity of paracrine signals sustains molecular circadian cycling in suprachiasmatic nucleus circuits. Proc Natl Acad Sci USA 108:14306–14311. doi:10.1073/pnas.1101767108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Nitabach MN, Taghert PH (2008) Organization of the Drosophila circadian control circuit. Curr Biol 18:R84–R93. doi:10.1016/j.cub.2007.11.061

    Article  CAS  PubMed  Google Scholar 

  4. Renn SC, Park JH, Rosbash M, Hall JC, Taghert PH (1999) A pdf neuropeptide gene mutation and ablation of PDF neurons each cause severe abnormalities of behavioral circadian rhythms in Drosophila. Cell 99:791–802. doi:10.1016/S0092-8674(00)81676-1

    Article  CAS  PubMed  Google Scholar 

  5. Lin Y, Stormo GD, Taghert PH (2004) The neuropeptide pigment-dispersing factor coordinates pacemaker interactions in the Drosophila circadian system. J Neurosci 24:7951–7957. doi:10.1523/JNEUROSCI.2370-04.2004

    Article  CAS  PubMed  Google Scholar 

  6. Hall JC (2003) Genetics and molecular biology of rhythms in Drosophila and other insects. Adv Genet 48:1–280. doi:10.1016/S0065-2660(03)48000-0

    CAS  PubMed  Google Scholar 

  7. Ashmore LJ, Sehgal A (2003) A fly’s eye view of circadian entrainment. J Biol Rhythms 18:206–216. doi:10.1177/0748730403253385

    Article  PubMed  Google Scholar 

  8. Helfrich-Förster C, Winter C, Hofbauer A, Hall JC, Stanewsky R (2001) The circadian clock of fruit flies is blind after elimination of all known photoreceptors. Neuron 30:249–261. doi:10.1016/S0896-6273(01)00277-X

    Article  PubMed  Google Scholar 

  9. Emery P, So WV, Kaneko M, Hall JC, Rosbash M (1998) CRY, a Drosophila clock and light-regulated cryptochrome, is a major contributor to circadian rhythm resetting and photosensitivity. Cell 95:669–679. doi:10.1016/S0092-8674(00)81637-2

    Article  CAS  PubMed  Google Scholar 

  10. Schibler U, Gotic I, Saini C, Gos P, Curie T, Emmenegger Y, Sinturel F, Gosselin P, Gerber A, Fleury-Olela F, Rando G, Demarque M, Franken P (2015) Clock-talk: interactions between central and peripheral circadian oscillators in mammals. Cold Spring Harb Sym 80:223–232. doi:10.1101/sqb.2015.80.027490

    Article  Google Scholar 

  11. Poletini MO, Moraes MN, Ramos BC, Jerônimo R, Castrucci AM (2015) TRP channels: a missing bond in the entrainment mechanism of peripheral clocks throughout evolution. Temperature 2:522–534. doi:10.1080/23328940.2015.1115803

    Article  Google Scholar 

  12. Tahara Y, Aoyama S, Shibata S (2016) The mammalian circadian clock and its entrainment by stress and exercise. J Physiol Sci. doi:10.1007/s12576-016-0450-7

    PubMed  PubMed Central  Google Scholar 

  13. Mehta N, Cheng H-YM (2013) Micro-managing the circadian clock: the role of microRNAs in biological timekeeping. J Mol Biol 425:3609–3624. doi:10.1016/j.jmb.2012.10.022

    Article  CAS  PubMed  Google Scholar 

  14. Lowrey PL, Takahashi JS (2011) Genetics of circadian rhythms in mammalian model organisms. Adv Genet 74:175–230. doi:10.1016/B978-0-12-387690-4.00006-4

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Landgraf D, Wang LL, Diemer T, Welsh DK (2016) NPAS2 compensates for loss of CLOCK in peripheral circadian oscillators. PLoS Genet 12:e1005882. doi:10.1371/journal.pgen.1005882

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Koike N, Yoo SH, Huang HC, Kumar V, Lee C, Kim TK, Takahashi JS (2012) Transcriptional architecture and chromatin landscape of the core circadian clock in mammals. Science 338:349–354. doi:10.1126/science.1226339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ye R, Selby CP, Chiou YY, Ozkan-Dagliyan I, Gaddameedhi S, Sancar A (2014) Dual modes of CLOCK:BMAL1 inhibition mediated by Cryptochrome and Period proteins in the mammalian circadian clock. Gene Dev 28:1989–1998. doi:10.1101/gad.249417.114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hardin PE (2011) Molecular genetic analysis of circadian timekeeping in Drosophila. Adv Genet 74:141–173. doi:10.1016/B978-0-12-387690-4.00005-2

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Kadener S, Stoleru D, McDonald M, Nawathean P, Rosbash M (2007) Clockwork Orange is a transcriptional repressor and a new Drosophila circadian pacemaker component. Gene Dev 21:1675–1686. doi:10.1101/gad.1552607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Matsumoto A, Ukai-Tadenuma M, Yamada RG, Houl J, Uno KD, Kasukawa T, Dauwalder B, Itoh TQ, Takahashi K, Ueda R, Hardin PE, Tanimura T, Ueda HR (2007) A functional genomics strategy reveals clockwork orange as a transcriptional regulator in the Drosophila circadian clock. Gene Dev 21:1687–1700. doi:10.1101/gad.1552207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Roenneberg T, Merrow M (2016) The circadian clock and human health. Curr Biol 26:R432–R443. doi:10.1016/j.cub.2016.04.011

    Article  CAS  PubMed  Google Scholar 

  22. García-González E, Escamilla-Del-Arenal M, Arzate-Mejía R, Recillas-Targa F (2016) Chromatin remodeling effects on enhancer activity. Cell Mol Life Sci 73:2897–2910. doi:10.1007/s00018-016-2184-3

    Article  PubMed  CAS  Google Scholar 

  23. Groth A, Rocha W, Verreault A, Almouzni G (2007) Chromatin challenges during DNA replication and repair. Cell 128:721–733. doi:10.1016/j.cell.2007.01.030

    Article  CAS  PubMed  Google Scholar 

  24. Bannister AJ, Kouzarides T (2011) Regulation of chromatin by histone modifications. Cell Res 21:381–395. doi:10.1038/cr.2011.22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Shahbazian MD, Grunstein M (2007) Functions of site-specific histone acetylation and deacetylation. Annu Rev Biochem 76:75–100. doi:10.1146/annurev.biochem.76.052705.162114

    Article  CAS  PubMed  Google Scholar 

  26. Schmitt A, Gutierrez GJ, Lénárt P, Ellenberg J, Nebreda AR (2002) Histone H3 phosphorylation during Xenopus oocyte maturation: regulation by the MAP kinase/p90Rsk pathway and uncoupling from DNA condensation. FEBS Lett 518:23–28. doi:10.1016/S0014-5793(02)02630-3

    Article  CAS  PubMed  Google Scholar 

  27. Dong Z, Bode AM (2006) The role of histone H3 phosphorylation (Ser10 and Ser28) in cell growth and cell transformation. Mol Carcinog 45:416–421. doi:10.1002/mc.20220

    Article  CAS  PubMed  Google Scholar 

  28. Pal S, Sif S (2007) Interplay between chromatin remodelers and protein arginine methyltransferases. J Cell Physiol 213:306–315. doi:10.1002/jcp.21180

    Article  CAS  PubMed  Google Scholar 

  29. Kouzarides T (2007) Chromatin modifications and their function. Cell 128:693–705. doi:10.1016/j.cell.2007.02.005

    Article  CAS  PubMed  Google Scholar 

  30. Crosio C, Cermakian N, Allis CD, Sassone-Corsi P (2000) Light induces chromatin modification in cells of the mammalian circadian clock. Nat Neurosci 3:1241–1247. doi:10.1038/81767

    Article  CAS  PubMed  Google Scholar 

  31. Ripperger JA, Schibler U (2006) Rhythmic CLOCK-BMAL1 binding to multiple E-box motifs drives circadian Dbp transcription and chromatin transitions. Nat Genet 38:369–374. doi:10.1038/ng1738

    Article  CAS  PubMed  Google Scholar 

  32. Etchegaray JP, Yang X, DeBruyne JP, Peters AH, Weaver DR, Jenuwein T, Reppert SM (2006) The polycomb group protein EZH2 is required for mammalian circadian clock function. J Biol Chem 281:21209–21215. doi:10.1074/jbc.M603722200

