{"gene":"CRY1","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":1999,"finding":"Mice lacking both CRY1 and CRY2 show complete and instantaneous loss of free-running circadian rhythmicity, establishing that these proteins are essential components for maintenance of circadian rhythmicity; CRY1-deficient mice alone display accelerated (shorter) free-running locomotor period.","method":"Genetic knockout (Cry1-/-, Cry2-/-, and double knockout mice), behavioral locomotor activity assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined behavioral phenotype, replicated across multiple genotypes in a landmark study","pmids":["10217146"],"is_preprint":false},{"year":2014,"finding":"Crystal structure of the mouse CRY1 photolyase homology region (PHR) in complex with a C-terminal fragment of PER2 revealed that PER2 winds around CRY1, covering the FBXL3 and CLOCK/BMAL1 binding sites but not the FAD binding pocket. An unexpected zinc ion at the interface stabilizes the CRY1-PER2 interaction in vivo, and complex formation is modulated by interplay between zinc binding and CRY1 disulfide bond formation.","method":"X-ray crystallography, in vivo interaction assays, mutagenesis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with mutagenesis and in vivo validation in a single rigorous study","pmids":["24855952"],"is_preprint":false},{"year":2017,"finding":"A dominant CRY1 coding variant (exon 11 splice variant, CRY1Δ11) found in familial delayed sleep phase disorder creates a transcriptional inhibitor with enhanced affinity for CLOCK and BMAL1, reduces expression of key transcriptional targets, and lengthens the period of circadian molecular rhythms.","method":"Human genetics (family-based sequencing), functional cell-based circadian period assays, CLOCK/BMAL1 binding affinity measurements","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — human variant with direct functional characterization using multiple orthogonal methods across independent families","pmids":["28388406"],"is_preprint":false},{"year":2017,"finding":"CRY1 binds directly to the PAS domain core of CLOCK:BMAL1, driven primarily by interaction with the CLOCK PAS-B domain. Integrative modeling and solution X-ray scattering positioned a key loop of CLOCK PAS-B in the secondary pocket of CRY1 (analogous to the antenna chromophore-binding pocket of photolyase). Single point mutations at either CRY1 or CLOCK disrupted ternary complex formation.","method":"Biochemical binding assays, small-angle X-ray scattering (SAXS), integrative structural modeling, mutagenesis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural method (SAXS + modeling) combined with mutagenesis and functional validation in one rigorous study","pmids":["28143926"],"is_preprint":false},{"year":2018,"finding":"Macroautophagy selectively degrades CRY1 via LC3-interacting region (LIR) motifs on CRY1. Two distinct LIRs were identified by mutational analysis; their disruption alters circadian glycemic control. Autophagic CRY1 degradation occurs in a diurnal window and is accelerated by high-fat feeding, contributing to obesity-associated hyperglycemia.","method":"Mutational analysis of LIR motifs, lysosomal fractionation, co-immunoprecipitation with LC3, in vivo mouse studies","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (mutagenesis, fractionation, Co-IP, in vivo) in a single comprehensive study","pmids":["29937374"],"is_preprint":false},{"year":2015,"finding":"Genotoxic stress stimulates CRY1 phosphorylation and its deubiquitination by Hausp (USP7), stabilizing CRY1 and shifting circadian clock time. DNA damage also increases CRY2 interaction with FBXL3, destabilizing CRY2; thus genotoxic stress increases the CRY1/CRY2 ratio.","method":"Post-translational modification assays, deubiquitination assays, protein stability measurements, circadian phase-shift assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal biochemical methods with functional circadian readout in one detailed study","pmids":["25756610"],"is_preprint":false},{"year":2006,"finding":"The C-terminal extension of CRY1 harbors a nuclear localization signal and a putative coiled-coil domain that drive nuclear localization via two independent mechanisms and shift CRY1/PER2 complexes toward the nucleus. Deletion of the complete C-terminus prevents CRY1 from repressing CLOCK/BMAL1-mediated transcription; fusion of the last 100 aa of CRY1 core and C-terminus to plant photolyase confers CLOCK/BMAL1 repressor function.","method":"Deletion mutagenesis, nuclear localization assays, transcriptional repression assays, chimeric protein fusion experiments","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple domain-deletion and chimeric constructs with functional readouts demonstrating mechanism","pmids":["16478995"],"is_preprint":false},{"year":2012,"finding":"USP2a, a circadian-controlled deubiquitinating enzyme, interacts with CRY1 and stabilizes it via deubiquitination upon serum shock. Depletion of Usp2a enhances CRY1 ubiquitination and dampens CRY1 protein oscillation amplitude. TNF-α increases CRY1 protein level in a USP2a-dependent manner.","method":"Co-immunoprecipitation, shRNA knockdown, ubiquitination assays, luciferase reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, functional ubiquitination assays, and in vivo mouse liver validation with multiple methods","pmids":["22669941"],"is_preprint":false},{"year":2015,"finding":"CUL4-DDB1-CDT2 E3 ligase ubiquitinates CRY1 at lysine 585 and promotes its degradation both in vitro and in vivo. Depletion of DDB1, CDT2, or PCNA stabilizes CRY1; a CRY1-K585A mutant is resistant to CUL4A-DDB1-mediated ubiquitination and degradation, and enhances the oscillatory amplitude of Bmal1 promoter activity.","method":"In vitro ubiquitination assay, site-directed mutagenesis (K585A), shRNA knockdown, luciferase reporter assay, in vivo mouse liver studies","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of ubiquitination plus mutagenesis of target lysine and in vivo validation","pmids":["26431207"],"is_preprint":false},{"year":2017,"finding":"DDB1 promotes FOXO1-driven hepatic gluconeogenesis by degrading CRY1 via the DDB1-CUL4A ubiquitin E3 ligase. In the absence of CRY1, insulin fails to reduce nuclear FOXO1 abundance or suppress gluconeogenic gene expression; hepatocyte-specific Ddb1 deletion reduces CRY1 degradation and protects against high-fat diet-induced hyperglycemia.","method":"Hepatocyte-specific knockout mice, Western blotting, gluconeogenesis assays, FOXO1 localization studies","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO with mechanistic pathway placement and multiple functional readouts","pmids":["28790135"],"is_preprint":false},{"year":2016,"finding":"SREBP1c activated by insulin induces CRY1 expression, and CRY1 decreases hepatic gluconeogenesis through promoting FOXO1 degradation by increasing its binding to the ubiquitin E3 ligase MDM2. SREBP1c-/- and CRY1-/- mice show higher blood glucose in pyruvate tolerance tests, and CRY1 overexpression attenuates hyperglycemia in db/db mice.","method":"Knockout mice, adenovirus-mediated CRY1 overexpression, co-immunoprecipitation, glucose metabolism assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic models, Co-IP identifying molecular mechanism, and in vivo metabolic validation","pmids":["27412556"],"is_preprint":false},{"year":2020,"finding":"The CRY1 tail (particularly the region encoded by exon 11) modulates the affinity of the PHR domain for CLOCK:BMAL1 by providing an intramolecular inhibitory interaction. The PHR-binding epitope in exon 11 is necessary and sufficient to disrupt the CRY1-CLOCK interaction, and PHR-tail interactions are reduced when CRY1 is bound to PER2.","method":"NMR, biochemical binding assays, mutagenesis, functional circadian period rescue assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structural data combined with mutagenesis and functional rescue experiments","pmids":["33106415"],"is_preprint":false},{"year":2016,"finding":"Multisite phosphorylation of CRY1 can serve as a cumulative timer in the mammalian circadian clock. CRY1-PER2 interaction confers robust circadian rhythmicity. Residues surrounding the flexible P loop and C-lid domains of CRY1 determine circadian period without changing CRY1 degradation rate, indicating that CRY1 determines circadian period through both degradation-dependent and -independent pathways.","method":"Knockout-rescue mouse system with phosphorylation-mimetic CRY1 mutants, circadian behavioral assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — comprehensive panel of phosphomimetic mutants in KO-rescue mice with rigorous in vivo circadian phenotyping","pmids":["28017587"],"is_preprint":false},{"year":2017,"finding":"CRY1 and CRY2 function as co-repressors for PPARδ in muscle, repressing a distinct subset of PPARδ target genes. Cry1-/-;Cry2-/- myotubes and muscles exhibit elevated expression of PPARδ target genes particularly during exercise; genetic disruption of Cry1 and Cry2 enhances sprint exercise performance in vivo.","method":"Cell-based transcriptional assays, KO mouse muscle gene expression analysis, in vivo exercise performance testing","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO cell and mouse studies with defined transcriptional and physiological phenotypes for a specific nuclear receptor co-repressor function","pmids":["28683290"],"is_preprint":false},{"year":2017,"finding":"CRY1 and CRY2 serve as co-repressors for many nuclear hormone receptors (NRs), binding independently of other core clock factors at genomic sites enriched for NR recognition motifs, contributing to diurnal modulation of drug metabolism.","method":"ChIP-seq, transcriptional reporter assays, Co-IP","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq with multiple orthogonal functional assays establishing co-repressor role for broad NR family","pmids":["28751364"],"is_preprint":false},{"year":2021,"finding":"CRY1 is androgen-responsive and stabilized by DNA damage in cancer cells. Stabilized CRY1 temporally regulates expression of homologous recombination genes, promotes efficient DNA repair and G2/M transition, and is required for survival following DNA damage in prostate cancer.","method":"CRY1 cistrome (ChIP-seq) and transcriptome mapping, CRY1 