Alternative titles; symbols
HGNC Approved Gene Symbol: CRY1
Cytogenetic location: 12q23.3 Genomic coordinates (GRCh38) : 12:106,991,364-107,093,549 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q23.3 | {Delayed sleep phase disorder, susceptibility to} | 614163 | Autosomal dominant | 3 |
CRY1 and its pattern of circadian expression are central to the core autoregulatory loop of the mammalian circadian clock. CRY1 predominantly displays evening-time expression and serves as a strong repressor of morning-time elements (E box/E-prime box) when bound to the BMAL1 (ARNTL; 602550)/CLOCK (601851) complex (summary by Ukai-Tadenuma et al., 2011).
Photolyases are enzymes that mediate photoreactivation, a repair mechanism that removes UV-induced DNA damage. Most photolyases contain 2 chromophores: flavin adenine dinucleotide (FAD), and a second, variable chromophore. Class I photolyases include microbial photolyases and several plant blue-light photoreceptors, in contrast to class II photolyases, which have been found in higher eukaryotes. Van der Spek et al. (1996) identified an EST clone with homology to a bacterial photolyase. They cloned the full-length cDNA that encodes a 586-amino acid polypeptide that is 25% identical to plant blue-light receptors. Sequence conservation suggested that human photolyase-1 has FAD-binding ability. Northern blot analysis showed that the gene is constitutively expressed, suggesting that photolyase-1 may have function(s) other than repair of UV-damaged DNA.
Todo et al. (1996) isolated a cDNA from a human brain cDNA library that they referred to as the human (6-4)photolyase homologous protein. The amino acid sequence of the human protein had 48% identity to that of Drosophila (6-4)photolyase. The 3-kb mRNA was expressed in multiple tissues.
Hsu et al. (1996) determined that the human (6-4)photolyase (CRY1) protein has 73% amino acid identity with CRY2 (603732). Hsu et al. (1996) purified the human CRY1 and CRY2 proteins and characterized them as maltose-binding fusion proteins that contain FAD and a pterin cofactor. Both CRY1 and CRY2 proteins lacked photolyase activity. Hsu et al. (1996) concluded that these proteins are not photolyases, but may function as blue-light photoreceptors in humans. Kobayashi et al. (1998) demonstrated that, while Cry1 is localized to the mitochondria, Cry2 is found mainly in the nucleus. The N terminus of mouse Cry1 contains a mitochondrial transport signal. Cry1 protein bound tightly to DNA Sepharose, while Cry2 protein did not.
Griffin et al. (1999) examined the activity of human CRY1 and CRY2 in an assay in which a heterodimeric activator consisting of CLOCK and BMAL1 drives a luciferase reporter gene from mouse Per1 gene (602260) E boxes in cultured cells. When the cells were kept in total darkness from the time of transfection until harvesting, both CRY1 and CRY2 strongly inhibited CLOCK-BMAL1 activity, with CRY1 consistently showing a somewhat more potent inhibition than CRY2. To determine whether light could modulate CRY activity, Griffin et al. (1999) performed transcriptional reporter assays in paired sets of cells that had been kept in constant darkness or constant light. No differences were observed. Using a yeast 2-hybrid assay in which yeast transformants were grown in duplicate sets under constant light or darkness, CRY1 and CRY2 showed specific interactions with mammalian clock components that were independent of light. Human CRY1 produced strong interaction signals with both mouse Per1 and BMAL1, a modest but reproducible interaction signal with mouse Per1, and no interaction signal above background with CLOCK or TIM (603887). CRY2 was similar to CRY1 in that it produced a strong interaction signal with mouse Per2 (603426), but different in that it produced weak but reproducible interaction signals with CLOCK and TIM and no detectable interaction signal with mouse Per1 or BMAL1. Griffin et al. (1999) concluded that these results strongly suggest that CRY1 and CRY2 inhibit the CLOCK-BMAL1 heterodimer in mammalian cells by forming direct contacts with it, possibly within a multiprotein complex including PER and TIM proteins. Additional experiments by Griffin et al. (1999) indicated a specific functional antagonism between CRYs and TIM and suggested cross-regulation among the proteins inhibiting CLOCK-BMAL1 activity within the circadian clock feedback loop. Griffin et al. (1999) suggested that Drosophila CRY exemplifies the ancestral role of the photoreceptor acting as a light-dependent regulator of the circadian feedback loop, whereas mammalian CRYs have preserved the role within the circadian feedback loop but have shed their direct photoreceptor function.