    Article  CAS  PubMed  Google Scholar 

  33. Sun Z, Feng D, Everett LJ, Bugge A, Lazar MA (2011) Circadian epigenomic remodeling and hepatic lipogenesis: lessons from HDAC3. Cold Spring Harb Sym 76:49. doi:10.1101/sqb.2011.76.011494

    Article  CAS  Google Scholar 

  34. Azzi A, Dallmann R, Casserly A, Rehrauer H, Patrignani A, Maier B, Kramer A, Brown SA (2014) Circadian behavior is light-reprogrammed by plastic DNA methylation. Nat Neurosci 17:377–382. doi:10.1038/nn.3651

    Article  CAS  PubMed  Google Scholar 

  35. Menet JS, Pescatore S, Rosbash M (2014) CLOCK:BMAL1 is a pioneer-like transcription factor. Gene Dev 28:8–13. doi:10.1101/gad.228536.113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Etchegaray J, Lee C, Wade PA, Reppert SM (2003) Rhythmic histone acetylation underlies transcription in the mammalian circadian clock. Nature 421:177–182. doi:10.1038/nature01314

    Article  CAS  PubMed  Google Scholar 

  37. Curtis AM, Seo SP, Westgate EJ, Rudic RD, Smyth EM, Chakravarti D, FitzGerald GA, McNamara P (2004) Histone acetyltransferase-dependent chromatin remodeling and the vascular clock. J Biol Chem 279:7091–7097. doi:10.1074/jbc.M311973200

    Article  CAS  PubMed  Google Scholar 

  38. Cho H, Orphanides G, Sun X, Yang XJ, Ogryzko V, Lees E, Nakatani Y, Reinberg D (1998) A human RNA polymerase II complex containing factors that modify chromatin structure. Mol Cell Biol 18:5355–5363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Doi M, Hirayama J, Sassone-Corsi P (2006) Circadian regulator CLOCK is a histone acetyltransferase. Cell 125:497–508. doi:10.1016/j.cell.2006.03.033

    Article  CAS  PubMed  Google Scholar 

  40. Yamamoto T, Horikoshi M (1997) Novel substrate specificity of the histone acetyltransferase activity of HIV-1-Tat interactive protein Tip60. J Biol Chem 272:30595–30598. doi:10.1074/jbc.272.49.30595

    Article  CAS  PubMed  Google Scholar 

  41. Hirayama J, Sahar S, Grimaldi B, Tamaru T, Takamatsu K, Nakahata Y, Sassone-Corsi P (2007) CLOCK-mediated acetylation of BMAL1 controls circadian function. Nature 450:1086–1090. doi:10.1038/nature06394

    Article  CAS  PubMed  Google Scholar 

  42. DiTacchio L, Le HD, Vollmers C, Hatori M, Witcher M, Secombe J, Panda S (2011) Histone lysine demethylase JARID1a activates CLOCK-BMAL1 and influences the circadian clock. Science 333:1881–1885. doi:10.1126/science.1206022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Katada S, Sassone-Corsi P (2010) The histone methyltransferase MLL1 permits the oscillation of circadian gene expression. Nat Struct Mol Biol 17:1414–1421. doi:10.1038/nsmb.1961

    Article  CAS  PubMed  Google Scholar 

  44. Valekunja UK, Edgar RS, Oklejewicz M, van der Horst GTJ, O’Neill JS, Tamanini F, Turner DJ, Reddy AB (2013) Histone methyltransferase MLL3 contributes to genome-scale circadian transcription. Proc Natl Acad Sci USA 110:1554–1559. doi:10.1073/pnas.1214168110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Duong HA, Robles MS, Knutti D, Weitz CJ (2011) A molecular mechanism for circadian clock negative feedback. Science 332:1436–1439. doi:10.1126/science.1196766

    Article  CAS  PubMed  Google Scholar 

  46. Naruse Y, Oh-hashi K, Iijima N, Naruse M, Yoshioka H, Tanaka M (2004) Circadian and light-induced transcription of clock gene Per1 depends on histone acetylation and deacetylation. Mol Cell Biol 24:6278–6287. doi:10.1128/MCB.24.14.6278-6287.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Duong HA, Weitz CJ (2014) Temporal orchestration of repressive chromatin modifiers by circadian clock PERIOD complexes. Nat Struct Mol Biol 21:126–132. doi:10.1038/nsmb.2746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Brown SA, Ripperger J, Kadener S, Fleury-Olela F, Vilbois F, Rosbash M, Schibler U (2005) PERIOD1-associated proteins modulate the negative limb of the mammalian circadian oscillator. Science 308:693–696. doi:10.1126/science.1107373

    Article  CAS  PubMed  Google Scholar 

  49. Kim JY, Kwak PB, Weitz CJ (2014) Specificity in circadian clock feedback from targeted reconstitution of the NuRD corepressor. Mol Cell 56:738–748. doi:10.1016/j.molcel.2014.10.017

    Article  CAS  PubMed  Google Scholar 

  50. Nakahata Y, Kaluzova M, Grimaldi B, Sahar S, Hirayama J, Chen D, Guarente LP, Sassone-Corsi P (2008) The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell 134:329–340. doi:10.1016/j.cell.2008.07.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Asher G, Gatfield D, Stratmann M, Reinke H, Dibner C, Kreppel F, Mostoslavsky R, Alt FW, Schibler U (2008) SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell 134:317–328. doi:10.1016/j.cell.2008.06.050

    Article  CAS  PubMed  Google Scholar 

  52. Aguilar-Arnal L, Katada S, Orozco-Solis R, Sassone-Corsi P (2015) NAD+-SIRT1 control of H3K4 trimethylation through circadian deacetylation of MLL1. Nat Struct Mol Biol 22:312–318. doi:10.1038/nsmb.2990

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Nakahata Y, Sahar S, Astarita G, Kaluzova M, Sassone-Corsi P (2009) Circadian control of the NAD+ salvage pathway by CLOCK-SIRT1. Science 324:654–657. doi:10.1126/science.1170803

    Article  CAS  PubMed  Google Scholar 

  54. Masri S, Rigor P, Cervantes M, Ceglia N, Sebastian C, Xiao C, Roqueta-Rivera M, Deng C, Osborne TF, Mostoslavsky R, Baldi P, Sassone-Corsi P (2014) Partitioning circadian transcription by SIRT6 leads to segregated control of cellular metabolism. Cell 158:659–672. doi:10.1016/j.cell.2014.06.050

    Article  CAS  PubMed  Google Scholar 

  55. Ginty DD, Kornhauser JM, Thompson MA, Bading H, Mayo KE, Takahashi JS, Greenberg ME (1993) Regulation of CREB phosphorylation in the suprachiasmatic nucleus by light and a circadian clock. Science 260:238–241. doi:10.1126/science.8097062

    Article  CAS  PubMed  Google Scholar 

  56. Travnickova-Bendova Z, Cermakian N, Reppert SM, Sassone-Corsi P (2002) Bimodal regulation of mPeriod promoters by CREB-dependent signaling and CLOCK/BMAL1 activity. Proc Natl Acad Sci USA 99:7728–7733. doi:10.1073/pnas.102075599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Tischkau SA, Mitchell JW, Tyan S-H, Buchanan GF, Gillette MU (2003) Ca2+/cAMP response element-binding protein (CREB)-dependent activation of Per1 is required for light-induced signaling in the suprachiasmatic nucleus circadian clock. J Biol Chem 278:718–723. doi:10.1074/jbc.M209241200

    Article  CAS  PubMed  Google Scholar 

  58. Lee B, Li A, Hansen KF, Cao R, Yoon JH, Obrietan K (2010) CREB influences timing and entrainment of the SCN circadian clock. J Biol Rhythms 25:410–420. doi:10.1177/0748730410381229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Sakamoto K, Norona FE, Alzate-Correa D, Scarberry D, Hoyt KR, Obrietan K (2013) Clock and light regulation of the CREB coactivator CRTC1 in the suprachiasmatic circadian clock. J Neurosci 33:9021–9027. doi:10.1523/JNEUROSCI.4202-12.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Jagannath A, Butler R, Godinho SI, Couch Y, Brown LA, Vasudevan SR, Flanagan KC, Anthony D, Churchill GC, Wood MJ, Steiner G, Ebeling M, Hossbach M, Wettstein JG, Duffield GE, Gatti S, Hankins MW, Foster RG, Peirson SN (2013) The CRTC1-SIK1 pathway regulates entrainment of the circadian clock. Cell 154:1100–1111. doi:10.1016/j.cell.2013.08.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Sun X, Dang F, Zhang D, Yuan Y, Zhang C, Wu Y, Wang Y, Liu Y (2015) Glucagon-CREB/CRTC2 signaling cascade regulates hepatic BMAL1 protein. J Biol Chem 290:2189–2197. doi:10.1074/jbc.M114.612358