knockdown/knockout, DNA damage assays, in vitro and in vivo tumor models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide cistrome mapping combined with loss-of-function and in vivo validation with multiple orthogonal readouts","pmids":["33452241"],"is_preprint":false},{"year":2019,"finding":"CRY1 is a negative regulator of HIF-1α: CRY1 interacts with the bHLH domain of HIF-1α via its tail region, reduces HIF-1α half-life, and decreases HIF binding to target gene promoters. Genetic disruption of CRY1 (but not CRY2) induces cellular HIF levels, proliferation, and migration.","method":"Co-immunoprecipitation, protein stability assays, promoter-binding assays, CRISPR/Cas9 and shRNA knockouts","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding demonstrated by Co-IP with domain mapping, CRY1-specific KO with functional cellular phenotypes","pmids":["30875610"],"is_preprint":false},{"year":2020,"finding":"Cystathionine β-synthase (CBS), a central enzyme in one-carbon metabolism, functionally interacts with CRY1. CBS augments CRY1-mediated repression of CLOCK/BMAL1 and shortens circadian period. Reciprocally, CRY1 modulates CBS enzymatic activity; liver extracts from Cry1-/- mice show reduced CBS activity that normalizes upon addition of exogenous wild-type CRY1.","method":"Co-immunoprecipitation, circadian period assays, enzymatic activity assays, knockout mouse liver extracts, metabolomics","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional functional interaction established by multiple orthogonal biochemical methods with in vivo KO validation","pmids":["32383312"],"is_preprint":false},{"year":2018,"finding":"JMJD5 interacts with CRY1 in an FBXL3-dependent manner and facilitates targeting of CRY1 to the proteasome. Genetic deletion of JMJD5 results in greater CRY1 stability, reduced CRY1 association with the proteasome, and disruption of circadian gene expression. JMJD5 also cooperates with CRY1 to repress CLOCK-BMAL1; AMPK-induced CRY1 degradation is impaired in the absence of JMJD5.","method":"Co-immunoprecipitation, JMJD5 knockout cell lines, protein stability assays, luciferase reporter assays","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO cells with multiple functional readouts and direct protein interaction established by Co-IP","pmids":["30500822"],"is_preprint":false},{"year":2020,"finding":"CRY1 promotes p53 degradation by increasing the binding of p53 to its ubiquitin E3 ligase MDM2, thereby preventing paclitaxel-induced senescence in cisplatin-resistant bladder cancer cells.","method":"CRY1 knockdown, co-immunoprecipitation of p53-MDM2, SA-β-Gal senescence assay","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP mechanistic assay and KD phenotype, but single lab with limited mechanistic follow-up","pmids":["33650658"],"is_preprint":false},{"year":2002,"finding":"CRY1, CRY2, and PER2 activate BMAL1 transcription, while BMAL1-CLOCK dimers repress it, establishing an interlocked feedback loop. CRY transcriptional repressor potency was shown to be predominant within the mammalian clock.","method":"Luciferase reporter assay, BMAL1 promoter characterization, transfection of clock components","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reporter assays in cultured cells, single lab, but consistent with other mechanistic data in the field","pmids":["11798163"],"is_preprint":false},{"year":2001,"finding":"An intact flavin binding domain is required for CRY1 function in suppressing CLOCK/BMAL1 activity. In Xenopus CRY1, only mutation of the last of the three conserved tryptophan residues in the putative electron transport chain significantly affects CRY1 function, in contrast to CRY2 where any of the three tryptophan mutations inhibit function, demonstrating molecular differences between CRY1 and CRY2.","method":"Site-directed mutagenesis, transcriptional repression assays (luciferase), cell transfection","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of conserved residues with functional assay, single lab, Xenopus ortholog","pmids":["11747820"],"is_preprint":false},{"year":2013,"finding":"CRY1 is more potent than CRY2 as a transcriptional repressor within the SCN clockwork: stabilization of CRY1 (via Fbxl3Afh) prolongs the interval of transcriptional suppression and lengthens circadian period more potently than CRY2. CRY2 attenuates the period-lengthening effects of CRY1.","method":"Genetic epistasis (Fbxl3Afh mutation in CRY1- and CRY2-deficient mice), SCN bioluminescence assays, behavioral wheel-running assays","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis in multiple genetic backgrounds with both molecular and behavioral readouts establishes differential CRY1 vs CRY2 potency","pmids":["23616524"],"is_preprint":false},{"year":2012,"finding":"Cry1-/- mice require SCN intercellular coupling to sustain circadian rhythms: disruption of coupling in vivo by constant light reveals a cell-autonomous circadian defect in Cry1-/- SCN cells (fewer rhythmic single cells) that is normally compensated by intercellular coupling.","method":"Constant-light protocol to disrupt coupling, single-cell bioluminescence imaging of PER2::LUC in SCN slices","journal":"Journal of biological rhythms","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct live imaging at single-cell resolution in intact tissue with defined genetic background","pmids":["23223370"],"is_preprint":false},{"year":2020,"finding":"Arg-293 of CRY1 allosterically regulates the serine-rich loop adjacent to the secondary pocket, controlling CLOCK-CRY1 binding affinity. The p.Arg293His CRY1 variant shortens circadian period, reduces repressor activity on CLOCK/BMAL1 transcription, and reduces CRY1 affinity for BMAL1/CLOCK in the absence of PER2. Molecular dynamics simulations revealed altered communication between Arg-293 and the serine loop.","method":"Rescue assay in Cry1-/-Cry2-/- MEFs, luciferase reporter assay, binding affinity measurements, molecular dynamics simulation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cell-based assays with binding data, single lab; MD simulation is computational","pmids":["33028638"],"is_preprint":false},{"year":2008,"finding":"CRY1 knockdown in GV oocytes by RNA interference does not affect transcription of Wee1, Cry2, Per1, Per2, or Per3 (targets it represses in somatic cells), but reduces oocyte maturation ability, indicating CRY1 has a circadian-clock-independent role in meiosis.","method":"RNAi knockdown in mouse oocytes, RT-PCR, maturation assays","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct KD with defined phenotype, but single method and single lab; negative finding for clock function is informative","pmids":["19020302"],"is_preprint":false},{"year":2009,"finding":"A mutation in the conserved cysteine-proline dipeptide motif of CRY1 (C414A, CRY1-AP) when overexpressed causes rhythm splitting with very long free-running periods (~28 h) and abnormal light entrainment, indicating the CP motif is critical for CRY1 function in the clock.","method":"Transgenic mouse generation, circadian locomotor activity assays","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic mice with specific mutant CRY1 and defined behavioral circadian phenotype, single lab","pmids":["19159659"],"is_preprint":false},{"year":2016,"finding":"Phosphorylation of specific CRY1 residues alters circadian period length. Screen of phosphorylation-mimetic mutants identified 10 sites with abnormal period; several mutants (S71D, S247D, T249D, Y266D, Y273D, Y432D) showed reduced repression activity, and differences in protein stability and cellular localization. Results suggest phosphorylation regulates the ratio of functional CRY1 protein to determine period.","method":"Phosphomimetic and non-phosphomimetic mutagenesis screen, CRY-deficient cell rescue assay, luciferase reporter assay, protein stability assay, subcellular localization assay","journal":"Frontiers in neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic mutagenesis with functional readouts, single lab","pmids":["27721804"],"is_preprint":false},{"year":2019,"finding":"Phosphorylation of CRY1 serine 71 by AMPK was tested in vivo via germline Cry1-S71A knock-in mice. This mutation does not affect CRY1 steady-state protein levels or circadian rhythms under standard conditions, but female Cry1-S71A mice exhibit decreased voluntary locomotor activity, suggesting S71 phosphorylation may be involved in metabolic or physiological (non-circadian period) functions.","method":"Germline knock-in mouse (S71A), behavioral assays, protein level measurements","journal":"Journal of biological rhythms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knock-in mouse with defined phenotypes; negative result for circadian period is informative, single lab","pmids":["31258021"],"is_preprint":false},{"year":2020,"finding":"MAGEL2 modulates the ubiquitination of CRY1 as demonstrated by in vivo proximity labeling (BioID), immunofluorescence microscopy, and ubiquitination assays, suggesting a role for MAGEL2-deubiquitinase complexes in regulating CRY1 stability and circadian rhythm.","method":"BioID proximity labeling, immunofluorescence, ubiquitination assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple biochemical methods but limited mechanistic follow-up; functional consequence for circadian period not directly measured","pmids":["32315313"],"is_preprint":false},{"year":2022,"finding":"GSK3β-induced phosphorylation of CRY1 potentiates FBXL3-dependent proteasomal CRY1 degradation in the liver. In diabetic mice, elevated FBXL3 activity leads to reduced hepatic CRY1 protein; GSK3β inhibitors decrease HGP by facilitating CRY1-mediated FOXO1 degradation.","method":"In vivo mouse diabetes model, GSK3β inhibitor treatment, protein stability assays, glucose metabolism assays","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo pharmacological and genetic evidence, single lab","pmids":["35476750"],"is_preprint":false},{"year":2023,"finding":"CRY1 and CRY2 regulate rhythmic hepatic CYP2A5 expression through repression of E4BP4. CRY1/2 interact physically with E4BP4 and repress its inhibitory effect on Cyp2a5 transcription. Cry1-null mice show reduced hepatic CYP2A5 expression and loss of its diurnal rhythms.","method":"Cry1-null and Cry2-null mice, luciferase reporter