Kume et al. (1999) determined that the mouse Cry1 and Cry2 genes act in the negative limb of the clock feedback loop. They stated that mouse Cry1 and Cry2 are nuclear proteins that interact with each of the Per proteins, translocate each Per protein from cytoplasm to nucleus, and are rhythmically expressed in the suprachiasmatic circadian clock. Luciferase reporter gene assays showed that Cry1 or Cry2 alone abrogates Clock/Bmal1 E box-mediated transcription. The mouse Per and Cry proteins appeared to inhibit the transcriptional complex differentially.
To investigate the biologic role of NPAS2 (603347), Reick et al. (2001) prepared a neuroblastoma cell line capable of conditional induction of the NPAS2:BMAL1 heterodimer and identified putative target genes by representational difference analysis, DNA microarrays, and Northern blotting. Coinduction of NPAS2 and BMAL1 activated transcription of the endogenous Per1, Per2, and Cry1 genes, which encode negatively activating components of the circadian regulatory apparatus, and repressed transcription of the endogenous BMAL1 gene. Analysis of the frontal cortex of wildtype mice kept in a 24-hour light-dark cycle revealed that Per1, Per2, and Cry1 mRNA levels were elevated during darkness and reduced during light, whereas BMAL1 mRNA displayed the opposite pattern. In situ hybridization assays of mice kept in constant darkness revealed that Per2 mRNA abundance did not oscillate as a function of circadian cycle in NPAS2-deficient mice. Thus, NPAS2 likely functions as part of a molecular clock operative in the mammalian forebrain.
Etchegaray et al. (2003) demonstrated that transcriptional regulation of the core clock mechanism in mouse liver is accompanied by rhythms in H3 histone (see 602810) acetylation, and that H3 acetylation is a potential target of the inhibitory action of Cry. The promoter regions of the Per1, Per2, and Cry1 genes exhibited circadian rhythms in H3 acetylation and RNA polymerase II (see 180660) binding that were synchronous with the corresponding steady-state mRNA rhythms. The histone acetyltransferase p300 (602700) precipitated with Clock in vivo in a time-dependent manner. Moreover, the Cry proteins inhibited a p300-induced increase in Clock/Bmal1-mediated transcription. Etchegaray et al. (2003) concluded that the delayed timing of the Cry1 mRNA rhythm, relative to the Per rhythms, was due to the coordinated activities of Rev-Erb-alpha (602408) and Clock/Bmal1, and defined a novel mechanism for circadian phase control.
Busza et al. (2004) showed that Drosophila CRY binding to TIM (603887) is light-dependent in flies and irreversibly commits TIM to proteasomal degradation. In contrast, CRY degradation is dependent on continuous light exposure, indicating that the CRY-TIM interaction is transient. A novel CRY mutation reveals that CRY's photolyase homology domain is sufficient for light detection and phototransduction, whereas the carboxyl-terminal domain regulates CRY stability, CRY-TIM interaction, and circadian photosensitivity.
Toward a system-level understanding of the transcriptional circuitry regulating circadian clocks, Ueda et al. (2005) identified clock-controlled elements on 16 clock and clock-controlled genes in a comprehensive surveillance of evolutionarily conserved cis elements and measurement of the transcriptional dynamics. Ueda et al. (2005) found that E boxes (CACGTG) and E-prime boxes (CACGTT) controlled the expression of Per1 (602260), Nr1d2 (602304), Per2 (603426), Nr1d1 (602408), Dbp (124097), Bhlhb2 (604256), and Bhlhb3 (606200) transcription following a repressor-precedes-activator pattern, resulting in delayed transcriptional activity. RevErbA/ROR (600825)-binding (RRE) elements regulated the transcriptional activity of Arntl, Npas2 (603347), Nfil3 (605327), Clock, Cry1, and Rorc (602943) through a repressor-precedes-activator pattern as well. DBP/E4BP4-binding elements controlled the expression of Per1, Per2, Per3 (603427), Nr1d1, Nr1d2, Rora, and Rorb (601972) through a repressor-antiphasic-to-activator mechanism, which generates high-amplitude transcriptional activity. Ueda et al. (2005) suggested that regulation of E/E-prime boxes is a topologic vulnerability in mammalian circadian clocks, a concept that had been functionally verified using in vitro phenotype assay systems.