    Article  CAS  PubMed  Google Scholar 

  62. Koyanagi S, Hamdan AM, Horiguchi M, Kusunose N, Okamoto A, Matsunaga N, Ohdo S (2011) cAMP-response element (CRE)-mediated transcription by activating transcription factor-4 (ATF4) is essential for circadian expression of the Period2 gene. J Biol Chem 286:32416–32423. doi:10.1074/jbc.M111.258970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Tao W, Wu J, Zhang Q, Lai SS, Jiang S, Jiang C, Xu Y, Xue B, Du J, Li CJ (2015) EGR1 regulates hepatic clock gene amplitude by activating Per1 transcription. Sci Rep 5:15212. doi:10.1038/srep15212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Sakamoto KM, Fraser JK, Lee HJ, Lehman E, Gasson JC (1994) Granulocyte-macrophage colony-stimulating factor and interleukin-3 signaling pathways converge on the CREB-binding site in the human egr-1 promoter. Mol Cell Biol 14:5975–5985. doi:10.1128/MCB.14.9.5975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Kilduff TS, Vugrinic C, Lee SL, Milbrandt JD, Mikkelsen JD, O’Hara BF, Heller HC (1998) Characterization of the circadian system of NGFI-A and NGFI-A/NGFI-B deficient mice. J Biol Rhythms 13:347–357. doi:10.1177/074873098129000174

    Article  CAS  PubMed  Google Scholar 

  66. Kim SH, Yu HS, Park HG, Ahn YM, Kim YS, Lee YH, Ha K, Shin SY (2013) Egr1 regulates lithium-induced transcription of the Period 2 (PER2) gene. Biochim Biophys Acta 1832:1969–1979. doi:10.1016/j.bbadis.2013.06.010

    Article  CAS  PubMed  Google Scholar 

  67. Resuehr HE, Resuehr D, Olcese J (2009) Induction of mPer1 expression by GnRH in pituitary gonadotrope cells involves EGR-1. Mol Cell Endocrinol 311:120–125. doi:10.1016/j.mce.2009.07.005

    Article  CAS  PubMed  Google Scholar 

  68. Parsons MJ, Brancaccio M, Sethi S, Maywood ES, Satija R, Edwards JK, Jagannath A, Couch Y, Finelli MJ, Smyllie NJ, Esapa C, Butler R, Barnard AR, Chesham JE, Saito S, Joynson G, Wells S, Foster RG, Oliver PL, Simon MM, Mallon AM, Hastings MH, Nolan PM (2015) The regulatory factor ZFHX3 modifies circadian function in SCN via an AT motif-driven axis. Cell 162:607–621. doi:10.1016/j.cell.2015.06.060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Rossner MJ, Oster H, Wichert SP, Reinecke L, Wehr MC, Reinecke J, Eichele G, Taneja R, Nave KA (2008) Disturbed clockwork resetting in Sharp-1 and Sharp-2 single and double mutant mice. PLoS One 3:e2762. doi:10.1371/journal.pone.0002762

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Honma S, Kawamoto T, Takagi Y, Fujimoto K, Sato F, Noshiro M, Kato Y, Honma KI (2002) Dec1 and Dec2 are regulators of the mammalian molecular clock. Nature 419:841–844. doi:10.1038/nature01123

    Article  CAS  PubMed  Google Scholar 

  71. Kawamoto T, Noshiro M, Sato F, Maemura K, Takeda N, Nagai R, Iwata T, Fujimoto K, Furukawa M, Miyazaki K, Honma S, Honma KI, Kato Y (2004) A novel autofeedback loop of Dec1 transcription involved in circadian rhythm regulation. Biochem Bioph Res Commun 313:117–124. doi:10.1016/j.bbrc.2003.11.099

    Article  CAS  PubMed  Google Scholar 

  72. Li Y, Song X, Ma Y, Liu J, Yang D, Yan B (2004) DNA binding, but not interaction with Bmal1, is responsible for DEC1-mediated transcription regulation of the circadian gene mPer1. Biochem J 382:895–904. doi:10.1042/BJ20040592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Cavadini G, Petrzilka S, Kohler P, Jud C, Tobler I, Birchler T, Fontana A (2007) TNF-alpha suppresses the expression of clock genes by interfering with E-box-mediated transcription. Proc Natl Acad Sci USA 104:12843–12848. doi:10.1073/pnas.0701466104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Bellet MM, Zocchi L, Sassone-Corsi P (2012) The RelB subunit of NFκB acts as a negative regulator of circadian gene expression. Cell Cycle 11:3304–3311. doi:10.4161/cc.21669

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Ohno T, Onishi Y, Ishida N (2007) The negative transcription factor E4BP4 is associated with circadian clock protein PERIOD2. Biochem Bioph Res Commun 354:1010–1015. doi:10.1016/j.bbrc.2007.01.084

    Article  CAS  PubMed  Google Scholar 

  76. Ohno T, Onishi Y, Ishida N (2007) A novel E4BP4 element drives circadian expression of mPeriod2. Nucleic Acids Res 35:648–655. doi:10.1093/nar/gkl868

    Article  CAS  PubMed  Google Scholar 

  77. Tanoue S, Fujimoto K, Myung J, Hatanaka F, Kato Y, Takumi T (2015) DEC2-E4BP4 heterodimer represses the transcriptional enhancer activity of the EE element in the Per2 promoter. Front Neurol 6:166. doi:10.3389/fneur.2015.00166

    Article  PubMed  PubMed Central  Google Scholar 

  78. Mitsui S, Yamaguchi S, Matsuo T, Ishida Y, Okamura H (2001) Antagonistic role of E4BP4 and PAR proteins in the circadian oscillatory mechanism. Genes Dev 15:995–1006. doi:10.1101/gad.873501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Ueda HR, Hayashi S, Chen W, Sano M, Machida M, Shigeyoshi Y, Iino M, Hashimoto S (2005) System-level identification of transcriptional circuits underlying mammalian circadian clocks. Nat Genet 37:187–192. doi:10.1038/ng1504

    Article  CAS  PubMed  Google Scholar 

  80. Miki T, Matsumoto T, Zhao Z, Lee CC (2013) p53 regulates Period2 expression and the circadian clock. Nat Commun 4:2444. doi:10.1038/ncomms3444

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Gotoh T, Vila-Caballer M, Santos CS, Liu J, Yang J, Finkielstein CV (2014) The circadian factor Period 2 modulates p53 stability and transcriptional activity in unstressed cells. Mol Biol Cell 25:3081–3093. doi:10.1091/mbc.E14-05-0993

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Gotoh T, Vila-Caballer M, Liu J, Schiffhauer S, Finkielstein CV (2015) Association of the circadian factor Period 2 to p53 influences p53’s function in DNA-damage signaling. Mol Biol Cell 26:359–372. doi:10.1091/mbc.E14-05-0994

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Jiang W, Zhao S, Jiang X, Zhang E, Hu G, Hu B, Zheng P, Xiao J, Lu Z, Lu Y, Ni J, Chen C, Wang X, Yang L, Wan R (2016) The circadian clock gene Bmal1 acts as a potential anti-oncogene in pancreatic cancer by activating the p53 tumor suppressor pathway. Cancer Lett 371:314–325. doi:10.1016/j.canlet.2015.12.002

    Article  CAS  PubMed  Google Scholar 

  84. Miki T, Xu Z, Chen-Goodspeed M, Liu M, Van Oort-Jansen A, Rea MA, Zhao Z, Lee CC, Chang KS (2012) PML regulates PER2 nuclear localization and circadian function. EMBO J 31:1427–1439. doi:10.1038/emboj.2012.1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Fu L, Pelicano H, Liu J, Huang P, Lee C (2002) The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo. Cell 111:41–50. doi:10.1016/S0092-8674(02)00961-3

    Article  CAS  PubMed  Google Scholar 

  86. Altman BJ, Hsieh AL, Sengupta A, Krishnanaiah SY, Stine ZE, Walton ZE, Gouw AM, Venkataraman A, Li B, Goraksha-Hicks P, Diskin SJ, Bellovin DI, Simon MC, Rathmell JC, Lazar MA, Maris JM, Felsher DW, Hogenesch JB, Weljie AM, Dang CV (2015) MYC disrupts the circadian clock and metabolism in cancer cells. Cell Metab 22:1009–1019. doi:10.1016/j.cmet.2015.09.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Benegiamo G, Brown SA, Panda S (2016) RNA dynamics in the control of circadian rhythm. Adv Exp Med Biol 907:107–122. doi:10.1007/978-3-319-29073-7_5