assays, ChIP, Co-IP, enzymatic activity assays","journal":"Biochemical pharmacology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO mice, reporter assay, ChIP, Co-IP, activity assay) in a single study","pmids":["37797722"],"is_preprint":false},{"year":2013,"finding":"NPAS4 forms functional dimers with ARNT, ARNT2, and ARNTL and transactivates the Cry1 promoter through two conserved central midline elements (CRE). In the ovine pars tuberalis, melatonin induces Npas4, which drives Cry1 expression.","method":"Transcriptome sequencing, in situ hybridization, promoter-reporter assays with deletions and site-directed mutagenesis, in vivo melatonin treatment","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter dissection with mutagenesis and in vivo validation, single lab","pmids":["23598442"],"is_preprint":false},{"year":2018,"finding":"CRY1 knockdown promotes β-catenin expression and nuclear accumulation, suggesting that CRY1 regulates adipogenic differentiation by modulating the canonical Wnt/β-catenin signaling pathway. CRY1 expression increases during adipogenic differentiation and its knockdown inhibits adipogenic markers.","method":"shRNA knockdown in 3T3-L1 and C3H10T1/2 cells, Western blot for β-catenin localization, adipogenesis assays","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single knockdown approach with pathway marker assay, no direct mechanism established, single lab","pmids":["30384996"],"is_preprint":false},{"year":2009,"finding":"CRY1 and CRY2 are required for circadian rhythmicity of pineal melatonin synthesis. Cry1-/-/Cry2-/- mice show loss of circadian variation in pineal melatonin and absence of acute light-induced melatonin suppression, placing CRY1/2 as essential for SCN-mediated photic and circadian control of the pineal gland.","method":"Double knockout mice (C3H background), pineal melatonin measurements under LD and DD, light-pulse suppression assay","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with direct biochemical output (melatonin levels) under multiple lighting conditions","pmids":["20825493"],"is_preprint":false},{"year":2009,"finding":"In the Cry1(-/-)/Cry2(-/-) background, the SCN expresses short-period (~18 h) molecular rhythms; CRY-independent rhythms are not affected by the Fbxl3Afh mutation, confirming that Fbxl3Afh circadian action is exclusively mediated through CRY proteins.","method":"Genetic epistasis (Fbxl3Afh in double KO SCN), bioluminescence recording","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — rigorous epistasis with direct molecular phenotyping in SCN tissue","pmids":["23616524"],"is_preprint":false}],"current_model":"CRY1 is a core circadian transcriptional repressor that directly binds the CLOCK:BMAL1 complex (via its photolyase homology region secondary pocket engaging the CLOCK PAS-B domain) to inhibit E-box-driven transcription; its activity and stability are regulated by a network of post-translational modifications including phosphorylation (by AMPK, GSK3β) and ubiquitination/deubiquitination (by FBXL3/CUL4-DDB1-CDT2 for degradation, and USP7/USP2a for stabilization), its interaction with PER2 is stabilized by zinc binding at a specific interface, its C-terminal tail autoregulates CLOCK binding affinity, and beyond the clock it functions as a co-repressor of nuclear hormone receptors and PPARδ, suppresses HIF-1α stability, modulates hepatic gluconeogenesis through FOXO1 degradation, and regulates DNA repair gene expression in response to genotoxic stress."},"narrative":{"mechanistic_narrative":"CRY1 is a core component of the mammalian circadian clock, functioning as a potent transcriptional repressor that, redundantly with CRY2, is essential for maintenance of free-running circadian rhythmicity [PMID:10217146]. CRY1 directly engages the CLOCK:BMAL1 activator complex through its photolyase homology region (PHR), with a key loop of the CLOCK PAS-B domain inserting into the CRY1 secondary pocket analogous to the photolyase antenna-chromophore site; single point mutations at either interface abolish ternary complex formation and repression [PMID:28143926]. This binding affinity is autoregulated by the CRY1 C-terminal tail: the region encoded by exon 11 provides an intramolecular inhibitory interaction with the PHR that tunes CLOCK:BMAL1 engagement, and the tail also carries nuclear localization determinants required for repressor function [PMID:16478995, PMID:33106415]. CRY1 is a more potent and period-determining repressor than CRY2 [PMID:23616524], and its activity and abundance are set by a dense regulatory layer: stabilizing deubiquitination by USP7 and USP2a [PMID:25756610, PMID:22669941], proteasomal degradation via CUL4-DDB1-CDT2 (ubiquitinating Lys585) and FBXL3-directed pathways gated by GSK3β phosphorylation and JMJD5 [PMID:26431207, PMID:30500822, PMID:35476750], LC3-dependent macroautophagy [PMID:29937374], and multisite phosphorylation that adjusts the functional CRY1 pool and circadian period through both degradation-dependent and -independent routes [PMID:28017587]. Its assembly with PER2 is stabilized by a zinc ion at the interface that covers the FBXL3 and CLOCK:BMAL1 binding sites [PMID:24855952]. Beyond the canonical clock, CRY1 acts as a co-repressor of nuclear hormone receptors broadly and of PPARδ in muscle [PMID:28683290, PMID:28751364], suppresses HIF-1α stability and target-gene binding through its tail [PMID:30875610], drives hepatic glucose homeostasis by promoting FOXO1 degradation via MDM2 [PMID:27412556], and is recruited to chromatin to temporally control DNA-repair gene expression following genotoxic stress [PMID:25756610, PMID:33452241]. A dominant CRY1 exon-11 splice variant (CRY1Δ11) with enhanced CLOCK/BMAL1 affinity lengthens circadian period and causes familial delayed sleep phase disorder [PMID:28388406].","teleology":[{"year":1999,"claim":"Established that CRY proteins are not optional modulators but obligatory for circadian timekeeping, defining the genetic core of the mammalian clock.","evidence":"Single and double Cry knockout mice with locomotor behavioral phenotyping","pmids":["10217146"],"confidence":"High","gaps":["Did not resolve the molecular mechanism of repression","Redundancy with CRY2 obscures CRY1-specific roles"]},{"year":2002,"claim":"Placed CRY1 within an interlocked feedback architecture, showing it activates Bmal1 while repressing CLOCK:BMAL1, with predominant repressor potency in the clock.","evidence":"Luciferase reporter and BMAL1 promoter assays with transfected clock components","pmids":["11798163"],"confidence":"Medium","gaps":["Cell-based reporters do not establish endogenous chromatin behavior","Mechanism of repression not defined"]},{"year":2001,"claim":"Linked the flavin/electron-transport features of the photolyase-derived domain to repressor function and revealed molecular divergence between CRY1 and CRY2.","evidence":"Site-directed mutagenesis of conserved tryptophans and FAD domain in Xenopus CRY, transcriptional repression assays","pmids":["11747820"],"confidence":"Medium","gaps":["Ortholog (Xenopus) may not fully reflect mammalian CRY1","Does not address whether flavin acts catalytically or structurally"]},{"year":2006,"claim":"Identified the CRY1 C-terminal extension as a dual nuclear-localization and repression module, mapping function beyond the photolyase core.","evidence":"Deletion mutagenesis, nuclear localization and repression assays, chimeric photolyase fusions","pmids":["16478995"],"confidence":"High","gaps":["Did not define the structural basis of tail-mediated repression","Interplay with PHR not resolved at this stage"]},{"year":2012,"claim":"Defined opposing deubiquitination and ubiquitination arms that set CRY1 oscillation amplitude, showing USP2a stabilizes CRY1 and links its level to inflammatory and serum signals.","evidence":"Co-IP, shRNA knockdown, ubiquitination and luciferase assays","pmids":["22669941"],"confidence":"High","gaps":["Did not identify the opposing E3 ligase in this context","Physiological role of TNF-α-driven stabilization unclear"]},{"year":2013,"claim":"Demonstrated through epistasis that CRY1 is the dominant period-determining repressor in the SCN and that intercellular coupling masks a cell-autonomous defect in Cry1-null cells.","evidence":"Fbxl3Afh epistasis in Cry-deficient mice, SCN bioluminescence, single-cell imaging, behavioral assays","pmids":["23616524","23223370","23616524"],"confidence":"High","gaps":["Molecular basis of CRY1 vs CRY2 potency difference not fully resolved","Network-level coupling mechanism not identified"]},{"year":2014,"claim":"Provided the structural logic of the CRY1-PER2 complex, showing PER2 wraps the PHR to mask degron and activator-binding sites, with a zinc ion stabilizing the interface.","evidence":"X-ray crystallography of CRY1 PHR-PER2, in vivo interaction assays, mutagenesis","pmids":["24855952"],"confidence":"High","gaps":["Did not capture the full-length tail or CLOCK:BMAL1-bound state","Functional role of disulfide/zinc interplay in vivo only partly defined"]},{"year":2015,"claim":"Showed CRY1 stability is wired into the DNA-damage response, where USP7-mediated deubiquitination raises the CRY1/CRY2 ratio and shifts clock phase under genotoxic stress.","evidence":"Deubiquitination and stability assays, circadian phase-shift readouts","pmids":["25756610"],"confidence":"High","gaps":["Kinase responsible for stress-induced phosphorylation not fully defined","Connection to repair-gene transcription addressed only later"]},{"year":2015,"claim":"Identified CUL4-DDB1-CDT2 as a CRY1 E3 ligase ubiquitinating Lys585, establishing a specific degron controlling clock amplitude.","evidence":"In vitro ubiquitination, K585A mutagenesis, shRNA knockdown, luciferase and in vivo liver assays","pmids":["26431207"],"confidence":"High","gaps":["Relationship to FBXL3-mediated degradation not reconciled","PCNA dependence mechanistically incomplete"]},{"year":2016,"claim":"Integrated CRY1 into hepatic glucose control, showing insulin-induced SREBP1c drives CRY1 expression and CRY1 promotes FOXO1 degradation via MDM2 to suppress gluconeogenesis.","evidence":"Knockout mice, adenoviral overexpression, Co-IP, glucose metabolism assays","pmids":["27412556"],"confidence":"High","gaps":["Whether this is clock-dependent or independent