Transcriptional repressor which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, ARNTL/BMAL1, ARNTL2/BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and ARNTL/BMAL1 or ARNTL2/BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress ARNTL/BMAL1 transcription, respectively. CRY1 and CRY2 have redundant functions but also differential and selective contributions at least in defining the pace of the SCN circadian clock and its circadian transcriptional outputs. More potent transcriptional repressor in cerebellum and liver than CRY2, though more effective in lengthening the period of the SCN oscillator. On its side, CRY2 seems to play a critical role in tuning SCN circadian period by opposing the action of CRY1. With CRY2, is dispensable for circadian rhythm generation but necessary for the development of intercellular networks for rhythm synchrony. Capable of translocating circadian clock core proteins such as PER proteins to the nucleus. Interacts with CLOCK-ARNTL/BMAL1 independently of PER proteins and is found at CLOCK-ARNTL/BMAL1-bound sites, suggesting that CRY may act as a molecular gatekeeper to maintain CLOCK-ARNTL/BMAL1 in a poised and repressed state until the proper time for transcriptional activation. Represses the CLOCK-ARNTL/BMAL1 induced transcription of BHLHE40/DEC1, ATF4, MTA1, KLF10 and NAMPT. May repress circadian target genes expression in collaboration with HDAC1 and HDAC2 through histone deacetylation. Mediates the clock-control activation of ATR and modulates ATR-mediated DNA damage checkpoint. In liver, mediates circadian regulation of cAMP signaling and gluconeogenesis by binding to membrane-coupled G proteins and blocking glucagon-mediated increases in intracellular cAMP concentrations and CREB1 phosphorylation. Inhibits hepatic gluconeogenesis by decreasing nuclear FOXO1 levels that down-regulates gluconeogenic gene expression. Besides its role in the maintenance of the circadian clock, is also involved in the regulation of other processes. Represses glucocorticoid receptor NR3C1/GR-induced transcriptional activity by binding to glucocorticoid response elements (GREs). Plays a key role in glucose and lipid metabolism modulation, in part, through the transcriptional regulation of genes involved in these pathways, such as LEP or ACSL4. Represses PPARD and its target genes in the skeletal muscle and limits exercise capacity (PubMed:28683290). Plays an essential role in the generation of circadian rhythms in the retina (PubMed:29561690). Represses the transcriptional activity of NR1I2 (PubMed:28751364). Binds 1 FAD per subunit. Only a minority of the protein molecules contain bound FAD. Contrary to the situation in photolyases, the FAD is bound in a shallow, surface-exposed pocket. Binds 1 5,10-methenyltetrahydrofolate (MTHF) non-covalently per subunit. KL001 (N-[3-(9H-carbazol-9-yl)-2-hydroxypropyl]-N-(2-furanylmethyl)-methanesulfonamide) binds to CRY1 and stabilizes it by inhibiting FBXL3- and ubiquitin-dependent degradation of CRY1 resulting in lengthening of the circadian periods. KL001-mediated CRY1 stabilization can inhibit glucagon-induced gluconeogenesis in primary hepatocytes. Component of the circadian core oscillator, which includes the CRY proteins, CLOCK or NPAS2, ARNTL/BMAL1 or ARNTL2/BMAL2, CSNK1D and/or CSNK1E, TIMELESS, and the PER proteins (PubMed:11779462). Interacts directly with TIMELESS (PubMed:10428031, PubMed:24489120, PubMed:23418588). Interacts directly with PER1 and PER2; interaction with PER2 inhibits its ubiquitination and vice versa (PubMed:10428031, PubMed:11889036, PubMed:11875063, PubMed:14701732, PubMed:16478995, PubMed:23746849, PubMed:23418588, PubMed:21613214, PubMed:20159955). Interacts with PER3 (PubMed:10428031, PubMed:14701732). Interacts with FBXL21 (PubMed:18953409, PubMed:23452855, PubMed:23452856). Interacts with FBXL3 (PubMed:17462724, PubMed:23746849, PubMed:23452855, PubMed:23452856, PubMed:30500822). Interacts with PPP5C (via TPR repeats) (By similarity). Interacts with CLOCK-ARNTL/BMAL1 independently of PER2 and DNA (PubMed:21613214). Interacts with HDAC1, HDAC2 and SIN3B (PubMed:15226430). Interacts with nuclear receptors AR, NR1D1, NR3C1/GR, RORA and RORC; the interaction with at least NR3C1/GR is ligand dependent (PubMed:22170608, PubMed:28751364). Interacts with PRKDC (PubMed:24158435). Interacts with the G protein subunit alpha GNAS; the interaction may block GPCR-mediated regulation of cAMP concentrations (By similarity). Interacts with PRMT5 (PubMed:23133559). Interacts with EZH2 (PubMed:16717091). Interacts with MYBBP1A, DOCK7, HNRNPU, RPL7A, RPL8 and RPS3 (PubMed:19129230). Interacts with MAP1LC3B (PubMed:29937374). Interacts with CLOCK (PubMed:16717091, PubMed:19917250). Interacts with ARNTL/BMAL1 (PubMed:26776516, PubMed:16717091, PubMed:19917250, PubMed:23746849). Interacts weakly with