    Article  PubMed  Google Scholar 

  88. Preußner M, Heyd F (2016) Post-transcriptional control of the mammalian circadian clock: implications for health and disease. Pflug Arch Eur J Phy 468:983–991. doi:10.1007/s00424-016-1820-y

    Article  CAS  Google Scholar 

  89. Chiang CK, Mehta N, Patel A, Zhang P, Ning Z, Mayne J, Sun WYL, Cheng HY, Figeys D (2014) The proteomic landscape of the suprachiasmatic nucleus clock reveals large-scale coordination of key biological processes. PLoS Genet 10:e1004695. doi:10.1371/journal.pgen.1004695

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Mauvoisin D, Wang J, Jouffe C, Martin E, Atger F, Waridel P, Quadroni M, Gachon F, Naef F (2014) Circadian clock-dependent and -independent rhythmic proteomes implement distinct diurnal functions in mouse liver. Proc Natl Acad Sci USA 111:167–172. doi:10.1073/pnas.1314066111

    Article  CAS  PubMed  Google Scholar 

  91. Reddy AB, Karp NA, Maywood ES, Sage EA, Deery M, O’Neill JS, Wong GK, Chesham J, Odell M, Lilley KS, Kyriacou CP, Hastings MH (2006) Circadian orchestration of the hepatic proteome. Curr Biol 16:1107–1115. doi:10.1016/j.cub.2006.04.026

    Article  CAS  PubMed  Google Scholar 

  92. Elkon R, Ugalde AP, Agami R (2013) Alternative cleavage and polyadenylation: extent, regulation and function. Nat Rev Genet 14:496–506. doi:10.1038/nrg3482

    Article  CAS  PubMed  Google Scholar 

  93. Wang Y, Osterbur DL, Megaw PL, Tosini G, Fukuhara C, Green CB, Besharse JC (2001) Rhythmic expression of Nocturnin mRNA in multiple tissues of the mouse. BMC Dev Biol 1:9. doi:10.1186/1471-213X-1-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Kojima S, Gendreau KL, Sher-Chen EL, Gao P, Green CB (2015) Changes in poly(A) tail length dynamics from the loss of the circadian deadenylase Nocturnin. Sci Rep 5:17059. doi:10.1038/srep17059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Robinson BG, Frim DM, Schwartz WJ, Majzoub JA (1988) Vasopressin mRNA in the suprachiasmatic nuclei: daily regulation of polyadenylate tail length. Science 241:342–344. doi:10.1126/science.3388044

    Article  CAS  PubMed  Google Scholar 

  96. Gerstner JR, Vanderheyden WM, LaVaute T, Westmark CJ, Rouhana L, Pack AI, Wickens M, Landry CF (2012) Time of day regulates subcellular trafficking, tripartite synaptic localization, and polyadenylation of the astrocytic Fabp7 mRNA. J Neurosci 32:1383–1394. doi:10.1523/JNEUROSCI.3228-11.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Villalba A, Coll O, Gebauer F (2011) Cytoplasmic polyadenylation and translational control. Curr Opin Genet Dev 21:452–457. doi:10.1016/j.gde.2011.04.006

    Article  CAS  PubMed  Google Scholar 

  98. Kojima S, Sher-Chen EL, Green CB (2012) Circadian control of mRNA polyadenylation dynamics regulates rhythmic protein expression. Genes Dev 26:2724–2736. doi:10.1101/gad.208306.112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Derti A, Garrett-Engele P, Macisaac KD, Stevens RC, Sriram S, Chen R, Rohl CA, Johnson JM, Babak T (2012) A quantitative atlas of polyadenylation in five mammals. Genome Res 22:1173–1183. doi:10.1101/gr.132563.111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Tian B, Hu J, Zhang H, Lutz CS (2005) A large-scale analysis of mRNA polyadenylation of human and mouse genes. Nucleic Acids Res 33:201–212. doi:10.1093/nar/gki158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Di Giammartino DC, Nishida K, Manley JL (2011) Mechanisms and consequences of alternative polyadenylation. Mol Cell 43:853–866. doi:10.1016/j.molcel.2011.08.017

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Lai EC (2002) Micro RNAs are complementary to 3′ UTR sequence motifs that mediate negative post-transcriptional regulation. Nat Genet 30:363–364. doi:10.1038/ng865

    Article  CAS  PubMed  Google Scholar 

  103. Liu Y, Hu W, Murakawa Y, Yin J, Wang G, Landthaler M, Yan J (2013) Cold-induced RNA-binding proteins regulate circadian gene expression by controlling alternative polyadenylation. Sci Rep 3:2054. doi:10.1038/srep02054

    PubMed  PubMed Central  Google Scholar 

  104. Fustin JM, Doi M, Yamaguchi Y, Hida H, Nishimura S, Yoshida M, Isagawa T, Morioka MS, Kakeya H, Manabe I, Okamura H (2013) RNA-methylation-dependent RNA processing controls the speed of the circadian clock. Cell 155:793–806. doi:10.1016/j.cell.2013.10.026

    Article  CAS  PubMed  Google Scholar 

  105. Chen M, Manley JL (2009) Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches. Nat Rev Mol Cell Biol 10:741–754. doi:10.1038/nrm2777

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Majercak J, Chen WF, Edery I (2004) Splicing of the period gene 3′-terminal intron is regulated by light, circadian clock factors, and phospholipase C. Mol Cell Biol 24:3359–3372. doi:10.1128/MCB.24.8.3359-3372.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Low KH, Lim C, Ko HW, Edery I (2008) Natural variation in the splice site strength of a clock gene and species-specific thermal adaptation. Neuron 60:1054–1067. doi:10.1016/j.neuron.2008.10.048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Low KH, Chen WF, Yildirim E, Edery I (2012) Natural variation in the Drosophila melanogaster clock gene period modulates splicing of its 3′-terminal intron and mid-day siesta. PLoS One 7:e49536. doi:10.1371/journal.pone.0049536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Cheng Y, Gvakharia B, Hardin PE (1998) Two alternatively spliced transcripts from the Drosophila period gene rescue rhythms having different molecular and behavioral characteristics. Mol Cell Biol 18:6505–6514. doi:10.1128/MCB.18.11.6505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Majercak J, Sidote D, Hardin PE, Edery I (1999) How a circadian clock adapts to seasonal decreases in temperature and day length. Neuron 24:219–230. doi:10.1016/S0896-6273(00)80834-X

    Article  CAS  PubMed  Google Scholar 

  111. Sanchez SE, Petrillo E, Beckwith EJ, Zhang X, Rugnone ML, Hernando CE, Cuevas JC, Godoy Herz MA, Depetris-Chauvin A, Simpson CG, Brown JW, Cerdán PD, Borevitz JO, Mas P, Ceriani MF, Kornblihtt AR, Yanovsky MJ (2010) A methyl transferase links the circadian clock to the regulation of alternative splicing. Nature 468:112–116. doi:10.1038/nature09470

    Article  CAS  PubMed  Google Scholar 

  112. McGlincy NJ, Valomon A, Chesham JE, Maywood ES, Hastings MH, Ule J (2012) Regulation of alternative splicing by the circadian clock and food related cues. Genome Biol 13:R54. doi:10.1186/gb-2012-13-6-r54

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Preußner M, Wilhelmi I, Schultz AS, Finkernagel F, Michel M, Möröy T, Heyd F (2014) Rhythmic U2af26 alternative splicing controls PERIOD1 stability and the circadian clock in mice. Mol Cell 54:651–662. doi:10.1016/j.molcel.2014.04.015

    Article  PubMed  CAS  Google Scholar 

  114. Morf J, Rey G, Schneider K, Stratmann M, Fujita J, Naef F, Schibler U (2012) Cold-inducible RNA-binding protein modulates circadian gene expression posttranscriptionally. Science 338:379–383. doi:10.1126/science.1217726

    Article  CAS  PubMed  Google Scholar 

  115. Zhang J, Fang Z, Jud C, Vansteensel MJ, Kaasik K, Lee CC, Albrecht U, Tamanini F, Meijer JH, Oostra BA, Nelson DL (2008) Fragile X-related proteins regulate mammalian circadian behavioral rhythms. Am J Hum Genet 83:43–52. doi:10.1016/j.ajhg.2008.06.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Dockendorff TC, Su HS, McBride SM, Yang Z, Choi CH, Siwicki KK, Sehgal A, Jongens TA (2002) Drosophila lacking dfmr1 activity show defects in circadian output and fail to maintain courtship interest. Neuron 34:973–984. doi:10.1016/S0896-6273(02)00724-9