not fully separated","MDM2 recruitment mechanism not structurally defined"]},{"year":2016,"claim":"Established that multisite phosphorylation acts as a cumulative timer setting period through both degradation-dependent and -independent pathways.","evidence":"KO-rescue mice with phosphomimetic CRY1 mutants, circadian behavioral and reporter assays","pmids":["28017587","27721804"],"confidence":"High","gaps":["Kinases for many sites not assigned","Mechanism of degradation-independent period control unclear"]},{"year":2017,"claim":"Mapped the direct CRY1-CLOCK interface, positioning the CLOCK PAS-B loop in the CRY1 secondary pocket and identifying point mutations that disrupt repression.","evidence":"Biochemical binding, SAXS, integrative modeling, mutagenesis","pmids":["28143926"],"confidence":"High","gaps":["No high-resolution crystal structure of the ternary complex","Dynamics of pocket engagement not resolved"]},{"year":2017,"claim":"Connected a human CRY1 exon-11 splice variant with enhanced CLOCK/BMAL1 affinity to familial delayed sleep phase disorder, linking molecular gain-of-repression to a sleep phenotype.","evidence":"Family-based sequencing, cell-based period and binding-affinity assays","pmids":["28388406"],"confidence":"High","gaps":["Did not establish in vivo human physiology beyond circadian period","Structural basis of enhanced affinity defined only later"]},{"year":2017,"claim":"Broadened CRY1's transcriptional role beyond the clock, establishing it as a co-repressor of nuclear hormone receptors and of PPARδ in muscle, with physiological consequences for drug metabolism and exercise.","evidence":"ChIP-seq, reporter assays, Co-IP, KO mouse muscle and exercise phenotyping","pmids":["28751364","28683290"],"confidence":"High","gaps":["How CRY1 is recruited to NR sites independent of CLOCK:BMAL1 not defined","Selectivity for subsets of target genes unexplained"]},{"year":2017,"claim":"Linked CRY1 to insulin-regulated gluconeogenesis via DDB1-CUL4A degradation controlling nuclear FOXO1.","evidence":"Hepatocyte-specific Ddb1 knockout mice, FOXO1 localization and gluconeogenesis assays","pmids":["28790135"],"confidence":"High","gaps":["Reconciliation with MDM2-mediated FOXO1 degradation pathway incomplete","Diurnal timing of degradation not fully mapped"]},{"year":2018,"claim":"Revealed macroautophagy as a distinct, diet-responsive CRY1 degradation route via LIR motifs, coupling CRY1 turnover to glycemic control.","evidence":"LIR mutagenesis, lysosomal fractionation, LC3 Co-IP, in vivo mouse studies","pmids":["29937374"],"confidence":"High","gaps":["Relative contribution vs proteasomal degradation not quantified","Signal triggering diurnal autophagic window undefined"]},{"year":2018,"claim":"Identified JMJD5 as an FBXL3-dependent co-factor targeting CRY1 to the proteasome and cooperating in CLOCK:BMAL1 repression, integrating AMPK-driven turnover.","evidence":"Co-IP, JMJD5 knockout cells, stability and reporter assays","pmids":["30500822"],"confidence":"High","gaps":["Enzymatic role of JMJD5 in this process unclear","Direct vs scaffolding contribution not separated"]},{"year":2019,"claim":"Established CRY1 as a negative regulator of HIF-1α, with its tail binding the HIF-1α bHLH domain to reduce its stability and target-gene occupancy, a CRY1-specific (not CRY2) function.","evidence":"Co-IP with domain mapping, stability and promoter-binding assays, CRISPR/shRNA knockouts","pmids":["30875610"],"confidence":"High","gaps":["Mechanism by which CRY1 lowers HIF-1α half-life not defined","In vivo hypoxia relevance not established"]},{"year":2019,"claim":"Tested AMPK-target Ser71 phosphorylation in vivo, showing it is dispensable for steady-state period but tied to sex-specific locomotor/metabolic physiology.","evidence":"Germline Cry1-S71A knock-in mice, behavioral and protein-level assays","pmids":["31258021"],"confidence":"Medium","gaps":["Mechanism linking S71 to activity phenotype undefined","Single-site knock-in may be buffered by other sites"]},{"year":2020,"claim":"Resolved the autoinhibitory logic of the CRY1 tail, showing the exon-11 epitope competes intramolecularly for the PHR to lower CLOCK:BMAL1 affinity, releasing upon PER2 binding.","evidence":"NMR, biochemical binding, mutagenesis, circadian period rescue assays","pmids":["33106415"],"confidence":"High","gaps":["Full structural ensemble of tail-PHR states not captured","Quantitative coupling to in vivo period not complete"]},{"year":2020,"claim":"Defined an allosteric route (Arg-293 to the serine-rich loop) controlling CLOCK-CRY1 affinity and explaining a short-period human variant.","evidence":"Cry-deficient MEF rescue, reporter and binding assays, molecular dynamics simulation","pmids":["33028638"],"confidence":"Medium","gaps":["MD predictions of allostery not experimentally validated structurally","Single-lab functional data"]},{"year":2020,"claim":"Uncovered a bidirectional CRY1-CBS interaction connecting the clock to one-carbon metabolism, where CBS augments CRY1 repression and CRY1 modulates CBS activity.","evidence":"Co-IP, period and enzymatic assays, KO mouse liver extracts, metabolomics","pmids":["32383312"],"confidence":"High","gaps":["Structural basis of mutual regulation unknown","Metabolic significance in vivo only partly defined"]},{"year":2020,"claim":"Implicated CRY1 in p53 turnover via MDM2, linking it to chemotherapy-induced senescence in cancer cells.","evidence":"CRY1 knockdown, p53-MDM2 Co-IP, senescence assay","pmids":["33650658"],"confidence":"Medium","gaps":["Single-lab Co-IP without reciprocal structural validation","Generality beyond bladder cancer cells untested"]},{"year":2020,"claim":"Identified MAGEL2 as a proximity partner modulating CRY1 ubiquitination, implicating MAGEL2-deubiquitinase complexes in CRY1 stability.","evidence":"BioID proximity labeling, immunofluorescence, ubiquitination assays","pmids":["32315313"],"confidence":"Medium","gaps":["Functional consequence for circadian period not directly measured","Direct vs indirect interaction not resolved"]},{"year":2021,"claim":"Established a chromatin-level role for CRY1 in the DNA-damage response, where androgen- and damage-stabilized CRY1 temporally controls homologous-recombination gene expression and supports cancer-cell survival.","evidence":"CRY1 cistrome and transcriptome mapping, loss-of-function, DNA-damage and tumor models","pmids":["33452241"],"confidence":"High","gaps":["Direct DNA-binding vs co-factor recruitment not distinguished","Relationship to canonical clock targets unclear"]},{"year":2022,"claim":"Connected GSK3β phosphorylation to FBXL3-dependent CRY1 degradation in liver, defining a druggable node for hepatic glucose production.","evidence":"In vivo diabetic mouse model, GSK3β inhibitor treatment, stability and glucose assays","pmids":["35476750"],"confidence":"Medium","gaps":["GSK3β phosphosite on CRY1 not mapped","Single-lab in vivo evidence"]},{"year":2023,"claim":"Extended CRY1's diurnal control of xenobiotic metabolism, showing it represses E4BP4 to drive rhythmic hepatic CYP2A5 expression.","evidence":"Cry1/Cry2-null mice, reporter assays, ChIP, Co-IP, enzymatic activity assays","pmids":["37797722"],"confidence":"High","gaps":["Mechanism of CRY1-E4BP4 repression not structurally defined","Generalization to other CYPs not established"]},{"year":null,"claim":"How the many parallel CRY1 degradation routes (FBXL3, CUL4-DDB1-CDT2, autophagy, USP7/USP2a) and phosphorylation sites are integrated into a single coherent period-setting and tissue-specific metabolic program remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified model reconciling competing E3 ligases and DUBs","Tissue-specific selection of CRY1's clock vs non-clock functions unexplained","No full-length ternary CLOCK:BMAL1:CRY1:PER2 structure"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,3,6,14,20,22,31]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,10,16,19]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[14,15]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[6,15]}],"pathway":[{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[0,3,22,34]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,14,20,31]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[9,10,13,17,31]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4,5,7,8,18,30]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[5,15]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[4]}],"complexes":[],"partners":["PER2","CLOCK","BMAL1","FBXL3","USP7","USP2A","JMJD5","HIF1A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q16526","full_name":"Cryptochrome-1","aliases":[],"length_aa":586,"mass_kda":66.4,"function":"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, BMAL1, 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 BMAL1 or 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-BMAL1|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 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-BMAL1 independently of PER proteins and is found at CLOCK-BMAL1-bound sites, suggesting that CRY may act as a molecular gatekeeper to maintain CLOCK-BMAL1 in a poised and repressed state until the proper time for transcriptional activation. Represses the CLOCK-BMAL1 induced transcription of BHLHE40/DEC1. Represses the CLOCK-BMAL1 induced transcription of ATF4, MTA1, KLF10 and NAMPT (By similarity). 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 (By similarity). 