HDAC3; this interaction is enhanced in the presence of FBXL3 (PubMed:26776516). Interacts with TRIM28, KCTD5 and DDB1 (PubMed:27123980). Interacts with DTL (By similarity). Interacts with DDB1-CUL4A complex (PubMed:26431207). Interacts with FOXO1 (PubMed:28790135). Interacts with PSMD2 in a KDM8-dependent manner (PubMed:30500822). Interacts with KDM8 in a FBXL3-dependent manner (PubMed:30500822). Interacts with PPARA (PubMed:28683290). Interacts with PPARG in a ligand-dependent manner (PubMed:28683290). Interacts with PPARD (via domain NR LBD) in a ligand-dependent manner (PubMed:28683290, PubMed:28751364). Interacts with NR1I2 (via domain NR LBD) in a ligand-dependent manner (PubMed:28751364). Interacts with NR1I3, VDR and HNF4A (PubMed:28751364). Transloctaed to the nucleus through interaction with other clock proteins such as PER2 or ARNTL/BMAL1. Expressed in cones, amacrine cells, and retinal ganglion cells of the retina (at protein level) (PubMed:29561690). Expressed in all tissues examined including heart, brain, spleen, lung, liver, skeletal muscle, kidney and testis. Higher levels in brain, liver and testis. In the retina, highly expressed in the ganglion cell layer (GCL) and in the inner nuclear layer (INL). Evenly distributed in central and peripheral retina. In the brain, highly expressed in the suprachiasmatic nucleus (SCN). High levels in cerebral cortical layers particularly in the pyramidial cell layer of the hippocampus, the granular cell layer of the dentate gyrus (DG) and the pyramidal cell layer of the piriform cortex (PFC). Oscillates diurnally, rhythmic expression in the early night is critical for clock function (at protein level). In SCN, exhibits circadian rhythm expression with highest levels during the light phase at CT10. No detectable expression after 8 hours in the dark. Circadian oscillations also observed in liver, skeletal muscle and cerebellum, but not in testis. The LIR motifs (LC3-interacting region) 3 and 5 are required for its interaction with MAP1LC3B and for its autophagy-mediated degradation. Phosphorylation on Ser-247 by MAPK is important for the inhibition of CLOCK-ARNTL/BMAL1-mediated transcriptional activity. Phosphorylation by CSNK1E requires interaction with PER1 or PER2. Phosphorylation at Ser-71 and Ser-280 by AMPK decreases protein stability. Phosphorylation at Ser-588 exhibits a robust circadian rhythm with a peak at CT8, increases protein stability, prevents SCF(FBXL3)-mediated degradation and is antagonized by interaction with PRKDC. Ubiquitinated by the SCF(FBXL3) and SCF(FBXL21) complexes, regulating the balance between degradation and stabilization. The SCF(FBXL3) complex is mainly nuclear and mediates ubiquitination and subsequent degradation of CRY1. In contrast, cytoplasmic SCF(FBXL21) complex-mediated ubiquitination leads to stabilize CRY1 and counteract the activity of the SCF(FBXL3) complex. The SCF(FBXL3) and SCF(FBXL21) complexes probably mediate ubiquitination at different Lys residues. Ubiquitination at Lys-11 and Lys-107 are specifically ubiquitinated by the SCF(FBXL21) complex but not by the SCF(FBXL3) complex. Ubiquitination may be inhibited by PER2. Deubiquitinated by USP7 (PubMed:27123980). Undergoes autophagy-mediated degradation in the liver in a time-dependent manner. Autophagic degradation of CRY1 (an inhibitor of gluconeogenesis) occurs during periods of reduced feeding allowing induction of gluconeogenesis and maintenance of blood glucose levels. Mice show an advanced phase shift (around 4 hours) in the expression of DBP, NR1D1 and PER1 genes in the liver. Double knockouts of CRY1 and CRY2 show slightly decrease body weight and lose the cycling rhythmicity of feeding behavior, energy expenditure and glucocorticoids expression. Glucose homeostasis is severely disrupted and animals exhibit elevated blood glucose in response to acute feeding after an overnight fast as well as severely impaired glucose clearance in a glucose tolerance test. When challenged with high-fat diet, animals rapidly gain weight and surpass that of wild-type mice, despite displaying hypophagia. They exhibit hyperinsulinemia and selective insulin resistance in the liver and muscle but show high insulin sensitivity in adipose tissue and consequent increased lipid uptake. Mice display enlarged gonadal, subcutaneous and perirenal fat deposits with adipocyte hypertrophy and increased lipied accumulation in liver. Mice show loss of circadian rhythms in photopic ERG b-wave amplitudes, visual contrast sensitivity and pupillary light responses, with reduced robustness and stability of bioluminescent rhythms (PubMed:29561690). Both single CRY1 knockout and double CRY1 and CRY2 knockout mice show increased exercise performance and increased mitochondrial reserve capacity in primary myotubes (PubMed:28683290). Belongs to the DNA photolyase class-1 family.