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Reciprocal Control of the Circadian Clock and Cellular Redox State - a Critical Appraisal
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  • Journal title : Molecules and Cells
  • Volume 39, Issue 1,  2016, pp.6-19
  • Publisher : Korea Society for Molecular and Cellular Biology
  • DOI : 10.14348/molcells.2016.2323
 Title & Authors
Reciprocal Control of the Circadian Clock and Cellular Redox State - a Critical Appraisal
Putker, Marrit; O`Neill, John Stuart;
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Redox signalling comprises the biology of molecular signal transduction mediated by reactive oxygen (or nitrogen) species. By specific and reversible oxidation of redoxsensitive cysteines, many biological processes sense and respond to signals from the intracellular redox environment. Redox signals are therefore important regulators of cellular homeostasis. Recently, it has become apparent that the cellular redox state oscillates in vivo and in vitro, with a period of about one day (circadian). Circadian timekeeping allows cells and organisms to adapt their biology to resonate with the 24-hour cycle of day/night. The importance of this innate biological timekeeping is illustrated by the association of clock disruption with the early onset of several diseases (e.g. type II diabetes, stroke and several forms of cancer). Circadian regulation of cellular redox balance suggests potentially two distinct roles for redox signalling in relation to the cellular clock: one where it is regulated by the clock, and one where it regulates the clock. Here, we introduce the concepts of redox signalling and cellular timekeeping, and then critically appraise the evidence for the reciprocal regulation between cellular redox state and the circadian clock. We conclude there is a substantial body of evidence supporting circadian regulation of cellular redox state, but that it would be premature to conclude that the converse is also true. We therefore propose some approaches that might yield more insight into redox control of cellular timekeeping.
biological clock;circadian timekeeping;cysteine oxidation;redox signalling;
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Abate, C., Patel, L., Rauscher, F.J., and Curran, T. (1990). Redox regulation of fos and jun DNA-binding activity in vitro. Science 249, 1157-1161. crossref(new window)

Anea, C.B., Zhang, M., Chen, F., Ali, M.I., Hart, C.M.M., Stepp, D.W., Kovalenkov, Y.O., Merloiu, A.-M., Pati, P., Fulton, D., et al. (2013). Circadian clock control of Nox4 and reactive oxygen species in the vasculature. PLoS One 8, e78626. crossref(new window)

Aon, M. a., Cortassa, S., Marban, E., and O'Rourke, B. (2003). Synchronized whole cell oscillations in mitochondrial metabolism triggered by a local release of reactive oxygen species in cardiac myocytes. J. Biol. Chem. 278, 44735-44744. crossref(new window)

Asher, G., and Schibler, U. (2011). Crosstalk between components of circadian and metabolic cycles in mammals. Cell Metab. 13, 125-137. crossref(new window)

Asher, G., Gatfield, D., Stratmann, M., Reinke, H., Dibner, C., Kreppel, F., Mostoslavsky, R., Alt, F.W., and Schibler, U. (2008). SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell 134, 317-328. crossref(new window)

Atger, F., Gobet, C., Marquis, J., Martin, E., Wang, J., Weger, B., Lefebvre, G., Descombes, P., Naef, F., and Gachon, F. (2015). Circadian and feeding rhythms differentially affect rhythmic mRNA transcription and translation in mouse liver. Proc. Natl. Acad. Sci. USA 112, E6579-88. crossref(new window)

Bass, J. (2012). Circadian topology of metabolism. Nature 491, 348-356. crossref(new window)

Bass, J., and Takahashi, J.S. (2010). Circadian integration of metabolism and energetics. Science 330, 1349-1354. crossref(new window)

Bieler, J., Cannavo, R., Gustafson, K., Gobet, C., Gatfield, D., and Naef, F. (2014). Robust synchronization of coupled circadian and cell cycle oscillators in single mammalian cells. Mol. Syst. Biol. 10, 739. crossref(new window)

Bindoli, A., and Rigobello, M.P. (2012). Principles in redox signaling:from chemistry to functional significance. Antioxid. Redox Signal. 18, 1-97.