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 (By similarity). Represses PPARD and its target genes in the skeletal muscle and limits exercise capacity (By similarity). Plays an essential role in the generation of circadian rhythms in the retina (By similarity). Represses the transcriptional activity of NR1I2 (By similarity)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q16526/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CRY1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CSNK1E","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CRY1","total_profiled":1310},"omim":[{"mim_id":"619771","title":"VRK SERINE/THREONINE KINASE 3; VRK3","url":"https://www.omim.org/entry/619771"},{"mim_id":"615782","title":"CIRCADIAN-ASSOCIATED REPRESSOR OF TRANSCRIPTION; CIART","url":"https://www.omim.org/entry/615782"},{"mim_id":"615576","title":"MICRO RNA 185; MIR185","url":"https://www.omim.org/entry/615576"},{"mim_id":"614517","title":"BRAIN AND MUSCLE ARNT-LIKE PROTEIN 2; BMAL2","url":"https://www.omim.org/entry/614517"},{"mim_id":"614168","title":"PHOSPHOENOLPYRUVATE CARBOXYKINASE 1, SOLUBLE; PCK1","url":"https://www.omim.org/entry/614168"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear membrane","reliability":"Supported"},{"location":"Microtubules","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CRY1"},"hgnc":{"alias_symbol":[],"prev_symbol":["PHLL1"]},"alphafold":{"accession":"Q16526","domains":[{"cath_id":"3.40.50.620","chopping":"1-129","consensus_level":"medium","plddt":94.1037,"start":1,"end":129},{"cath_id":"1.25.40.80","chopping":"131-166_216-302","consensus_level":"medium","plddt":91.9815,"start":131,"end":302},{"cath_id":"1.10.579.10","chopping":"323-473","consensus_level":"high","plddt":95.7497,"start":323,"end":473}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16526","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q16526-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q16526-F1-predicted_aligned_error_v6.png","plddt_mean":84.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CRY1","jax_strain_url":"https://www.jax.org/strain/search?query=CRY1"},"sequence":{"accession":"Q16526","fasta_url":"https://rest.uniprot.org/uniprotkb/Q16526.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q16526/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16526"}},"corpus_meta":[{"pmid":"10217146","id":"PMC_10217146","title":"Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms.","date":"1999","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/10217146","citation_count":1087,"is_preprint":false},{"pmid":"28388406","id":"PMC_28388406","title":"Mutation of the Human Circadian Clock Gene CRY1 in Familial Delayed Sleep Phase Disorder.","date":"2017","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/28388406","citation_count":277,"is_preprint":false},{"pmid":"20072116","id":"PMC_20072116","title":"Differential association of circadian genes with mood disorders: CRY1 and NPAS2 are associated with unipolar major depression and CLOCK and VIP with bipolar disorder.","date":"2010","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/20072116","citation_count":273,"is_preprint":false},{"pmid":"24855952","id":"PMC_24855952","title":"Interaction of circadian clock proteins CRY1 and PER2 is modulated by zinc binding and disulfide bond formation.","date":"2014","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/24855952","citation_count":162,"is_preprint":false},{"pmid":"29937374","id":"PMC_29937374","title":"Autophagy Regulates the Liver Clock and Glucose Metabolism by Degrading CRY1.","date":"2018","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/29937374","citation_count":138,"is_preprint":false},{"pmid":"11798163","id":"PMC_11798163","title":"Interactivating feedback loops within the mammalian clock: BMAL1 is negatively autoregulated and upregulated by CRY1, CRY2, and PER2.","date":"2002","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11798163","citation_count":117,"is_preprint":false},{"pmid":"33452241","id":"PMC_33452241","title":"The circadian cryptochrome, CRY1, is a pro-tumorigenic factor that rhythmically modulates DNA repair.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33452241","citation_count":108,"is_preprint":false},{"pmid":"12829319","id":"PMC_12829319","title":"Melatonin induces Cry1 expression in the pars tuberalis of the rat.","date":"2003","source":"Brain research. 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(Chichester, England)","url":"https://pubmed.ncbi.nlm.nih.gov/1574926","citation_count":10,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48792,"output_tokens":8568,"usd":0.137448,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18357,"output_tokens":7231,"usd":0.13628,"stage2_stop_reason":"end_turn"},"total_usd":0.273728,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"Mice lacking both CRY1 and CRY2 show complete and instantaneous loss of free-running circadian rhythmicity, establishing that these proteins are essential components for maintenance of circadian rhythmicity; CRY1-deficient mice alone display accelerated (shorter) free-running locomotor period.\",\n      \"method\": \"Genetic knockout (Cry1-/-, Cry2-/-, and double knockout mice), behavioral locomotor activity assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined behavioral phenotype, replicated across multiple genotypes in a landmark study\",\n      \"pmids\": [\"10217146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure of the mouse CRY1 photolyase homology region (PHR) in complex with a C-terminal fragment of PER2 revealed that PER2 winds around CRY1, covering the FBXL3 and CLOCK/BMAL1 binding sites but not the FAD binding pocket. An unexpected zinc ion at the interface stabilizes the CRY1-PER2 interaction in vivo, and complex formation is modulated by interplay between zinc binding and CRY1 disulfide bond formation.\",\n      \"method\": \"X-ray crystallography, in vivo interaction assays, mutagenesis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with mutagenesis and in vivo validation in a single rigorous study\",\n      \"pmids\": [\"24855952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A dominant CRY1 coding variant (exon 11 splice variant, CRY1Δ11) found in familial delayed sleep phase disorder creates a transcriptional inhibitor with enhanced affinity for CLOCK and BMAL1, reduces expression of key transcriptional targets, and lengthens the period of circadian molecular rhythms.\",\n      \"method\": \"Human genetics (family-based sequencing), functional cell-based circadian period assays, CLOCK/BMAL1 binding affinity measurements\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human variant with direct functional characterization using multiple orthogonal methods across independent families\",\n      \"pmids\": [\"28388406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CRY1 binds directly to the PAS domain core of CLOCK:BMAL1, driven primarily by interaction with the CLOCK PAS-B domain. Integrative modeling and solution X-ray scattering positioned a key loop of CLOCK PAS-B in the secondary pocket of CRY1 (analogous to the antenna chromophore-binding pocket of photolyase). Single point mutations at either CRY1 or CLOCK disrupted ternary complex formation.\",\n      \"method\": \"Biochemical binding assays, small-angle X-ray scattering (SAXS), integrative structural modeling, mutagenesis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural method (SAXS + modeling) combined with mutagenesis and functional validation in one rigorous study\",\n      \"pmids\": [\"28143926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Macroautophagy selectively degrades CRY1 via LC3-interacting region (LIR) motifs on CRY1. Two distinct LIRs were identified by mutational analysis; their disruption alters circadian glycemic control. Autophagic CRY1 degradation occurs in a diurnal window and is accelerated by high-fat feeding, contributing to obesity-associated hyperglycemia.\",\n      \"method\": \"Mutational analysis of LIR motifs, lysosomal fractionation, co-immunoprecipitation with LC3, in vivo mouse studies\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (mutagenesis, fractionation, Co-IP, in vivo) in a single comprehensive study\",\n      \"pmids\": [\"29937374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Genotoxic stress stimulates CRY1 phosphorylation and its deubiquitination by Hausp (USP7), stabilizing CRY1 and shifting circadian clock time. DNA damage also increases CRY2 interaction with FBXL3, destabilizing CRY2; thus genotoxic stress increases the CRY1/CRY2 ratio.\",\n      \"method\": \"Post-translational modification assays, deubiquitination assays, protein stability measurements, circadian phase-shift assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal biochemical methods with functional circadian readout in one detailed study\",\n      \"pmids\": [\"25756610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The C-terminal extension of CRY1 harbors a nuclear localization signal and a putative coiled-coil domain that drive nuclear localization via two independent mechanisms and shift CRY1/PER2 complexes toward the nucleus. Deletion of the complete C-terminus prevents CRY1 from repressing CLOCK/BMAL1-mediated transcription; fusion of the last 100 aa of CRY1 core and C-terminus to plant photolyase confers CLOCK/BMAL1 repressor function.\",\n      \"method\": \"Deletion mutagenesis, nuclear localization assays, transcriptional repression assays, chimeric protein fusion experiments\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple domain-deletion and chimeric constructs with functional readouts demonstrating mechanism\",\n      \"pmids\": [\"16478995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"USP2a, a circadian-controlled deubiquitinating enzyme, interacts with CRY1 and stabilizes it via deubiquitination upon serum shock. Depletion of Usp2a enhances CRY1 ubiquitination and dampens CRY1 protein oscillation amplitude. TNF-α increases CRY1 protein level in a USP2a-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown, ubiquitination assays, luciferase reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, functional ubiquitination assays, and in vivo mouse liver validation with multiple methods\",\n      \"pmids\": [\"22669941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CUL4-DDB1-CDT2 E3 ligase ubiquitinates CRY1 at lysine 585 and promotes its degradation both in vitro and in vivo. Depletion of DDB1, CDT2, or PCNA stabilizes CRY1; a CRY1-K585A mutant is resistant to CUL4A-DDB1-mediated ubiquitination and degradation, and enhances the oscillatory amplitude of Bmal1 promoter activity.\",\n      \"method\": \"In vitro ubiquitination assay, site-directed mutagenesis (K585A), shRNA knockdown, luciferase reporter assay, in vivo mouse liver studies\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of ubiquitination plus mutagenesis of target lysine and in vivo validation\",\n      \"pmids\": [\"26431207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DDB1 promotes FOXO1-driven hepatic gluconeogenesis by degrading CRY1 via the DDB1-CUL4A ubiquitin E3 ligase. In the absence of CRY1, insulin fails to reduce nuclear FOXO1 abundance or suppress gluconeogenic gene expression; hepatocyte-specific Ddb1 deletion reduces CRY1 degradation and protects against high-fat diet-induced hyperglycemia.