Sandrelli et al. (2007) found that ls-tim, a mutant allele of Drosophila timeless that enhances diapause, attenuates photosensitivity of the circadian clock and causes decreased dimerization of the mutant protein to cryptochrome.
O'Neill et al. (2008) showed that cAMP signaling constitutes an additional bona fide component of the oscillatory network of the circadian rhythm. They proposed that daily activation of cAMP signaling, driven by the transcriptional oscillator, in turn sustains progression of transcriptional rhythms. In this way, clock output constitutes an input to subsequent cycles.
Studying mouse fibroblasts, Lamia et al. (2009) demonstrated that the nutrient-responsive adenosine monophosphate-activated protein kinase (AMPK; see 602739) phosphorylates and destabilizes the clock component CRY1. In mouse livers, AMPK activity and nuclear localization were rhythmic and inversely correlated with CRY1 nuclear protein abundance. Stimulation of AMPK destabilized cryptochromes and altered circadian rhythms, and mice in which the AMPK pathway was genetically disrupted showed alterations in peripheral clocks. Thus, Lamia et al. (2009) concluded that phosphorylation by AMPK enables cryptochrome to transduce nutrient signals to circadian clocks in mammalian peripheral organs.
Ukai-Tadenuma et al. (2011) noted that CRY1 contains an E box and an E-prime box, which are morning-time elements, in its regulatory region and 2 RRE elements, which are night-time elements, in intron 1. They identified functional D boxes, which are day-time elements, in the CRY1 promoter region. By transfecting Cry1 -/- Cry2 -/- cells, which lack circadian oscillation, with an array of Cry1 constructs, Ukai-Tadenuma et al. (2011) showed that the combination of D boxes and RREs gave rise to evening-time Cry1 expression and that a substantial delay of Cry1 expression was required for circadian rhythmicity.
Lamia et al. (2011) showed that 2 circadian coregulators, Cry1 and Cry2 (603732), interact with glucocorticoid receptor (138040) in a ligand-dependent fashion and globally alter the transcriptional response to glucocorticoids in mouse embryonic fibroblasts: cryptochrome deficiency vastly decreases gene repression and approximately doubles the number of dexamethasone-induced genes, suggesting that cryptochromes broadly oppose glucocorticoid receptor activation and promote repression. In mice, genetic loss of Cry1 and/or 2 results in glucose intolerance and constitutively high levels of circulating corticosterone, suggesting reduced suppression of the hypothalamic-pituitary-adrenal axis coupled with increased glucocorticoid transactivation in the liver. Genomically, cryptochromes 1 and 2 associate with a glucocorticoid response element in the phosphoenolpyruvate carboxykinase-1 (PCK1; 614168) promoter in a hormone-dependent manner, and dexamethasone-induced transcription of the Pck1 gene was strikingly increased in cryptochrome-deficient livers. Lamia et al. (2011) concluded that their results revealed a specific mechanism through which cryptochromes couple the activity of clock and receptor target genes to complex genomic circuits underpinning normal metabolic homeostasis.
In mammals, PERIOD (PER1; 602260 and PER2; 603426) and CRYPTOCHROME (CRY1 and CRY2; 603732) proteins accumulate, form a large nuclear complex (PER complex), and repress their own transcription. Padmanabhan et al. (2012) found that mouse PER complexes included RNA helicases DDX5 (180630) and DHX9 (603115), active RNA polymerase II large subunit (180660), Per and Cry pre-mRNAs, and SETX (608465), a helicase that promotes transcriptional termination. During circadian negative feedback, RNA polymerase II accumulated near termination sites on Per and Cry genes but not on control genes. Recruitment of PER complexes to the elongating polymerase at Per and Cry termination sites inhibited SETX action, impeding RNA polymerase II release and thereby repressing transcriptional reinitiation. Circadian clock negative feedback thus includes direct control of transcriptional termination.
Van der Spek et al. (1996) used in situ hybridization to map the photolyase 1 gene to human chromosome 12q23-q24.1. They noted that this region includes the locus for ulnar-mammary syndrome (181450) and keratosis follicularis (124200). Kobayashi et al. (1998) isolated and characterized the mouse Cry1 and Cry2 genes and mapped them to chromosomes 10C and 2E, respectively.