Brody, S., and Harris, S. (1973). Circadian rhythms in neurospora:spatial differences in pyridine nucleotide levels. Science 180, 498-500. crossref(new window)

Brunet, A., Sweeney, L.B., Sturgill, J.F., Chua, K.F., Greer, P.L., Lin, Y., Tran, H., Ross, S.E., Mostoslavsky, R., Cohen, H.Y., et al. (2004). Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303, 2011-2015. crossref(new window)

Bulleid, N.J., and Ellgaard, L. (2011). Multiple ways to make disulfides. Trends Biochem. Sci. 36, 485-492. crossref(new window)

Bunger, M.K., Wilsbacher, L.D., Moran, S.M., Clendenin, C., Radcliffe, L. a., Hogenesch, J.B., Simon, M.C., Takahashi, J.S., and Bradfield, C. a. (2000). Mop3 is an essential component of the master circadian pacemaker in mammals. Cell 103, 1009-1017. crossref(new window)

Burgoyne, J.R., Madhani, M., Cuello, F., Charles, R.L., Brennan, J.P., Schroder, E., Browning, D.D., and Eaton, P. (2007). Cysteine redox sensor in PKGIa enables oxidant-induced activation. Science 317, 1393-1397. crossref(new window)

Burgoyne, J.R., Rudyk, O., Cho, H., Prysyazhna, O., Hathaway, N., Weeks, A., Evans, R., Ng, T., Schroder, K., Brandes, R.P., et al. (2015). Deficient angiogenesis in redox-dead Cys17Ser $PKARI{\alpha}$ knock-in mice. Nat. Commun. 6, 7920. crossref(new window)

Cardone, L., Hirayama, J., Giordano, F., Tamaru, T., Palvimo, J., and Sassone-Corsi, P. (2005). Circadian clock control by SUMOylation of BMAL1. Science 309, 1390-1394. crossref(new window)

Causton, H.C., Feeney, K.A., Ziegler, C.A., and O'Neill, J.S. (2015). Metabolic cycles in yeast share features conserved among circadian rhythms. Curr. Biol. 25, 1056-1062. crossref(new window)

Chang, T.-S., Jeong, W., Woo, H.A., Lee, S.M., Park, S., and Rhee, S.G. (2004). Characterization of mammalian sulfiredoxin and its reactivation of hyperoxidized peroxiredoxin through reduction of cysteine sulfinic acid in the active site to cysteine. J. Biol. Chem. 279, 50994-51001. crossref(new window)

Chaudhury, D., Wang, L.M., and Colwell, C.S. (2005). Circadian regulation of hippocampal long-term potentiation. J. Biol. Rhythms 20, 225-236. crossref(new window)

Chen, R., Schirmer, A., Lee, Y., Lee, H., Kumar, V., Yoo, S.-H., Takahashi, J.S., and Lee, C. (2009). Rhythmic PER abundance defines a critical nodal point for negative feedback within the circadian clock mechanism. Mol. Cell 36, 417-430. crossref(new window)

Cho, C.S., Yoon, H.J., Kim, J.Y., Woo, H.A., and Rhee, S.G. (2014). Circadian rhythm of hyperoxidized peroxiredoxin II is determined by hemoglobin autoxidation and the 20S proteasome in red blood cells. Proc. Natl. Acad. Sci. USA 111, 12043-12048. crossref(new window)

Cotto-Rios, X.M., Bekes, M., Chapman, J., Ueberheide, B., and Huang, T.T. (2012). Deubiquitinases as a signaling target of oxidative stress. Cell Rep. 2, 1-10. crossref(new window)

Cremers, C.M., and Jakob, U. (2013). Oxidant sensing by reversible disulfide bond formation. J. Biol. Chem. 288, 26489-26496. crossref(new window)

Czech, M.P., Lawrence, J.C., and Lynn, W.S. (1974). Evidence for the involvement of sulfhydryl oxidation in the regulation of fat cell hexose transport by insulin. Proc. Natl. Acad. Sci. USA 71, 4173-4177. crossref(new window)