\",\n      \"method\": \"Hepatocyte-specific knockout mice, Western blotting, gluconeogenesis assays, FOXO1 localization studies\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO with mechanistic pathway placement and multiple functional readouts\",\n      \"pmids\": [\"28790135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SREBP1c activated by insulin induces CRY1 expression, and CRY1 decreases hepatic gluconeogenesis through promoting FOXO1 degradation by increasing its binding to the ubiquitin E3 ligase MDM2. SREBP1c-/- and CRY1-/- mice show higher blood glucose in pyruvate tolerance tests, and CRY1 overexpression attenuates hyperglycemia in db/db mice.\",\n      \"method\": \"Knockout mice, adenovirus-mediated CRY1 overexpression, co-immunoprecipitation, glucose metabolism assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic models, Co-IP identifying molecular mechanism, and in vivo metabolic validation\",\n      \"pmids\": [\"27412556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The CRY1 tail (particularly the region encoded by exon 11) modulates the affinity of the PHR domain for CLOCK:BMAL1 by providing an intramolecular inhibitory interaction. The PHR-binding epitope in exon 11 is necessary and sufficient to disrupt the CRY1-CLOCK interaction, and PHR-tail interactions are reduced when CRY1 is bound to PER2.\",\n      \"method\": \"NMR, biochemical binding assays, mutagenesis, functional circadian period rescue assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structural data combined with mutagenesis and functional rescue experiments\",\n      \"pmids\": [\"33106415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Multisite phosphorylation of CRY1 can serve as a cumulative timer in the mammalian circadian clock. CRY1-PER2 interaction confers robust circadian rhythmicity. Residues surrounding the flexible P loop and C-lid domains of CRY1 determine circadian period without changing CRY1 degradation rate, indicating that CRY1 determines circadian period through both degradation-dependent and -independent pathways.\",\n      \"method\": \"Knockout-rescue mouse system with phosphorylation-mimetic CRY1 mutants, circadian behavioral assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — comprehensive panel of phosphomimetic mutants in KO-rescue mice with rigorous in vivo circadian phenotyping\",\n      \"pmids\": [\"28017587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CRY1 and CRY2 function as co-repressors for PPARδ in muscle, repressing a distinct subset of PPARδ target genes. Cry1-/-;Cry2-/- myotubes and muscles exhibit elevated expression of PPARδ target genes particularly during exercise; genetic disruption of Cry1 and Cry2 enhances sprint exercise performance in vivo.\",\n      \"method\": \"Cell-based transcriptional assays, KO mouse muscle gene expression analysis, in vivo exercise performance testing\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO cell and mouse studies with defined transcriptional and physiological phenotypes for a specific nuclear receptor co-repressor function\",\n      \"pmids\": [\"28683290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CRY1 and CRY2 serve as co-repressors for many nuclear hormone receptors (NRs), binding independently of other core clock factors at genomic sites enriched for NR recognition motifs, contributing to diurnal modulation of drug metabolism.\",\n      \"method\": \"ChIP-seq, transcriptional reporter assays, Co-IP\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq with multiple orthogonal functional assays establishing co-repressor role for broad NR family\",\n      \"pmids\": [\"28751364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CRY1 is androgen-responsive and stabilized by DNA damage in cancer cells. Stabilized CRY1 temporally regulates expression of homologous recombination genes, promotes efficient DNA repair and G2/M transition, and is required for survival following DNA damage in prostate cancer.\",\n      \"method\": \"CRY1 cistrome (ChIP-seq) and transcriptome mapping, CRY1 knockdown/knockout, DNA damage assays, in vitro and in vivo tumor models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide cistrome mapping combined with loss-of-function and in vivo validation with multiple orthogonal readouts\",\n      \"pmids\": [\"33452241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CRY1 is a negative regulator of HIF-1α: CRY1 interacts with the bHLH domain of HIF-1α via its tail region, reduces HIF-1α half-life, and decreases HIF binding to target gene promoters. Genetic disruption of CRY1 (but not CRY2) induces cellular HIF levels, proliferation, and migration.\",\n      \"method\": \"Co-immunoprecipitation, protein stability assays, promoter-binding assays, CRISPR/Cas9 and shRNA knockouts\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding demonstrated by Co-IP with domain mapping, CRY1-specific KO with functional cellular phenotypes\",\n      \"pmids\": [\"30875610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cystathionine β-synthase (CBS), a central enzyme in one-carbon metabolism, functionally interacts with CRY1. CBS augments CRY1-mediated repression of CLOCK/BMAL1 and shortens circadian period. Reciprocally, CRY1 modulates CBS enzymatic activity; liver extracts from Cry1-/- mice show reduced CBS activity that normalizes upon addition of exogenous wild-type CRY1.\",\n      \"method\": \"Co-immunoprecipitation, circadian period assays, enzymatic activity assays, knockout mouse liver extracts, metabolomics\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional functional interaction established by multiple orthogonal biochemical methods with in vivo KO validation\",\n      \"pmids\": [\"32383312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"JMJD5 interacts with CRY1 in an FBXL3-dependent manner and facilitates targeting of CRY1 to the proteasome. Genetic deletion of JMJD5 results in greater CRY1 stability, reduced CRY1 association with the proteasome, and disruption of circadian gene expression. JMJD5 also cooperates with CRY1 to repress CLOCK-BMAL1; AMPK-induced CRY1 degradation is impaired in the absence of JMJD5.\",\n      \"method\": \"Co-immunoprecipitation, JMJD5 knockout cell lines, protein stability assays, luciferase reporter assays\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO cells with multiple functional readouts and direct protein interaction established by Co-IP\",\n      \"pmids\": [\"30500822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CRY1 promotes p53 degradation by increasing the binding of p53 to its ubiquitin E3 ligase MDM2, thereby preventing paclitaxel-induced senescence in cisplatin-resistant bladder cancer cells.\",\n      \"method\": \"CRY1 knockdown, co-immunoprecipitation of p53-MDM2, SA-β-Gal senescence assay\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP mechanistic assay and KD phenotype, but single lab with limited mechanistic follow-up\",\n      \"pmids\": [\"33650658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CRY1, CRY2, and PER2 activate BMAL1 transcription, while BMAL1-CLOCK dimers repress it, establishing an interlocked feedback loop. CRY transcriptional repressor potency was shown to be predominant within the mammalian clock.\",\n      \"method\": \"Luciferase reporter assay, BMAL1 promoter characterization, transfection of clock components\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reporter assays in cultured cells, single lab, but consistent with other mechanistic data in the field\",\n      \"pmids\": [\"11798163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"An intact flavin binding domain is required for CRY1 function in suppressing CLOCK/BMAL1 activity. In Xenopus CRY1, only mutation of the last of the three conserved tryptophan residues in the putative electron transport chain significantly affects CRY1 function, in contrast to CRY2 where any of the three tryptophan mutations inhibit function, demonstrating molecular differences between CRY1 and CRY2.\",\n      \"method\": \"Site-directed mutagenesis, transcriptional repression assays (luciferase), cell transfection\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of conserved residues with functional assay, single lab, Xenopus ortholog\",\n      \"pmids\": [\"11747820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CRY1 is more potent than CRY2 as a transcriptional repressor within the SCN clockwork: stabilization of CRY1 (via Fbxl3Afh) prolongs the interval of transcriptional suppression and lengthens circadian period more potently than CRY2. CRY2 attenuates the period-lengthening effects of CRY1.\",\n      \"method\": \"Genetic epistasis (Fbxl3Afh mutation in CRY1- and CRY2-deficient mice), SCN bioluminescence assays, behavioral wheel-running assays\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis in multiple genetic backgrounds with both molecular and behavioral readouts establishes differential CRY1 vs CRY2 potency\",\n      \"pmids\": [\"23616524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Cry1-/- mice require SCN intercellular coupling to sustain circadian rhythms: disruption of coupling in vivo by constant light reveals a cell-autonomous circadian defect in Cry1-/- SCN cells (fewer rhythmic single cells) that is normally compensated by intercellular coupling.\",\n      \"method\": \"Constant-light protocol to disrupt coupling, single-cell bioluminescence imaging of PER2::LUC in SCN slices\",\n      \"journal\": \"Journal of biological rhythms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct live imaging at single-cell resolution in intact tissue with defined genetic background\",\n      \"pmids\": [\"23223370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Arg-293 of CRY1 allosterically regulates the serine-rich loop adjacent to the secondary pocket, controlling CLOCK-CRY1 binding affinity. The p.Arg293His CRY1 variant shortens circadian period, reduces repressor activity on CLOCK/BMAL1 transcription, and reduces CRY1 affinity for BMAL1/CLOCK in the absence of PER2. Molecular dynamics simulations revealed altered communication between Arg-293 and the serine loop.