In affected members of 7 unrelated families, mostly of Turkish origin, with delayed sleep phase disorder (DSPD; 614163), Patke et al. (2017) identified a splice site mutation in the CRY1 gene (601933.0001). The mutation in the first family was found by a combination of candidate gene and whole-exome sequencing. The variant was found at a frequency of 0.6% in databases of human genetic variation: minor allele frequency of 0.0012 in the 1000 Genomes Project and 0.004335 in the ExAC databases; this frequency lies within the reported range of DSPD prevalence in the general population. In vitro functional expression studies showed that the mutant CRY1 increased circadian period via a gain of function. The mutant protein showed increased localization to the nucleus compared to wildtype, and had increased interaction with its target transcription factors CLOCK and ARNTL, resulting in increased transcriptional inhibition.
Van der Horst et al. (1999) disrupted the Cry1 and Cry2 genes in mice. Homozygous Cry1 -/-, Cry2 -/-, and double-mutant mice had normal 24-hour circadian rhythms when exposed to 12h/12h light/dark cycles. In total darkness, Cry1 -/- mice had a faster running clock (22.51 +/- 0.06 h, P = 0.00001) than wildtype mice, while Cry2 -/- mice had a slower clock (24.63 +/- 0.06 h, P = 0.00001). In total darkness, double-mutant mice showed a striking instantaneous arrhythmicity, indicating the absence of an internal circadian clock. The 'clock' mutant mouse differs in that it shows a more gradual onset of arrhythmicity. Mice with only 1 copy of wildtype Cry2 displayed a free-running rhythm even shorter than that of Cry1 knockouts, which gradually progressed into arrhythmicity. Once returned to a light/dark cycle, the normal 24-hour period resumed. Mice with only 1 functional allele of Cry1 showed rhythmic activity, with a period intermediate to that of Cry1 -/- and Cry2 -/- mice. Van der Horst et al. (1999) concluded that their results demonstrated that the Cry proteins are involved in maintaining period length and circadian rhythmicity, and that a critical balance between Cry1 and Cry2 is required for proper clock functioning.
Freedman et al. (1999) studied circadian behavior in mice deficient in both rods and cones. These mice maintained a light-entrained circadian rhythm, which they lost with enucleation. Lucas et al. (1999) studied pineal melatonin secretion in mice lacking both rods and cones. There was normal suppression of pineal melatonin in response to monochromatic light of wavelength 509 nm. The authors suggested that mammals have additional ocular photoreceptors that they use in the regulation of temporal physiology, and suggested Cry1 and Cry2 as candidates.
Okamura et al. (1999) demonstrated that, in mice lacking Cry1 and Cry2, cyclic expression of the clock genes Per1 and Per2 is abolished in the suprachiasmatic nucleus and peripheral tissues and that Per1 and Per2 mRNA levels are constitutively high. These findings indicated that the biologic clock is eliminated in the absence of both Cry1 and Cry2 and supported the idea that mammalian CRY proteins act in the negative limb of the circadian feedback loop. The Cry double mutant mice retained the ability to have Per1 and Per2 expression induced by a brief light stimulus known to phase-shift the biologic clock in wildtype animals. Thus, Cry1 and Cry2 are dispensable for light-induced phase shifting of the biologic clock.
Shearman et al. (2000) demonstrated that in the mouse, the core mechanism for the master circadian clock consists of interacting positive and negative transcription and translation feedback loops. Analysis of Clock/Clock mutant mice, homozygous Per2 mutants, and Cry-deficient mice revealed substantially altered Bmal1 rhythms, consistent with a dominant role of Per2 in the positive regulation of the Bmal1 loop. In vitro analysis of Cry inhibition of Clock:Bmal1-mediated transcription shows that the inhibition is through direct protein-protein interactions, independent of the Per and Tim proteins. Per2 is a positive regulator of the Bmal1 loop, and Cry1 and Cry2 are the negative regulators of the Period and Cryptochrome cycles.