Dansen, T.B., Smits, L.M.M., van Triest, M.H., de Keizer, P.L.J., van Leenen, D., Koerkamp, M.G., Szypowska, A., Meppelink, A., Brenkman, A.B., Yodoi, J., et al. (2009). Redox-sensitive cysteines bridge p300/CBP-mediated acetylation and FoxO4 activity. Nat. Chem. Biol. 5, 664-672. crossref(new window)

DeBruyne, J.P., Noton, E., Lambert, C.M., Maywood, E.S., Weaver, D.R., and Reppert, S.M. (2006). A clock shock: mouse CLOCK is not required for circadian oscillator function. Neuron 50, 465-477. crossref(new window)

Delaunay, A., Pflieger, D., Barrault, M.B., Vinh, J., and Toledano, M.B. (2002). A thiol peroxidase is an H2O2 receptor and redoxtransducer in gene activation. Cell 111, 471-481. crossref(new window)

Dickinson, B.C. (2015). Plugging the leak Synergistic MRSA combinations. Nat. Publ. Gr. 11, 831-832.

Dunlap, J.C. (1999). Molecular bases for circadian clocks. Cell 96, 271-290. crossref(new window)

Edgar, R.S., Green, E.W., Zhao, Y., van Ooijen, G., Olmedo, M., Qin, X., Xu, Y., Pan, M., Valekunja, U.K., Feeney, K.A., et al. (2012). Peroxiredoxins are conserved markers of circadian rhythms. Nature 485, 459-464. crossref(new window)

Eide, E.J., Woolf, M.F., Kang, H., Woolf, P., Hurst, W., Camacho, F., Vielhaber, E.L., Giovanni, A., and Virshup, D.M. (2005). Control of mammalian circadian rhythm by CKIepsilon-regulated proteasome-mediated PER2 degradation. Mol. Cell. Biol. 25, 2795-2807. crossref(new window)

Ezeriņa, D., Morgan, B., and Dick, T.P. (2014). Imaging dynamic redox processes with genetically encoded probes. J. Mol. Cell. Cardiol. 73, 43-49. crossref(new window)

Fan, Y., Hida, A., Anderson, D. a., Izumo, M., and Johnson, C.H. (2007). Cycling of CRYPTOCHROME proteins is not necessary for circadian-clock function in mammalian fibroblasts. Curr. Biol. 17, 1091-1100. crossref(new window)

Feillet, C., Krusche, P., Tamanini, F., Janssens, R.C., Downey, M.J., Martin, P., Teboul, M., Saito, S., Levi, F. a., Bretschneider, T., et al. (2014). Phase locking and multiple oscillating attractors for the coupled mammalian clock and cell cycle. Proc. Natl. Acad. Sci. USA 111, 9828-9833. crossref(new window)

Fogg, P.C.M., O'Neill, J.S., Dobrzycki, T., Calvert, S., Lord, E.C., McIntosh, R.L.L., Elliott, C.J.H., Sweeney, S.T., Hastings, M.H., and Chawla, S. (2014). Class IIa histone deacetylases are conserved regulators of circadian function. J. Biol. Chem. 289, 34341-34348. crossref(new window)

Fourquet, S., Huang, M.E., D'Autreaux, B., and Toledano, M.B. (2008). The dual functions of thiol-based peroxidases in H2O2 scavenging and signaling. Antioxid. Redox Signal. 10, 1565-1576. crossref(new window)

Fujimoto, Y., Yagita, K., and Okamura, H. (2006). Does mPER2 protein oscillate without its coding mRNA cycling?: posttranscriptional regulation by cell clock. Genes Cells 11, 525-530. crossref(new window)

Gibbs, J., Ince, L., Matthews, L., Mei, J., Bell, T., Yang, N., Saer, B., Begley, N., Poolman, T., Pariollaud, M., et al. (2014). An epithelial circadian clock controls pulmonary inflammation and glucocorticoid action. Nat. Med. 20, 919-926. crossref(new window)

Godinho, S.I.H., Maywood, E.S., Shaw, L., Tucci, V., Barnard, A.R., Busino, L., Pagano, M., Kendall, R., Quwailid, M.M., Romero, M.R., et al. (2007). The after-hours mutant reveals a role for Fbxl3 in determining mammalian circadian period. Science 316, 897-900. crossref(new window)