\",\n      \"method\": \"Rescue assay in Cry1-/-Cry2-/- MEFs, luciferase reporter assay, binding affinity measurements, molecular dynamics simulation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cell-based assays with binding data, single lab; MD simulation is computational\",\n      \"pmids\": [\"33028638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CRY1 knockdown in GV oocytes by RNA interference does not affect transcription of Wee1, Cry2, Per1, Per2, or Per3 (targets it represses in somatic cells), but reduces oocyte maturation ability, indicating CRY1 has a circadian-clock-independent role in meiosis.\",\n      \"method\": \"RNAi knockdown in mouse oocytes, RT-PCR, maturation assays\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct KD with defined phenotype, but single method and single lab; negative finding for clock function is informative\",\n      \"pmids\": [\"19020302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A mutation in the conserved cysteine-proline dipeptide motif of CRY1 (C414A, CRY1-AP) when overexpressed causes rhythm splitting with very long free-running periods (~28 h) and abnormal light entrainment, indicating the CP motif is critical for CRY1 function in the clock.\",\n      \"method\": \"Transgenic mouse generation, circadian locomotor activity assays\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic mice with specific mutant CRY1 and defined behavioral circadian phenotype, single lab\",\n      \"pmids\": [\"19159659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Phosphorylation of specific CRY1 residues alters circadian period length. Screen of phosphorylation-mimetic mutants identified 10 sites with abnormal period; several mutants (S71D, S247D, T249D, Y266D, Y273D, Y432D) showed reduced repression activity, and differences in protein stability and cellular localization. Results suggest phosphorylation regulates the ratio of functional CRY1 protein to determine period.\",\n      \"method\": \"Phosphomimetic and non-phosphomimetic mutagenesis screen, CRY-deficient cell rescue assay, luciferase reporter assay, protein stability assay, subcellular localization assay\",\n      \"journal\": \"Frontiers in neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic mutagenesis with functional readouts, single lab\",\n      \"pmids\": [\"27721804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Phosphorylation of CRY1 serine 71 by AMPK was tested in vivo via germline Cry1-S71A knock-in mice. This mutation does not affect CRY1 steady-state protein levels or circadian rhythms under standard conditions, but female Cry1-S71A mice exhibit decreased voluntary locomotor activity, suggesting S71 phosphorylation may be involved in metabolic or physiological (non-circadian period) functions.\",\n      \"method\": \"Germline knock-in mouse (S71A), behavioral assays, protein level measurements\",\n      \"journal\": \"Journal of biological rhythms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knock-in mouse with defined phenotypes; negative result for circadian period is informative, single lab\",\n      \"pmids\": [\"31258021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MAGEL2 modulates the ubiquitination of CRY1 as demonstrated by in vivo proximity labeling (BioID), immunofluorescence microscopy, and ubiquitination assays, suggesting a role for MAGEL2-deubiquitinase complexes in regulating CRY1 stability and circadian rhythm.\",\n      \"method\": \"BioID proximity labeling, immunofluorescence, ubiquitination assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple biochemical methods but limited mechanistic follow-up; functional consequence for circadian period not directly measured\",\n      \"pmids\": [\"32315313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GSK3β-induced phosphorylation of CRY1 potentiates FBXL3-dependent proteasomal CRY1 degradation in the liver. In diabetic mice, elevated FBXL3 activity leads to reduced hepatic CRY1 protein; GSK3β inhibitors decrease HGP by facilitating CRY1-mediated FOXO1 degradation.\",\n      \"method\": \"In vivo mouse diabetes model, GSK3β inhibitor treatment, protein stability assays, glucose metabolism assays\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo pharmacological and genetic evidence, single lab\",\n      \"pmids\": [\"35476750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CRY1 and CRY2 regulate rhythmic hepatic CYP2A5 expression through repression of E4BP4. CRY1/2 interact physically with E4BP4 and repress its inhibitory effect on Cyp2a5 transcription. Cry1-null mice show reduced hepatic CYP2A5 expression and loss of its diurnal rhythms.\",\n      \"method\": \"Cry1-null and Cry2-null mice, luciferase reporter assays, ChIP, Co-IP, enzymatic activity assays\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KO mice, reporter assay, ChIP, Co-IP, activity assay) in a single study\",\n      \"pmids\": [\"37797722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NPAS4 forms functional dimers with ARNT, ARNT2, and ARNTL and transactivates the Cry1 promoter through two conserved central midline elements (CRE). In the ovine pars tuberalis, melatonin induces Npas4, which drives Cry1 expression.\",\n      \"method\": \"Transcriptome sequencing, in situ hybridization, promoter-reporter assays with deletions and site-directed mutagenesis, in vivo melatonin treatment\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter dissection with mutagenesis and in vivo validation, single lab\",\n      \"pmids\": [\"23598442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CRY1 knockdown promotes β-catenin expression and nuclear accumulation, suggesting that CRY1 regulates adipogenic differentiation by modulating the canonical Wnt/β-catenin signaling pathway. CRY1 expression increases during adipogenic differentiation and its knockdown inhibits adipogenic markers.\",\n      \"method\": \"shRNA knockdown in 3T3-L1 and C3H10T1/2 cells, Western blot for β-catenin localization, adipogenesis assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single knockdown approach with pathway marker assay, no direct mechanism established, single lab\",\n      \"pmids\": [\"30384996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CRY1 and CRY2 are required for circadian rhythmicity of pineal melatonin synthesis. Cry1-/-/Cry2-/- mice show loss of circadian variation in pineal melatonin and absence of acute light-induced melatonin suppression, placing CRY1/2 as essential for SCN-mediated photic and circadian control of the pineal gland.\",\n      \"method\": \"Double knockout mice (C3H background), pineal melatonin measurements under LD and DD, light-pulse suppression assay\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with direct biochemical output (melatonin levels) under multiple lighting conditions\",\n      \"pmids\": [\"20825493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In the Cry1(-/-)/Cry2(-/-) background, the SCN expresses short-period (~18 h) molecular rhythms; CRY-independent rhythms are not affected by the Fbxl3Afh mutation, confirming that Fbxl3Afh circadian action is exclusively mediated through CRY proteins.\",\n      \"method\": \"Genetic epistasis (Fbxl3Afh in double KO SCN), bioluminescence recording\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rigorous epistasis with direct molecular phenotyping in SCN tissue\",\n      \"pmids\": [\"23616524\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CRY1 is a core circadian transcriptional repressor that directly binds the CLOCK:BMAL1 complex (via its photolyase homology region secondary pocket engaging the CLOCK PAS-B domain) to inhibit E-box-driven transcription; its activity and stability are regulated by a network of post-translational modifications including phosphorylation (by AMPK, GSK3β) and ubiquitination/deubiquitination (by FBXL3/CUL4-DDB1-CDT2 for degradation, and USP7/USP2a for stabilization), its interaction with PER2 is stabilized by zinc binding at a specific interface, its C-terminal tail autoregulates CLOCK binding affinity, and beyond the clock it functions as a co-repressor of nuclear hormone receptors and PPARδ, suppresses HIF-1α stability, modulates hepatic gluconeogenesis through FOXO1 degradation, and regulates DNA repair gene expression in response to genotoxic stress.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CRY1 is a core component of the mammalian circadian clock, functioning as a potent transcriptional repressor that, redundantly with CRY2, is essential for maintenance of free-running circadian rhythmicity [#0]. CRY1 directly engages the CLOCK:BMAL1 activator complex through its photolyase homology region (PHR), with a key loop of the CLOCK PAS-B domain inserting into the CRY1 secondary pocket analogous to the photolyase antenna-chromophore site; single point mutations at either interface abolish ternary complex formation and repression [#3]. This binding affinity is autoregulated by the CRY1 C-terminal tail: the region encoded by exon 11 provides an intramolecular inhibitory interaction with the PHR that tunes CLOCK:BMAL1 engagement, and the tail also carries nuclear localization determinants required for repressor function [#6, #11]. CRY1 is a more potent and period-determining repressor than CRY2 [#22], and its activity and abundance are set by a dense regulatory layer: stabilizing deubiquitination by USP7 and USP2a [#5, #7], proteasomal degradation via CUL4-DDB1-CDT2 (ubiquitinating Lys585) and FBXL3-directed pathways gated by GSK3\\u03b2 phosphorylation and JMJD5 [#8, #18, #30], LC3-dependent macroautophagy [#4], and multisite phosphorylation that adjusts the functional CRY1 pool and circadian period through both degradation-dependent and -independent routes [#12]. Its assembly with PER2 is stabilized by a zinc ion at the interface that covers the FBXL3 and CLOCK:BMAL1 binding sites [#1]. Beyond the canonical clock, CRY1 acts as a co-repressor of nuclear hormone receptors broadly and of PPAR\\u03b4 in muscle [#13, #14], suppresses HIF-1\\u03b1 stability and target-gene binding through its tail [#16], drives hepatic glucose homeostasis by promoting FOXO1 degradation via MDM2 [#10], and is recruited to chromatin to temporally control DNA-repair gene expression following genotoxic stress [#5, #15]. A dominant CRY1 exon-11 splice variant (CRY1\\u039411) with enhanced CLOCK/BMAL1 affinity lengthens circadian period and causes familial delayed sleep phase disorder [#2].