    Article  CAS  PubMed  Google Scholar 

  117. Kim M, Bellini M, Ceman S (2009) Fragile X mental retardation protein FMRP binds mRNAs in the nucleus. Mol Cell Biol 29:214–228. doi:10.1128/MCB.01377-08

    Article  CAS  PubMed  Google Scholar 

  118. Ji X, Kong J, Liebhaber SA (2011) An RNA-protein complex links enhanced nuclear 3′ processing with cytoplasmic mRNA stabilization. EMBO J 30:2622–2633. doi:10.1038/emboj.2011.171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Misquitta CM, Iyer VR, Werstiuk ES, Grover AK (2001) The role of 3′-untranslated region (3′-UTR) mediated mRNA stability in cardiovascular pathophysiology. Mol Cell Biochem 224:53–67. doi:10.1023/A:1011982932645

    Article  CAS  PubMed  Google Scholar 

  120. Woo KC, Ha DC, Lee KH, Kim DY, Kim TD, Kim KT (2010) Circadian amplitude of cryptochrome 1 is modulated by mRNA stability regulation via cytoplasmic hnRNP D oscillation. Mol Cell Biol 30:197–205. doi:10.1128/MCB.01154-09

    Article  CAS  PubMed  Google Scholar 

  121. Lee PT, Chao PK, Ou LC, Chuang JY, Lin YC, Chen SC, Chang HF, Law PY, Loh HH, Chao YS, Su TP, Yeh SH (2014) Morphine drives internal ribosome entry site-mediated hnRNP K translation in neurons through opioid receptor-dependent signaling. Nucleic Acids Res 42:13012–13025. doi:10.1093/nar/gku1016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Woo KC, Kim TD, Lee KH, Kim DY, Kim W, Lee KY, Kim KT (2009) Mouse period 2 mRNA circadian oscillation is modulated by PTB-mediated rhythmic mRNA degradation. Nucleic Acids Res 37:26–37. doi:10.1093/nar/gkn893

    Article  CAS  PubMed  Google Scholar 

  123. Kim SH, Lee KH, Kim DY, Kwak E, Kim S, Kim KT (2015) Rhythmic control of mRNA stability modulates circadian amplitude of mouse Period3 mRNA. J Neurochem 132:642–656. doi:10.1111/jnc.13027

    Article  CAS  PubMed  Google Scholar 

  124. Huang Y, Ainsley JA, Reijmers LG, Jackson FR (2013) Translational profiling of clock cells reveals circadianly synchronized protein synthesis. PLoS Biol 11:e1001703. doi:10.1371/journal.pbio.1001703

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Huang Y, McNeil GP, Jackson FR (2014) Translational regulation of the DOUBLETIME/CKIδ/ε kinase by LARK contributes to circadian period modulation. PLoS Genet 10:e1004536. doi:10.1371/journal.pgen.1004536

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Lim C, Lee J, Choi C, Kilman VL, Kim J, Park SM, Jang SK, Allada R, Choe J (2011) The novel gene twenty-four defines a critical translational step in the Drosophila clock. Nature 470:399–403. doi:10.1038/nature09728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Zhang Y, Ling J, Yuan C, Dubruille R, Emery P (2013) A role for Drosophila ATX2 in activation of PER translation and circadian behavior. Science 340:879–882. doi:10.1126/science.1234746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Lim C, Allada R (2013) ATAXIN-2 activates PERIOD translation to sustain circadian rhythms in Drosophila. Science 340:875–879. doi:10.1126/science.1234785

    Article  CAS  PubMed  Google Scholar 

  129. Jouffe C, Cretenet G, Symul L, Martin E, Atger F, Naef F, Gachon F (2013) The circadian clock coordinates ribosome biogenesis. PLoS Biol 11:e1001455. doi:10.1371/journal.pbio.1001455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Cao R, Lee B, Cho HY, Saklayen S, Obrietan K (2008) Photic regulation of the mTOR signaling pathway in the suprachiasmatic circadian clock. Mol Cell Neurosci 38:312–324. doi:10.1016/j.mcn.2008.03.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Cao R, Anderson FE, Jung YJ, Dziema H, Obrietan K (2011) Circadian regulation of mammalian target of rapamycin signaling in the mouse suprachiasmatic nucleus. Neuroscience 181:79–88. doi:10.1016/j.neuroscience.2011.03.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Cao R, Li A, Cho HY, Lee B, Obrietan K (2010) Mammalian target of rapamycin signaling modulates photic entrainment of the suprachiasmatic circadian clock. J Neurosci 30:6302–6314. doi:10.1523/JNEUROSCI.5482-09.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Zheng X, Sehgal A (2010) AKT and TOR signaling set the pace of the circadian pacemaker. Curr Biol 20:1203–1208. doi:10.1016/j.cub.2010.05.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Cao R, Robinson B, Xu H, Gkogkas C, Khoutorsky A, Alain T, Yanagiya A, Nevarko T, Liu AC, Amir S, Sonenberg N (2013) Translational control of entrainment and synchrony of the suprachiasmatic circadian clock by mTOR/4E-BP1 signaling. Neuron 79:712–724. doi:10.1016/j.neuron.2013.06.026

    Article  CAS  PubMed  Google Scholar 

  135. Cao R, Gkogkas CG, de Zavalia N, Blum ID, Yanagiya A, Tsukumo Y, Xu H, Lee C, Storch KF, Liu AC, Amir S, Sonenberg N (2015) Light-regulated translational control of circadian behavior by eIF4E phosphorylation. Nat Neurosci 18:855–862. doi:10.1038/nn.4010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Butcher GQ, Lee B, Hsieh F, Obrietan K (2004) Light- and clock-dependent regulation of ribosomal S6 kinase activity in the suprachiasmatic nucleus. Eur J Neurosci 19:907–915. doi:10.1111/j.0953-816X.2004.03155.x

    Article  PubMed  Google Scholar 

  137. Tangredi MM, Ng FS, Jackson FR (2012) The C-terminal kinase and ERK-binding domains of Drosophila S6KII (RSK) are required for phosphorylation of the protein and modulation of circadian behavior. J Biol Chem 287:16748–16758. doi:10.1074/jbc.M111.315929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Akten B, Tangredi MM, Jauch E, Roberts MA, Ng F, Raabe T, Jackson FR (2009) Ribosomal s6 kinase cooperates with casein kinase 2 to modulate the Drosophila circadian molecular oscillator. J Neurosci 29:466–475. doi:10.1523/JNEUROSCI.4034-08.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Yates LA, Norbury CJ, Gilbert RJ (2013) The long and short of microRNA. Cell 153:516–519. doi:10.1016/j.cell.2013.04.003

    Article  CAS  PubMed  Google Scholar 

  140. Xu S, Witmer PD, Lumayag S, Kovacs B, Valle D (2007) MicroRNA (miRNA) transcriptome of mouse retina and identification of a sensory organ-specific miRNA cluster. J Biol Chem 282:25053–25066. doi:10.1074/jbc.M700501200

    Article  CAS  PubMed  Google Scholar 

  141. Na YJ, Sung JH, Lee SC, Lee YJ, Choi YJ, Park WY, Shin HS, Kim JH (2009) Comprehensive analysis of microRNA-mRNA co-expression in circadian rhythm. Exp Mol Med 41:638–647. doi:10.3858/emm.2009.41.9.070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Yang M, Lee JE, Padgett RW, Edery I (2008) Circadian regulation of a limited set of conserved microRNAs in Drosophila. BMC Genom 9:83. doi:10.1186/1471-2164-9-83

    Article  CAS  Google Scholar 

  143. Kadener S, Menet JS, Sugino K, Horwich MD, Weissbein U, Nawathean P, Vagin VV, Zamore PD, Nelson SB, Rosbash M (2009) A role for microRNAs in the Drosophila circadian clock. Genes Dev 23:2179–2191. doi:10.1101/gad.1819509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Chen R, D’Alessandro M, Lee C (2013) miRNAs are required for generating a time delay critical for the circadian oscillator. Curr Biol 23:1959–1968. doi:10.1016/j.cub.2013.08.005

    Article  CAS  PubMed  Google Scholar 

  145. Du NH, Arpat AB, De Matos M, Gatfield D (2014) MicroRNAs shape circadian hepatic gene expression on a transcriptome-wide scale. Elife 3:e02510. doi:10.7554/eLife.02510