Goldman, R., Stoyanovsky, D. a, Day, B.W., and Kagan, V.E. (1995). Reduction of phenoxyl radicals by thioredoxin results in selective oxidation of its SH-groups to disulfides. An antioxidant function of thioredoxin. Biochemistry 34, 4765-4772. crossref(new window)

Gorrini, C., Harris, I.S., and Mak, T.W. (2013). Modulation of oxidative stress as an anticancer strategy. Nat. Rev. Drug Discov. 12, 931-947. crossref(new window)

Grek, C.L., Zhang, J., Manevich, Y., Townsend, D.M., and Tew, K.D. (2013). Causes and consequences of cysteine Sglutathionylation. J. Biol. Chem. 288, 26497-26504. crossref(new window)

Gyongyosi, N., Nagy, D., Makara, K., Ella, K., and Kaldi, K. (2013). Reactive oxygen species can modulate circadian phase and period in Neurospora crassa. Free Radic. Biol. Med. 58, 134-143. crossref(new window)

Hanschmann, E.-M., Godoy, J.R., Berndt, C., Hudemann, C., and Lillig, C.H. (2013). Thioredoxins, glutaredoxins, and peroxiredoxins--molecular mechanisms and health significance:from cofactors to antioxidants to redox signaling. Antioxid. Redox Signal. 19, 1539-1605. crossref(new window)

Hardin, P.E., Hall, J.C., and Rosbash, M. (1990). Feedback of the Drosophila period gene product on circadian cycling of its messenger RNA levels. Nature 343, 536-540. crossref(new window)

Hastings, M.H., Maywood, E.S., and O'Neill, J.S. (2008). Cellular circadian pacemaking and the role of cytosolic rhythms. Curr. Biol. 18, R805-R815. crossref(new window)

Hayes, J.D., and Dinkova-Kostova, A.T. (2014). The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem. Sci. 39, 199-218. crossref(new window)

Homma, T., Okano, S., Lee, J., Ito, J., Otsuki, N., Kurahashi, T., Kang, E.S., Nakajima, O., and Fujii, J. (2015). SOD1 deficiency induces the systemic hyperoxidation of peroxiredoxin in the mouse. Biochem. Biophys. Res. Commun. 463, 1040-1046. crossref(new window)

Horst, G.T.J. Van Der, and Muijtjens, M. (1999). Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms. 3495, 627-630.

Van der Horst, A., Tertoolen, L.G.J., de Vries-Smits, L.M.M., Frye, R. a, Medema, R.H., and Burgering, B.M.T. (2004). FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1). J. Biol. Chem. 279, 28873-28879. crossref(new window)

Hoyle, N.P., and O'Neill, J.S. (2014). Oxidation-reduction cycles of peroxiredoxin proteins and nontranscriptional aspects of timekeeping. Biochemistry 54, 184-193.

Jacobi, D., Liu, S., Burkewitz, K., Kory, N., Knudsen, N.H., Alexander, R.K., Unluturk, U., Li, X., Kong, X., Hyde, A.L., et al. (2015). Hepatic Bmal1 regulates rhythmic mitochondrial dynamics and promotes metabolic fitness. Cell Metab. 22, 709-720. crossref(new window)

Jang, C., Lahens, N.F., Hogenesch, J.B., and Sehgal, A. (2015). Ribosome profiling reveals an important role for translational control in circadian gene expression. Genome Res. 25, 1836-1847. crossref(new window)

Jarvis, R.M., Hughes, S.M., and Ledgerwood, E.C. (2012). Peroxiredoxin 1 functions as a signal peroxidase to receive, transduce, and transmit peroxide signals in mammalian cells. Free Radic. Biol. Med. 53, 1522-1530. crossref(new window)

Kaasik, K., Kivimae, S., Allen, J.J.J., Chalkley, R.J.J., Huang, Y., Baer, K., Kissel, H., Burlingame, A.L.L., Shokat, K.M.M., Ptacek, L.J.J., et al. (2013). Glucose sensor O-GlcNAcylation coordinates with phosphorylation to regulate circadian clock. Cell Metab. 17, 291-302. crossref(new window)