Yagita et al. (2001) used wildtype and Cry1 -/- and Cry2 -/- deficient cell lines derived from Cry mutant mice to demonstrate that the peripheral oscillator in cultured fibroblasts is identical to the oscillator in the suprachiasmatic nucleus in (1) temporal expression profiles of all known clock genes; (2) the phase of the various mRNA rhythms (i.e., antiphase oscillation of Bmal1 and Per); (3) the delay between maximum mRNA levels and appearance of nuclear Per1 and Per2 protein; (4) the inability to produce oscillations in the absence of functional Cry genes; and (5) the control of period length by Cry proteins.
Mice carrying a mutant Per2 gene gradually lose circadian rhythmicity when kept in constant darkness. Oster et al. (2002) crossed mice with a mutation in the Per2 PAS protein interaction domain with Cry1 -/- or Cry2 -/- mice. Double-homozygous mutant animals were born at the expected mendelian ratio, appeared fertile, and were morphologically indistinguishable from wildtype animals. Per2 mutant-Cry2 -/- mice maintained circadian rhythmicity and normal clock gene expression patterns when kept in constant darkness, suggesting that Cry2 functions as a nonallelic suppressor of Per2. In marked contrast, Per2 mutant-Cry1 -/- mice did not maintain circadian rhythmicity, but instead showed complete behavioral arrhythmicity in constant darkness.
Van Gelder et al. (2003) tested pupillary light responses of cryptochrome mutant mice (Cry1 -/-; Cry2 -/-), outer retinal degenerate (rd/rd) mice, and mice mutant for all of these loci, as well as littermate controls. There was substantial loss of constriction in rd/rd mice compared with control mice. The double mutants for the cryptochromes showed a pupillary response similar in magnitude to that in control mice. Almost no pupillary constriction was observed in the triple knockouts at a 470-nm light intensity. Pupillary responses of the triple mutants were about 5% as sensitive to blue light as those of the rd/rd mice. Some pupillary responses were retained in the triple mutant mice under very bright light, although pupillary movement was somewhat sluggish. The 50% constriction threshold of pupillary responses was noted in Cry1 -/-;rd/rd and Cry2 -/-;rd/rd mice, and was comparable to those of rd/rd mice, indicating that either Cry1 or Cry2 function is sufficient for retention of pupillary responses in rd/rd animals. Since all mice were of the same strain background, strain differences were unlikely to account for the observed differences in pupillary light responses. Van Gelder et al. (2003) suggested that murine cryptochromes may function as inner retinal photopigments.
Ikeda et al. (2007) found that, when maintained in a light-dark cycle, Cry1 -/- Cry2 -/- double-mutant mice showed normal circadian locomotor activity, including feeding. However circadian rhythmicity of oxygen consumption, heart rate, and body temperature were abolished. Cry1 -/- Cry2 -/- mice also showed impaired glucose tolerance due to decreased insulin secretion.
In affected members of 7 unrelated families, mostly of Turkish origin, with delayed sleep phase disorder (DSPD; 614163), Patke et al. (2017) identified an A-to-C transversion (c.1657+3A-C) in intron 11 of the CRY1 gene, resulting in a splice site alteration. Analysis of cells from 1 patient confirmed that the mutation resulted in deletion of exon 11 with an in-frame deletion of 24 residues in the C-terminal region. The mutation in the first family was found by a combination of candidate gene and whole-exome sequencing. The mutation segregated with the disorder in all families; there were 31 heterozygous carriers and 8 homozygous carriers, and there were no phenotypic differences between heterozygous and homozygous carriers. The variant was found at a frequency of 0.6% in databases of human genetic variation: minor allele frequency of 0.0012 in the 1000 Genomes Project and 0.004335 in the ExAC databases; this frequency lies within the reported range of DSPD prevalence in the general population. In vitro functional expression studies in mouse embryonic fibroblasts showed that mutant CRY1 increased the circadian period by approximately half an hour compared to wildtype, which was similar to the human phenotype. The mutant protein showed increased localization to the nucleus compared to wildtype, and it had increased interaction with its target transcription factors CLOCK (601851) and ARNTL (602550), resulting in increased transcriptional inhibition consistent with a gain of function. Chromatin immunoprecipitation studies indicated that the CRY1 mutation displaced the CLOCK and ARNTL transcription factors from chromatin at their target gene promoters, resulting in decreased expression of these target genes.