    Article  PubMed  PubMed Central  Google Scholar 

  146. Cheng HY, Papp JW, Varlamova O, Dziema H, Russell B, Curfman JP, Nakazawa T, Shimizu K, Okamura H, Impey S, Obrietan K (2007) microRNA modulation of circadian-clock period and entrainment. Neuron 54:813–829. doi:10.1016/j.neuron.2007.05.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Gatfield D, Le Martelot G, Vejnar CE, Gerlach D, Schaad O, Fleury-Olela F, Ruskeepää AL, Oresic M, Esau CC, Zdobnov EM, Schibler U (2009) Integration of microRNA miR-122 in hepatic circadian gene expression. Genes Dev 23:1313–1326. doi:10.1101/gad.1781009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Chen W, Liu Z, Li T, Zhang R, Xue Y, Zhong Y, Bai W, Zhou D, Zhao Z (2014) Regulation of Drosophila circadian rhythms by miRNA let-7 is mediated by a regulatory cycle. Nat Commun 5:5549. doi:10.1038/ncomms6549

    Article  CAS  PubMed  Google Scholar 

  149. Vodala S, Pescatore S, Rodriguez J, Buescher M, Chen YW, Weng R, Cohen SM, Rosbash M (2012) The oscillating miRNA 959-964 cluster impacts Drosophila feeding time and other circadian outputs. Cell Metab 16:601–612. doi:10.1016/j.cmet.2012.10.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Luo W, Sehgal A (2012) Regulation of circadian behavioral output via a MicroRNA-JAK/STAT circuit. Cell 148:765–779. doi:10.1016/j.cell.2011.12.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Zhang Y, Lamba P, Guo P, Emery P (2016) miR-124 regulates the phase of Drosophila circadian locomotor behavior. J Neurosci 36:2007–2013. doi:10.1523/JNEUROSCI.3286-15.2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Shende VR, Goldrick MM, Ramani S, Earnest DJ (2011) Expression and rhythmic modulation of circulating microRNAs targeting the clock gene Bmal1 in mice. PLoS One 6:e22586. doi:10.1371/journal.pone.0022586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Tan X, Zhang P, Zhou L, Yin B, Pan H, Peng X (2012) Clock-controlled mir-142-3p can target its activator, Bmal1. BMC Mol Biol 13:27. doi:10.1186/1471-2199-13-27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Shende VR, Neuendorff N, Earnest DJ (2013) Role of miR-142-3p in the post-transcriptional regulation of the clock gene Bmal1 in the mouse SCN. PLoS One 8:e65300. doi:10.1371/journal.pone.0065300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Shende VR, Kim SM, Neuendorff N, Earnest DJ (2014) MicroRNAs function as cis- and trans-acting modulators of peripheral circadian clocks. FEBS Lett 588:3015–3022. doi:10.1016/j.febslet.2014.05.058

    Article  CAS  PubMed  Google Scholar 

  156. Nagel R, Clijsters L, Agami R (2009) The miRNA-192/194 cluster regulates the Period gene family and the circadian clock. FEBS J 276:5447–5455. doi:10.1111/j.1742-4658.2009.07229.x

    Article  CAS  PubMed  Google Scholar 

  157. Lee KH, Kim SH, Lee HR, Kim W, Kim DY, Shin JC, Yoo SH, Kim KT (2013) MicroRNA-185 oscillation controls circadian amplitude of mouse Cryptochrome 1 via translational regulation. Mol Biol Cell 24:2248–2255. doi:10.1091/mbc.E12-12-0849

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Alvarez-Saavedra M, Antoun G, Yanagiya A, Oliva-Hernandez R, Cornejo-Palma D, Perez-Iratxeta C, Sonenberg N, Cheng HY (2011) miRNA-132 orchestrates chromatin remodeling and translational control of the circadian clock. Hum Mol Genet 20:731–751. doi:10.1093/hmg/ddq519

    Article  CAS  PubMed  Google Scholar 

  159. Querfurth C, Diernfellner AC, Gin E, Malzahn E, Höfer T, Brunner M (2011) Circadian conformational change of the Neurospora clock protein FREQUENCY triggered by clustered hyperphosphorylation of a basic domain. Mol Cell 43:713–722. doi:10.1016/j.molcel.2011.06.033

    Article  CAS  PubMed  Google Scholar 

  160. Curtin KD, Huang ZJ, Rosbash M (1995) Temporally regulated nuclear entry of the Drosophila period protein contributes to the circadian clock. Neuron 14:365–372. doi:10.1016/0896-6273(95)90292-9

    Article  CAS  PubMed  Google Scholar 

  161. Meyer P, Saez L, Young MW (2006) PER-TIM interactions in living Drosophila cells: an interval timer for the circadian clock. Science 311:226–229. doi:10.1126/science.1118126

    Article  CAS  PubMed  Google Scholar 

  162. Chang DC, Reppert SM (2003) A novel C-terminal domain of drosophila PERIOD inhibits dCLOCK:CYCLE-mediated transcription. Curr Biol 13:758–762. doi:10.1016/S0960-9822(03)00286-0

    Article  CAS  PubMed  Google Scholar 

  163. Saez L, Derasmo M, Meyer P, Stieglitz J, Young MW (2011) A key temporal delay in the circadian cycle of Drosophila is mediated by a nuclear localization signal in the timeless protein. Genetics 188:591–600. doi:10.1534/genetics.111.127225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Jang AR, Moravcevic K, Saez L, Young MW, Sehgal A (2015) Drosophila TIM binds importin α1, and acts as an adapter to transport PER to the nucleus. PLoS Genet 11:e1004974. doi:10.1371/journal.pgen.1004974

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  165. Lee Y, Jang AR, Francey LJ, Sehgal A, Hogenesch JB (2015) KPNB1 mediates PER/CRY nuclear translocation and circadian clock function. Elife 4:1–16. doi:10.7554/eLife.08647

    Google Scholar 

  166. Sakakida Y, Miyamoto Y, Nagoshi E, Akashi M, Nakamura TJ, Mamine T, Kasahara M, Minami Y, Yoneda Y, Takumi T (2005) Importin alpha/beta 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. doi:10.1074/jbc.M413236200

    Article  CAS  PubMed  Google Scholar 

  167. Martinek S, Inonog S, Manoukian AS, Young MW (2001) A role for the segment polarity gene shaggy/GSK-3 in the Drosophila circadian clock. Cell 105:769–779. doi:10.1016/S0092-8674(01)00383-X

    Article  CAS  PubMed  Google Scholar 

  168. Iitaka C, Miyazaki K, Akaike T, Ishida N (2005) A role for glycogen synthase kinase-3beta in the mammalian circadian clock. J Biol Chem 280:29397–29402. doi:10.1074/jbc.M503526200

    Article  CAS  PubMed  Google Scholar 

  169. Lin J-M, Kilman VL, Keegan K, Paddock B, Emery-Le M, Rosbash M, Allada R (2002) A role for casein kinase 2alpha in the Drosophila circadian clock. Nature 420:816–820. doi:10.1038/nature01235

    Article  CAS  PubMed  Google Scholar 

  170. Akten B, Jauch E, Genova GK, Kim EY, Edery I, Raabe T, Jackson FR (2003) A role for CK2 in the Drosophila circadian oscillator. Nat Neurosci 6:251–257. doi:10.1038/nn1007

    Article  CAS  PubMed  Google Scholar 

  171. Top D, Harms E, Syed S, Adams EL, Saez L (2016) GSK-3 and CK2 kinases converge on timeless to regulate the master clock. Cell Rep 16:357–367. doi:10.1016/j.celrep.2016.06.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Ko HW, Kim EY, Chiu J, Vanselow JT, Kramer A, Edery I (2010) A hierarchical phosphorylation cascade that regulates the timing of PERIOD nuclear entry reveals novel roles for proline-directed kinases and GSK-3beta/SGG in circadian clocks. J Neurosci 30:12664–12675. doi:10.1523/JNEUROSCI.1586-10.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Lin J-M, Schroeder A, Allada R (2005) In vivo circadian function of casein kinase 2 phosphorylation sites in Drosophila PERIOD. J Neurosci 25:11175–11183. doi:10.1523/JNEUROSCI.2159-05.2005

    Article  CAS  PubMed  Google Scholar 

  174. Dusik V, Senthilan PR, Mentzel B, Hartlieb H, Wülbeck C, Yoshii T, Raabe T, Helfrich-Förster C (2014) The MAP kinase p38 is part of Drosophila melanogaster’s circadian clock. PLoS Genet 10:e1004565. doi:10.1371/journal.pgen.1004565