De Keizer, P.L.J., Burgering, B.M.T., and Dansen, T.B. (2011). Forkhead box o as a sensor, mediator, and regulator of redox signaling. Antioxid. Redox Signal. 14, 1093-1106. crossref(new window)

Kil, I.S., Lee, S.K., Ryu, K.W., Woo, H.A., Hu, M.C., Bae, S.H., and Rhee, S.G. (2012). Feedback Control of Adrenal Steroidogenesis via H2O2-Dependent, Reversible Inactivation of Peroxiredoxin III in Mitochondria. Mol. Cell 46, 584-594. crossref(new window)

Kil, I.S., Ryu, K.W., Lee, S.K., Kim, J.Y., Chu, S.Y., Kim, J.H., Park, S., and Rhee, S.G. (2015). Circadian Oscillation of Sulfiredoxin in the Mitochondria. Mol. Cell 59, 651-663. crossref(new window)

Ko, C.H., Yamada, Y.R., Welsh, D.K., Buhr, E.D., Liu, A.C., Zhang, E.E., Ralph, M.R., Kay, S. a, Forger, D.B., and Takahashi, J.S. (2010). Emergence of noise-induced oscillations in the central circadian pacemaker. PLoS Biol. 8, e1000513. crossref(new window)

Kondratov, R. V., Kondratova, A. a., Gorbacheva, V.Y., Vykhovanets, O. V., and Antoch, M.P. (2006). Early aging and age-related pathologies in mice deficient in BMAL1, the core component of the circadian clock. Genes Dev. 20, 1868-1873. crossref(new window)

Kondratov, R. V., Vykhovanets, O., Kondratova, A. a., and Antoch, M.P. (2009). Antioxidant N-acetyl-L-cysteine ameliorates symptoms of premature aging associated with the deficiency of the circadian protein BMAL1. Aging 1, 979-987. crossref(new window)

Kruiswijk, F., Labuschagne, C.F., and Vousden, K.H. (2015). p53 in survival, death and metabolic health: a lifeguard with a licence to kill. Nat. Rev. Mol. Cell Biol. 16, 393-405. crossref(new window)

Kulathu, Y., Garcia, F.J., Mevissen, T.E.T., Busch, M., Arnaudo, N., Carroll, K.S., Barford, D., and Komander, D. (2013). Regulation of A20 and other OTU deubiquitinases by reversible oxidation. Nat. Commun. 4, 1569. crossref(new window)

Lamia, K. a, Sachdeva, U.M., DiTacchio, L., Williams, E.C., Alvarez, J.G., Egan, D.F., Vasquez, D.S., Juguilon, H., Panda, S., Shaw, R.J., et al. (2009). AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science 326, 437-440. crossref(new window)

Langner, R., and Rensing, L. (1972). Circadian rhythm of oxygen consumption in rat liver suspension culture: changes of pattern. Z. Naturforsch. B. 27, 1117-1118.

Lee, S.-R., Kwon, K.S., Kim, S.R., and Rhee, S.G. (1998). Reversible Inactivation of Protein-tyrosine Phosphatase 1B in A431 Cells Stimulated with Epidermal Growth Factor. J. Biol. Chem. 273, 15366-15372. crossref(new window)

Lee, C., Etchegaray, J.P., Cagampang, F.R., Loudon, a S., and Reppert, S.M. (2001). Posttranslational mechanisms regulate the mammalian circadian clock. Cell 107, 855-867. crossref(new window)

Lee, J., Moulik, M., Fang, Z., Saha, P., Zou, F., Xu, Y., Nelson, D.L., Ma, K., Moore, D.D., and Yechoor, V.K. (2013a). Bmal1 and ${\beta}$-cell clock are required for adaptation to circadian disruption, and their loss of function leads to oxidative stress-induced ${\beta}$-cell failure in mice. Mol. Cell. Biol. 33, 2327-2338. crossref(new window)