Busza, A., Emery-Le, M., Rosbash, M., Emery, P. Roles of the two Drosophila CRYPTOCHROME structural domains in circadian photoreception. Science 304: 1503-1506, 2004. [PubMed: 15178801] [Full Text: https://doi.org/10.1126/science.1096973]
Etchegaray, J.-P., Lee, C., Wade, P. A., Reppert, S. M. Rhythmic histone acetylation underlies transcription in the mammalian circadian clock. Nature 421: 177-182, 2003. [PubMed: 12483227] [Full Text: https://doi.org/10.1038/nature01314]
Freedman, M. S., Lucas, R. J., Soni, B., von Schantz, M., Munoz, M., David-Gray, Z., Foster, R. Regulation of mammalian circadian behavior by non-rod, non-cone, ocular photoreceptors. Science 284: 502-504, 1999. [PubMed: 10205061] [Full Text: https://doi.org/10.1126/science.284.5413.502]
Griffin, E. A., Jr., Staknis, D., Weitz, C. J. Light-independent role of CRY1 and CRY2 in the mammalian circadian clock. Science 286: 768-771, 1999. [PubMed: 10531061] [Full Text: https://doi.org/10.1126/science.286.5440.768]
Hsu, D. S., Zhao, X., Zhao, S., Kazantsev, A., Wang, R.-P., Todo, T., Wei, Y.-F., Sancar, A. Putative human blue-light photoreceptors hCRY1 and hCRY2 are flavoproteins. Biochemistry 35: 13871-13877, 1996. [PubMed: 8909283] [Full Text: https://doi.org/10.1021/bi962209o]
Ikeda, H., Yong, Q., Kurose, T., Todo, T., Mizunoya, W., Fushiki, T., Seino, Y., Yamada, Y. Clock gene defect disrupts light-dependency of autonomic nerve activity. Biochem. Biophys. Res. Commun. 364: 457-463, 2007. [PubMed: 17964540] [Full Text: https://doi.org/10.1016/j.bbrc.2007.10.058]
Kobayashi, K., Kanno, S., Smit, B., van der Horst, G. T. J., Takao, M., Yasui, A. Characterization of photolyase/blue-light receptor homologs in mouse and human cells. Nucleic Acids Res. 26: 5086-5092, 1998. [PubMed: 9801304] [Full Text: https://doi.org/10.1093/nar/26.22.5086]
Kume, K., Zylka, M. J., Sriram, S., Shearman, L. P., Weaver, D. R., Jin, X., Maywood, E. S., Hastings, M. H., Reppert, S. M. mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop. Cell 98: 193-205, 1999. [PubMed: 10428031] [Full Text: https://doi.org/10.1016/s0092-8674(00)81014-4]
Lamia, K. A., Papp, S. J., Yu, R. T., Barish, G. D., Uhlenhaut, N. H., Jonker, J. W., Downes, M., Evans, R. M. Cryptochromes mediate rhythmic repression of the glucocorticoid receptor. Nature 480: 552-556, 2011. [PubMed: 22170608] [Full Text: https://doi.org/10.1038/nature10700]
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., Thompson, C. B., Evans, R. M. AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science 326: 437-440, 2009. [PubMed: 19833968] [Full Text: https://doi.org/10.1126/science.1172156]
Lucas, R. J., Freedman, M. S., Munoz, M., Garcia-Fernandez, J.-M., Foster, R. G. Regulation of the mammalian pineal by non-rod, non-cone, ocular photoreceptors. Science 284: 505-507, 1999. [PubMed: 10205062] [Full Text: https://doi.org/10.1126/science.284.5413.505]
O'Neill, J. S., Maywood, E. S., Chesham, J. E., Takahashi, J. S., Hastings, M. H. cAMP-dependent signaling as a core component of the mammalian circadian pacemaker. Science 320: 949-953, 2008. [PubMed: 18487196] [Full Text: https://doi.org/10.1126/science.1152506]
Okamura, H., Miyake, S., Sumi, Y., Yamaguchi, S., Yasui, A., Muijtjens, M., Hoeijmakers, J. H. J., van der Horst, G. T. J. Photic induction of mPer1 and mPer2 in Cry-deficient mice lacking a biological clock. Science 286: 2531-2534, 1999. [PubMed: 10617474] [Full Text: https://doi.org/10.1126/science.286.5449.2531]