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  175. Kim EY, Jeong EH, Park S, Jeong H-J, Edery I, Cho JW (2012) A role for O-GlcNAcylation in setting circadian clock speed. Genes Dev 26:490–502. doi:10.1101/gad.182378.111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Takano A, Isojima Y, Nagai K (2004) Identification of mPer1 phosphorylation sites responsible for the nuclear entry. J Biol Chem 279:32578–32585. doi:10.1074/jbc.M403433200

    Article  CAS  PubMed  Google Scholar 

  177. Mehta N, Cheng AH, Chiang C-K, Mendoza-Viveros L, Ling HH, Patel A, Xu B, Figeys D, Cheng H-YM (2015) GRK2 fine-tunes circadian clock speed and entrainment via transcriptional and post-translational control of PERIOD proteins. Cell Rep 12:1272–1288. doi:10.1016/j.celrep.2015.07.037

    Article  CAS  PubMed  Google Scholar 

  178. Kurabayashi N, Hirota T, Sakai M, Sanada K, Fukada Y (2010) DYRK1A and glycogen synthase kinase 3beta, a dual-kinase mechanism directing proteasomal degradation of CRY2 for circadian timekeeping. Mol Cell Biol 30:1757–1768. doi:10.1128/MCB.01047-09

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Gallego M, Virshup DM (2007) Post-translational modifications regulate the ticking of the circadian clock. Nat Rev Mol Cell Biol 8:139–148. doi:10.1038/nrm2106

    Article  CAS  PubMed  Google Scholar 

  180. Glickman MH, Ciechanover A (2002) The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev 82:373–428. doi:10.1152/physrev.00027.2001

    Article  CAS  PubMed  Google Scholar 

  181. Godinho SIH, Maywood ES, Shaw L, Tucci V, Barnard AR, Busino L, Pagano M, Kendall R, Quwailid MM, Romero MR, O’neill J, Chesham JE, Brooker D, Lalanne Z, Hastings MH, Nolan PM (2007) The after-hours mutant reveals a role for Fbxl3 in determining mammalian circadian period. Science 316:897–900. doi:10.1126/science.1141138

    Article  CAS  PubMed  Google Scholar 

  182. Siepka SM, Yoo S-H, Park J, Song W, Kumar V, Hu Y, Lee C, Takahashi JS (2007) Circadian mutant Overtime reveals F-box protein FBXL3 regulation of cryptochrome and period gene expression. Cell 129:1011–1023. doi:10.1016/j.cell.2007.04.030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Busino L, Bassermann F, Maiolica A, Lee C, Nolan PM, Godinho SIH, Draetta GF, Pagano M (2007) SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins. Science 316:900–904. doi:10.1126/science.1141194

    Article  CAS  PubMed  Google Scholar 

  184. Hirano A, Yumimoto K, Tsunematsu R, Matsumoto M, Oyama M, Kozuka-Hata H, Nakagawa T, Lanjakornsiripan D, Nakayama KI, Fukada Y (2013) FBXL21 regulates oscillation of the circadian clock through ubiquitination and stabilization of cryptochromes. Cell 152:1106–1118. doi:10.1016/j.cell.2013.01.054

    Article  CAS  PubMed  Google Scholar 

  185. Yoo S-H, Mohawk JA, Siepka SM, Shan Y, Huh SK, Hong H-K, Kornblum I, Kumar V, Koike N, Xu M, Nussbaum J, Liu X, Chen Z, Chen ZJ, Green CB, Takahashi JS (2013) Competing E3 ubiquitin ligases govern circadian periodicity by degradation of CRY in nucleus and cytoplasm. Cell 152:1091–1105. doi:10.1016/j.cell.2013.01.055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Lamia KA, Sachdeva UM, DiTacchio L, Williams EC, Alvarez JG, Egan DF, Vasquez DS, Juguilon H, Panda S, Shaw RJ, Thompson CB, Evans RM (2009) AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science 326:437–440. doi:10.1126/science.1172156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Gao P, Yoo S-H, Lee K-J, Rosensweig C, Takahashi JS, Chen BP, Green CB (2013) Phosphorylation of the cryptochrome 1 C-terminal tail regulates circadian period length. J Biol Chem 288:35277–35286. doi:10.1074/jbc.M113.509604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Tong X, Buelow K, Guha A, Rausch R, Yin L (2012) USP2a protein deubiquitinates and stabilizes the circadian protein CRY1 in response to inflammatory signals. J Biol Chem 287:25280–25291. doi:10.1074/jbc.M112.340786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Ohsaki K, Oishi K, Kozono Y, Nakayama K, Nakayama KI, Ishida N (2008) The role of β-TrCP1 and β-TrCP2 in circadian rhythm generation by mediating degradation of clock protein PER2. J Biochem 144:609–618. doi:10.1093/jb/mvn112

    Article  CAS  PubMed  Google Scholar 

  190. Eide EJ, Woolf MF, Kang H, Woolf P, Hurst W, Camacho F, Vielhaber EL, Giovanni A, Virshup DM (2005) Control of mammalian circadian rhythm by CKIepsilon-regulated proteasome-mediated PER2 degradation. Mol Cell Biol 25:2795–2807. doi:10.1128/MCB.25.7.2795-2807.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Shirogane T, Jin J, Ang XL, Harper JW (2005) SCFbeta-TRCP controls clock-dependent transcription via casein kinase 1-dependent degradation of the mammalian period-1 (Per1) protein. J Biol Chem 280:26863–26872. doi:10.1074/jbc.M502862200

    Article  CAS  PubMed  Google Scholar 

  192. Grima B, Lamouroux A, Chélot E, Papin C, Limbourg-Bouchon B, Rouyer F (2002) The F-box protein slimb controls the levels of clock proteins period and timeless. Nature 420:178–182. doi:10.1038/nature01122

    Article  CAS  PubMed  Google Scholar 

  193. Ko HW, Jiang J, Edery I (2002) Role for Slimb in the degradation of Drosophila Period protein phosphorylated by Doubletime. Nature 420:673–678. doi:10.1038/nature01272

    Article  CAS  PubMed  Google Scholar 

  194. Meng Q-J, Logunova L, Maywood ES, Gallego M, Lebiecki J, Brown TM, Sládek M, Semikhodskii AS, Glossop NRJ, Piggins HD, Chesham JE, Bechtold DA, Yoo S-H, Takahashi JS, Virshup DM, Boot-Handford RP, Hastings MH, Loudon ASI (2008) Setting clock speed in mammals: the CK1 epsilon tau mutation in mice accelerates circadian pacemakers by selectively destabilizing PERIOD proteins. Neuron 58:78–88. doi:10.1016/j.neuron.2008.01.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Price JL, Blau J, Rothenfluh A, Abodeely M, Kloss B, Young MW (1998) double-time is a novel Drosophila clock gene that regulates PERIOD protein accumulation. Cell 94:83–95. doi:10.1016/S0092-8674(00)81224-6

    Article  CAS  PubMed  Google Scholar 

  196. Chiu JC, Vanselow JT, Kramer A, Edery I (2008) The phospho-occupancy of an atypical SLIMB-binding site on PERIOD that is phosphorylated by DOUBLETIME controls the pace of the clock. Genes Dev 22:1758–1772. doi:10.1101/gad.1682708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Syed S, Saez L, Young MW (2011) Kinetics of doubletime kinase-dependent degradation of the Drosophila period protein. J Biol Chem 286:27654–27662. doi:10.1074/jbc.M111.243618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Shanware NP, Hutchinson JA, Kim SH, Zhan L, Bowler MJ, Tibbetts RS (2011) Casein kinase 1-dependent phosphorylation of familial advanced sleep phase syndrome-associated residues controls PERIOD 2 stability. J Biol Chem 286:12766–12774. doi:10.1074/jbc.M111.224014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Toh KL, Jones CR, He Y, Eide EJ, Hinz WA, Virshup DM, Ptácek LJ, Fu YH (2001) An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science 291:1040–1043. doi:10.1126/science.1057499

    Article  CAS  PubMed  Google Scholar 

  200. Lee B, Almad A, Butcher GQ, Obrietan K (2007) Protein kinase C modulates the phase-delaying effects of light in the mammalian circadian clock. Eur J Neurosci 26:451–462. doi:10.1111/j.1460-9568.2007.05664.x

    Article  PubMed  Google Scholar 

  201. Jakubcakova V, Oster H, Tamanini F, Cadenas C, Leitges M, van der Horst GTJ, Eichele G (2007) Light entrainment of the mammalian circadian clock by a PRKCA-dependent posttranslational mechanism. Neuron 54:831–843. doi:10.1016/j.neuron.2007.04.031