Lee, J.-G., Baek, K., Soetandyo, N., and Ye, Y. (2013b). Reversible inactivation of deubiquitinases by reactive oxygen species in vitro and in cells. Nat. Commun. 4, 1568. crossref(new window)

Leise, T.L., Wang, C.W., Gitis, P.J., and Welsh, D.K. (2012). Persistent cell-autonomous circadian oscillations in fibroblasts revealed by six-week single-cell imaging of PER2::LUC bioluminescence. PLoS One 7, e33334. crossref(new window)

Lipton, J.O., Yuan, E.D., Boyle, L.M., Ebrahimi-Fakhari, D., Kwiatkowski, E., Nathan, A., Güttler, T., Davis, F., Asara, J.M., and Sahin, M. (2015). The circadian protein BMAL1 regulates translation in response to S6K1-mediated phosphorylation. Cell 161, 1138-1151. crossref(new window)

Lowrey, P.L., Shimomura, K., Antoch, M.P., Yamazaki, S., Zemenides, P.D., Ralph, M.R., Menaker, M., and Takahashi, J.S. (2000). Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. Science 288, 483-492. crossref(new window)

Maier, B., Wendt, S., Vanselow, J.T., Wallach, T., Reischl, S., Oehmke, S., Schlosser, A., and Kramer, A. (2009). A large-scale functional RNAi screen reveals a role for CK2 in the mammalian circadian clock. Genes Dev. 23, 708-718. crossref(new window)

Maiorino, M., Roveri, A., Benazzi, L., Bosello, V., Mauri, P., Toppo, S., Tosatto, S.C.E., and Ursini, F. (2005). Functional interaction of phospholipid hydroperoxide glutathione peroxidase with sperm mitochondrion-associated cysteine-rich protein discloses the adjacent cysteine motif as a new substrate of the selenoperoxidase. J. Biol. Chem. 280, 38395-38402. crossref(new window)

Masri, S., Rigor, P., Cervantes, M., Ceglia, N., Sebastian, C., Xiao, C., Roqueta-Rivera, M., Deng, C., Osborne, T.F., Mostoslavsky, R., et al. (2014). Partitioning circadian transcription by SIRT6 leads to segregated control of cellular metabolism. Cell 158, 659-672. crossref(new window)

Matsuo, T., Yamaguchi, S., Mitsui, S., Emi, A., Shimoda, F., and Okamura, H. (2003). Control mechanism of the circadian clock for timing of cell division in vivo. Science 302, 255-259. crossref(new window)

Mauvoisin, D., Wang, J., Jouffe, C., Martin, E., Atger, F., Waridel, P., Quadroni, M., Gachon, F., and Naef, F. (2014). Circadian clockdependent and -independent rhythmic proteomes implement distinct diurnal functions in mouse liver. Proc. Natl. Acad. Sci. USA 111, 167-172. crossref(new window)

Maywood, E.S., Chesham, J.E., Brien, J.A.O., and Hastings, M.H. (2011). A diversity of paracrine signals sustains molecular circadian cycling in suprachiasmatic nucleus circuits. Proc. Natl. Acad. Sci. USA 108, 14306-14311. crossref(new window)

McCord, J.M., and Fridovich, I. (1969). Superoxide dismutase: and enzymatic function for erythrocuprein (hemocuprein). J. Biol. Chem. 244, 6049-6055.

Meng, Q.-J., Logunova, L., Maywood, E.S., Gallego, M., Lebiecki, J., Brown, T.M., Sladek, M., Semikhodskii, A.S., Glossop, N.R.J., Piggins, H.D., et al. (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. crossref(new window)

Mitsuishi, Y., Taguchi, K., Kawatani, Y., Shibata, T., Nukiwa, T., Aburatani, H., Yamamoto, M., and Motohashi, H. (2012). Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell 22, 66-79. crossref(new window)

Mohawk, J. a., Green, C.B., and Takahashi, J.S. (2012). Central and peripheral circadian clocks in mammals. Annu. Rev. Neurosci. 35, 445-462. crossref(new window)

Monteiro, H.P., and Stern, A. (1996). Redox modulation of tyrosine phosphorylation-dependent signal transduction pathways. Free Radic. Biol. Med. 21, 323-333. crossref(new window)

Musiek, E.S. (2015). Circadian clock disruption in neurodegenerative diseases: cause and effect? Front. Pharmacol. 6, 29.