Oster, H., Yasui, A., van der Horst, G. T. J., Albrecht, U. Disruption of mCry2 restores circadian rhythmicity in mPer2 mutant mice. Genes Dev. 16: 2633-2638, 2002. [PubMed: 12381662] [Full Text: https://doi.org/10.1101/gad.233702]
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. [PubMed: 22767893] [Full Text: https://doi.org/10.1126/science.1221592]
Patke, A., Murphy, P. J., Onat, O. E., Krieger, A. C., Ozcelik, T., Campbell, S. S., Young, M. S. Mutation of the human circadian clock gene CRY1 in familial delayed sleep phase disorder. Cell 169: 203-215, 2017. [PubMed: 28388406] [Full Text: https://doi.org/10.1016/j.cell.2017.03.027]
Reick, M., Garcia, J. A., Dudley, C., McKnight, S. L. NPAS2: an analog of clock operative in the mammalian forebrain. Science 293: 506-509, 2001. [PubMed: 11441147] [Full Text: https://doi.org/10.1126/science.1060699]
Sandrelli, F., Tauber, E., Pegoraro, M., Mazzotta, G., Cisotto, P., Landskron, J., Stanewsky, R., Piccin, A., Rosato, E., Zordan, M., Costa, R., Kyriacou, C. P. A molecular basis for natural selection at the timeless locus in Drosophila melanogaster. Science 316: 1898-1900, 2007. [PubMed: 17600216] [Full Text: https://doi.org/10.1126/science.1138426]
Shearman, L. P., Sriram, S., Weaver, D. R., Maywood, E. S., Chaves, I., Zheng, B., Kume, K., Lee, C. C., van der Horst, G. T. J., Hastings, M. H., Reppert, S. M. Interacting molecular loops in the mammalian circadian clock. Science 288: 1013-1019, 2000. [PubMed: 10807566] [Full Text: https://doi.org/10.1126/science.288.5468.1013]
Todo, T., Ryo, H., Yamamoto, K., Toh, H., Inui, T., Ayaki, H., Nomura, T., Ikenaga, M. Similarity among the Drosophila (6-4)photolyase, a human photolyase homolog, and the DNA photolyase--blue-light photoreceptor family. Science 272: 109-112, 1996. [PubMed: 8600518] [Full Text: https://doi.org/10.1126/science.272.5258.109]
Ueda, H. R., Hayashi, S., Chen, W., Sano, M., Machida, M., Shigeyoshi, Y., Iino, M., Hashimoto, S. System-level identification of transcriptional circuits underlying mammalian circadian clocks. Nature Genet. 37: 187-192, 2005. [PubMed: 15665827] [Full Text: https://doi.org/10.1038/ng1504]
Ukai-Tadenuma, M., Yamada, R. G., Xu, H., Ripperger, J. A., Liu, A. C., Ueda, H. R. Delay in feedback repression by Cryptochrome 1 is required for circadian clock function. Cell 144: 268-281, 2011. [PubMed: 21236481] [Full Text: https://doi.org/10.1016/j.cell.2010.12.019]
van der Horst, G. T. J., Muijtjens, M., Kobayashi, K., Takano, R., Kanno, S., Takao, M., de Wit, J., Verkerk, A., Eker, A. P. M., van Leenen, D., Buijs, R., Bootsma, D., Hoeijmakers, J. H. J., Yasui, A. Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms. Nature 398: 627-630, 1999. [PubMed: 10217146] [Full Text: https://doi.org/10.1038/19323]
van der Spek, P. J., Kobayashi, K., Bootsma, D., Takao, M., Eker, A. P. M., Yasui, A. Cloning, tissue expression, and mapping of a human photolyase homolog with similarity to plant blue-light receptors. Genomics 37: 177-182, 1996. [PubMed: 8921389] [Full Text: https://doi.org/10.1006/geno.1996.0539]
Van Gelder, R. N., Wee, R., Lee, J. A., Tu, D. C. Reduced pupillary light responses in mice lacking cryptochromes. Science 299: 222 only, 2003. [PubMed: 12522242] [Full Text: https://doi.org/10.1126/science.1079536]
Yagita, K., Tamanini, F., van der Horst, G. T. J., Okamura, H. Molecular mechanisms of the biological clock in cultured fibroblasts. Science 292: 278-281, 2001. [PubMed: 11303101] [Full Text: https://doi.org/10.1126/science.1059542]