    Article  CAS  PubMed  Google Scholar 

  202. Lee H, Chen R, Kim H, Etchegaray J-P, Weaver DR, Lee C (2011) 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. doi:10.1073/pnas.1107178108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Fang Y, Sathyanarayanan S, Sehgal A (2007) Post-translational regulation of the Drosophila circadian clock requires protein phosphatase 1 (PP1). Genes Dev 21:1506–1518. doi:10.1101/gad.1541607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Gallego M, Kang H, Virshup DM (2006) Protein phosphatase 1 regulates the stability of the circadian protein PER2. Biochem J 399:169–175. doi:10.1042/BJ20060678

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Sathyanarayanan S, Zheng X, Xiao R, Sehgal A (2004) Posttranslational regulation of Drosophila PERIOD protein by protein phosphatase 2A. Cell 116:603–615. doi:10.1016/S0092-8674(04)00128-X

    Article  CAS  PubMed  Google Scholar 

  206. Lee J, Lee Y, Lee MJ, Park E, Kang SH, Chung CH, Lee KH, Kim K (2008) Dual modification of BMAL1 by SUMO2/3 and ubiquitin promotes circadian activation of the CLOCK/BMAL1 complex. Mol Cell Biol 28:6056–6065. doi:10.1128/MCB.00583-08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Cardone L, Hirayama J, Giordano F, Tamaru T, Palvimo JJ, Sassone-Corsi P (2005) Circadian clock control by SUMOylation of BMAL1. Science 309:1390–1394. doi:10.1126/science.1110689

    Article  CAS  PubMed  Google Scholar 

  208. Sahar S, Zocchi L, Kinoshita C, Borrelli E, Sassone-Corsi P (2010) Regulation of BMAL1 protein stability and circadian function by GSK3beta-mediated phosphorylation. PLoS ONE 5:e8561. doi:10.1371/journal.pone.0008561

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  209. Zhang L, Abraham D, Lin S-T, Oster H, Eichele G, Fu Y-H, Ptáček LJ (2012) PKCγ participates in food entrainment by regulating BMAL1. Proc Natl Acad Sci USA 109:20679–20684. doi:10.1073/pnas.1218699110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Li M-D, Ruan H-B, Hughes ME, Lee J-S, Singh JP, Jones SP, Nitabach MN, Yang X (2013) O-GlcNAc signaling entrains the circadian clock by inhibiting BMAL1/CLOCK ubiquitination. Cell Metab 17:303–310. doi:10.1016/j.cmet.2012.12.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Ma Y-T, Luo H, Guan W-J, Zhang H, Chen C, Wang Z, Li J-D (2013) O-GlcNAcylation of BMAL1 regulates circadian rhythms in NIH3T3 fibroblasts. Biochem Biophys Res Commun 431:382–387. doi:10.1016/j.bbrc.2013.01.043

    Article  CAS  PubMed  Google Scholar 

  212. Gossan NC, Zhang F, Guo B, Jin D, Yoshitane H, Yao A, Glossop N, Zhang YQ, Fukada Y, Meng Q-J (2014) 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. doi:10.1093/nar/gku225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Scoma HD, Humby M, Yadav G, Zhang Q, Fogerty J, Besharse JC (2011) The de-ubiquitinylating enzyme, USP2, is associated with the circadian clockwork and regulates its sensitivity to light. PLoS One 6:e25382. doi:10.1371/journal.pone.0025382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Lamaze A, Lamouroux A, Vias C, Hung H-C, Weber F, Rouyer F (2011) The E3 ubiquitin ligase CTRIP controls CLOCK levels and PERIOD oscillations in Drosophila. EMBO Rep 12:549–557. doi:10.1038/embor.2011.64

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Luo W, Li Y, Tang C-HA, Abruzzi KC, Rodriguez J, Pescatore S, Rosbash M (2012) CLOCK deubiquitylation by USP8 inhibits CLK/CYC transcription in Drosophila. Genes Dev 26:2536–2549. doi:10.1101/gad.200584.112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Spengler ML, Kuropatwinski KK, Schumer M, Antoch MP (2009) A serine cluster mediates BMAL1-dependent CLOCK phosphorylation and degradation. Cell Cycle 8:4138–4146. doi:10.4161/cc.8.24.10273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Yu W, Zheng H, Price JL, Hardin PE (2009) DOUBLETIME plays a noncatalytic role to mediate CLOCK phosphorylation and repress CLOCK-dependent transcription within the Drosophila circadian clock. Mol Cell Biol 29:1452–1458. doi:10.1128/MCB.01777-08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Yu W, Zheng H, Houl JH, Dauwalder B, Hardin PE (2006) PER-dependent rhythms in CLK phosphorylation and E-box binding regulate circadian transcription. Genes Dev 20:723–733. doi:10.1101/gad.1404406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Kim EY, Edery I (2006) Balance between DBT/CKIepsilon kinase and protein phosphatase activities regulate phosphorylation and stability of Drosophila CLOCK protein. Proc Natl Acad Sci USA 103:6178–6183. doi:10.1073/pnas.0511215103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Szabó A, Papin C, Zorn D, Ponien P, Weber F, Raabe T, Rouyer F (2013) The CK2 kinase stabilizes CLOCK and represses its activity in the Drosophila circadian oscillator. PLoS Biol 11:e1001645. doi:10.1371/journal.pbio.1001645

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  221. Andreazza S, Bouleau S, Martin B, Lamouroux A, Ponien P, Papin C, Chélot E, Jacquet E, Rouyer F (2015) Daytime CLOCK dephosphorylation is controlled by STRIPAK complexes in Drosophila. Cell Rep 11:1266–1279. doi:10.1016/j.celrep.2015.04.033

    Article  CAS  PubMed  Google Scholar 

  222. Koh K, Zheng X, Sehgal A (2006) JETLAG resets the Drosophila circadian clock by promoting light-induced degradation of TIMELESS. Science 312:1809–1812. doi:10.1126/science.1124951

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Stoleru D, Nawathean P, Fernández M de la P, Menet JS, Ceriani MF, Rosbash M (2007) The Drosophila circadian network is a seasonal timer. Cell 129:207–219. doi:10.1016/j.cell.2007.02.038

    Article  CAS  PubMed  Google Scholar 

  224. Peschel N, Chen KF, Szabo G, Stanewsky R (2009) Light-dependent interactions between the Drosophila circadian clock factors cryptochrome, jetlag, and timeless. Curr Biol 19:241–247. doi:10.1016/j.cub.2008.12.042

    Article  CAS  PubMed  Google Scholar 

  225. Knowles A, Koh K, Wu J-T, Chien C-T, Chamovitz DA, Blau J (2009) The COP9 signalosome is required for light-dependent timeless degradation and Drosophila clock resetting. J Neurosci 29:1152–1162. doi:10.1523/JNEUROSCI.0429-08.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by grants to H.-Y.M.C. from the Canadian Institute of Health Research (CIHR) and the Natural Sciences and Engineering Research Council (NSERC) of Canada. H.-Y.M.C. is a Tier II Canada Research Chair (CRC) in Molecular Genetics of Biological Clocks. L.M.-V. is supported by a graduate scholarship from the Consejo Nacional de Ciencia y Tecnologia (CONACYT) of Mexico. P.B.-C., S.H. and A.H.C. are supported by NSERC Post-Graduate Scholarships. A.H.C. was previously supported by a CIHR-funded training fellowship from Sleep and Biological Rhythms Toronto. This work is dedicated to the memory of Harrod Ho Pak Ling, enthusiast of all things rhythmic.

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    1. Department of Biology, University of Toronto Mississauga, 3359 Mississauga Road, Mississauga, ON, L5L 1C6, Canada

      Lucia Mendoza-Viveros, Pascale Bouchard-Cannon, Sara Hegazi, Arthur H. Cheng, Stephen Pastore & Hai-Ying Mary Cheng

    2. Department of Cell and Systems Biology, University of Toronto, 25 Harbord Street, Toronto, ON, M5S 3G5, Canada

      Lucia Mendoza-Viveros, Pascale Bouchard-Cannon, Sara Hegazi, Arthur H. Cheng, Stephen Pastore & Hai-Ying Mary Cheng

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    L. Mendoza-Viveros, P. Bouchard-Cannon and S. Hegazi contributed equally.

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    Mendoza-Viveros, L., Bouchard-Cannon, P., Hegazi, S. et al. Molecular modulators of the circadian clock: lessons from flies and mice. Cell. Mol. Life Sci. 74, 1035–1059 (2017). https://doi.org/10.1007/s00018-016-2378-8

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