Musiek, E.S., Lim, M.M., Yang, G., Bauer, A.Q., Qi, L., Lee, Y., Roh, J.H., Ortiz-gonzalez, X., Dearborn, J.T., Culver, J.P., et al. (2013). Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration. J. Clin. Invest. 123, 5389-5400. crossref(new window)

Nadeau, P.J., Charette, S.J., Toledano, M.B., and Landry, J. (2007). Disulfide Bond-mediated multimerization of Ask1 and its reduction by thioredoxin-1 regulate H(2)O(2)-induced c-Jun NH(2)-terminal kinase activation and apoptosis. Mol. Biol. Cell 18, 3903-3913. crossref(new window)

Nagy, P., Karton, A., Betz, A., Peskin, A.V, Pace, P., O'Reilly, R.J., Hampton, M.B., Radom, L., and Winterbourn, C.C. (2011). Model for the exceptional reactivity of peroxiredoxins 2 and 3 with hydrogen peroxide: a kinetic and computational study. J. Biol. Chem. 286, 18048-18055. crossref(new window)

Nakahata, Y., Sahar, S., Astarita, G., Kaluzova, M., and Sassone-Corsi, P. (2009). Circadian control of the $NAD^+$ salvage pathway by CLOCK-SIRT1. Science 324, 654-657. crossref(new window)

Nakajima, M., Imai, K., Ito, H., Nishiwaki, T., Murayama, Y., Iwasaki, H., Oyama, T., and Kondo, T. (2005). Reconstitution of circadian oscillation of cyanobacterial KaiC phosphorylation in vitro. Science 308, 414-415. crossref(new window)

Nangle, S.N., Rosensweig, C., Koike, N., Tei, H., Takahashi, J.S., Green, C.B., and Zheng, N. (2014). Molecular assembly of the period-cryptochrome circadian transcriptional repressor complex. Elife 15, e30674.

O'Neill, J.S., and Reddy, A.B. (2011). Circadian clocks in human red blood cells. Nature 469, 498-503. crossref(new window)

O'Neill, J.S., and Reddy, A.B. (2012). The essential role of cAMP / $Ca^{2+}$ signalling in mammalian circadian timekeeping. Biochem. Soc. Trans. 40, 44-50. crossref(new window)

O'Neill, J.S., Maywood, E.S., Chesham, J.E., Takahashi, J.S., and Hastings, M.H. (2008). cAMP-dependent signaling as a core component of the mammalian circadian pacemaker. Science 320, 949-953. crossref(new window)

O'Neill, J.S., Ooijen, G. Van, Dixon, L.E., Troein, C., Corellou, F., Bouget, F.-Y., Reddy, A.B., Millar, A.J., and van Ooijen, G. (2011). Circadian rhythms persist without transcription in a eukaryote. Nature 469, 554-558. crossref(new window)

O'Neill, J.S., Maywood, E.S., and Hastings, M.H. (2013). Cellular mechanisms of circadian pacemaking: beyond transcriptional loops. Handb. Exp. Pharmacol. 2013, 67-103.

Okano, S., Akashi, M., Hayasaka, K., and Nakajima, O. (2009). Unusual circadian locomotor activity and pathophysiology in mutant CRY1 transgenic mice. Neurosci. Lett. 451, 246-251. crossref(new window)

Ono, D., Honma, S., and Honma, K. (2013). Cryptochromes are critical for the development of coherent circadian rhythms in the mouse suprachiasmatic nucleus. Nat. Commun. 4, 1666. crossref(new window)

Papp, S.J., Huber, A.-L., Jordan, S.D., Kriebs, A., Nguyen, M., Moresco, J.J., Yates, J.R., and Lamia, K.A. (2015). DNA damage shifts circadian clock time via Hausp-dependent Cry1 stabilization. Elife 4, doi: 10.7554/eLife.04883. crossref(new window)