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established that CRY proteins are not optional modulators but obligatory for circadian timekeeping, defining the genetic core of the mammalian clock.\",\n      \"evidence\": \"Single and double Cry knockout mice with locomotor behavioral phenotyping\",\n      \"pmids\": [\"10217146\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the molecular mechanism of repression\", \"Redundancy with CRY2 obscures CRY1-specific roles\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Placed CRY1 within an interlocked feedback architecture, showing it activates Bmal1 while repressing CLOCK:BMAL1, with predominant repressor potency in the clock.\",\n      \"evidence\": \"Luciferase reporter and BMAL1 promoter assays with transfected clock components\",\n      \"pmids\": [\"11798163\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-based reporters do not establish endogenous chromatin behavior\", \"Mechanism of repression not defined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Linked the flavin/electron-transport features of the photolyase-derived domain to repressor function and revealed molecular divergence between CRY1 and CRY2.\",\n      \"evidence\": \"Site-directed mutagenesis of conserved tryptophans and FAD domain in Xenopus CRY, transcriptional repression assays\",\n      \"pmids\": [\"11747820\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ortholog (Xenopus) may not fully reflect mammalian CRY1\", \"Does not address whether flavin acts catalytically or structurally\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified the CRY1 C-terminal extension as a dual nuclear-localization and repression module, mapping function beyond the photolyase core.\",\n      \"evidence\": \"Deletion mutagenesis, nuclear localization and repression assays, chimeric photolyase fusions\",\n      \"pmids\": [\"16478995\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the structural basis of tail-mediated repression\", \"Interplay with PHR not resolved at this stage\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined opposing deubiquitination and ubiquitination arms that set CRY1 oscillation amplitude, showing USP2a stabilizes CRY1 and links its level to inflammatory and serum signals.\",\n      \"evidence\": \"Co-IP, shRNA knockdown, ubiquitination and luciferase assays\",\n      \"pmids\": [\"22669941\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the opposing E3 ligase in this context\", \"Physiological role of TNF-\\u03b1-driven stabilization unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated through epistasis that CRY1 is the dominant period-determining repressor in the SCN and that intercellular coupling masks a cell-autonomous defect in Cry1-null cells.\",\n      \"evidence\": \"Fbxl3Afh epistasis in Cry-deficient mice, SCN bioluminescence, single-cell imaging, behavioral assays\",\n      \"pmids\": [\"23616524\", \"23223370\", \"23616524\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of CRY1 vs CRY2 potency difference not fully resolved\", \"Network-level coupling mechanism not identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided the structural logic of the CRY1-PER2 complex, showing PER2 wraps the PHR to mask degron and activator-binding sites, with a zinc ion stabilizing the interface.\",\n      \"evidence\": \"X-ray crystallography of CRY1 PHR-PER2, in vivo interaction assays, mutagenesis\",\n      \"pmids\": [\"24855952\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not capture the full-length tail or CLOCK:BMAL1-bound state\", \"Functional role of disulfide/zinc interplay in vivo only partly defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed CRY1 stability is wired into the DNA-damage response, where USP7-mediated deubiquitination raises the CRY1/CRY2 ratio and shifts clock phase under genotoxic stress.\",\n      \"evidence\": \"Deubiquitination and stability assays, circadian phase-shift readouts\",\n      \"pmids\": [\"25756610\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for stress-induced phosphorylation not fully defined\", \"Connection to repair-gene transcription addressed only later\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified CUL4-DDB1-CDT2 as a CRY1 E3 ligase ubiquitinating Lys585, establishing a specific degron controlling clock amplitude.\",\n      \"evidence\": \"In vitro ubiquitination, K585A mutagenesis, shRNA knockdown, luciferase and in vivo liver assays\",\n      \"pmids\": [\"26431207\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship to FBXL3-mediated degradation not reconciled\", \"PCNA dependence mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Integrated CRY1 into hepatic glucose control, showing insulin-induced SREBP1c drives CRY1 expression and CRY1 promotes FOXO1 degradation via MDM2 to suppress gluconeogenesis.\",\n      \"evidence\": \"Knockout mice, adenoviral overexpression, Co-IP, glucose metabolism assays\",\n      \"pmids\": [\"27412556\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this is clock-dependent or independent not fully separated\", \"MDM2 recruitment mechanism not structurally defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established that multisite phosphorylation acts as a cumulative timer setting period through both degradation-dependent and -independent pathways.\",\n      \"evidence\": \"KO-rescue mice with phosphomimetic CRY1 mutants, circadian behavioral and reporter assays\",\n      \"pmids\": [\"28017587\", \"27721804\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinases for many sites not assigned\", \"Mechanism of degradation-independent period control unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Mapped the direct CRY1-CLOCK interface, positioning the CLOCK PAS-B loop in the CRY1 secondary pocket and identifying point mutations that disrupt repression.\",\n      \"evidence\": \"Biochemical binding, SAXS, integrative modeling, mutagenesis\",\n      \"pmids\": [\"28143926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution crystal structure of the ternary complex\", \"Dynamics of pocket engagement not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected a human CRY1 exon-11 splice variant with enhanced CLOCK/BMAL1 affinity to familial delayed sleep phase disorder, linking molecular gain-of-repression to a sleep phenotype.\",\n      \"evidence\": \"Family-based sequencing, cell-based period and binding-affinity assays\",\n      \"pmids\": [\"28388406\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish in vivo human physiology beyond circadian period\", \"Structural basis of enhanced affinity defined only later\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Broadened CRY1's transcriptional role beyond the clock, establishing it as a co-repressor of nuclear hormone receptors and of PPAR\\u03b4 in muscle, with physiological consequences for drug metabolism and exercise.\",\n      \"evidence\": \"ChIP-seq, reporter assays, Co-IP, KO mouse muscle and exercise phenotyping\",\n      \"pmids\": [\"28751364\", \"28683290\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CRY1 is recruited to NR sites independent of CLOCK:BMAL1 not defined\", \"Selectivity for subsets of target genes unexplained\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked CRY1 to insulin-regulated gluconeogenesis via DDB1-CUL4A degradation controlling nuclear FOXO1.\",\n      \"evidence\": \"Hepatocyte-specific Ddb1 knockout mice, FOXO1 localization and gluconeogenesis assays\",\n      \"pmids\": [\"28790135\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation with MDM2-mediated FOXO1 degradation pathway incomplete\", \"Diurnal timing of degradation not fully mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed macroautophagy as a distinct, diet-responsive CRY1 degradation route via LIR motifs, coupling CRY1 turnover to glycemic control.\",\n      \"evidence\": \"LIR mutagenesis, lysosomal fractionation, LC3 Co-IP, in vivo mouse studies\",\n      \"pmids\": [\"29937374\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution vs proteasomal degradation not quantified\", \"Signal triggering diurnal autophagic window undefined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified JMJD5 as an FBXL3-dependent co-factor targeting CRY1 to the proteasome and cooperating in CLOCK:BMAL1 repression, integrating AMPK-driven turnover.\",\n      \"evidence\": \"Co-IP, JMJD5 knockout cells, stability and reporter assays\",\n      \"pmids\": [\"30500822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzymatic role of JMJD5 in this process unclear\", \"Direct vs scaffolding contribution not separated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established CRY1 as a negative regulator of HIF-1\\u03b1, with its tail binding the HIF-1\\u03b1 bHLH domain to reduce its stability and target-gene occupancy, a CRY1-specific (not CRY2) function.\",\n      \"evidence\": \"Co-IP with domain mapping, stability and promoter-binding assays, CRISPR/shRNA knockouts\",\n      \"pmids\": [\"30875610\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CRY1 lowers HIF-1\\u03b1 half-life not defined\", \"In vivo hypoxia relevance not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Tested AMPK-target Ser71 phosphorylation in vivo, showing it is dispensable for steady-state period but tied to sex-specific locomotor/metabolic physiology.\",\n      \"evidence\": \"Germline Cry1-S71A knock-in mice, behavioral and protein-level assays\",\n      \"pmids\": [\"31258021\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking S71 to activity phenotype undefined\", \"Single-site knock-in may be buffered by other sites\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved the autoinhibitory logic of the CRY1 tail, showing the exon-11 epitope competes intramolecularly for the PHR to lower CLOCK:BMAL1 affinity, releasing upon PER2 binding.\",\n      \"evidence\": \"NMR, biochemical binding, mutagenesis, circadian period rescue assays\",\n      \"pmids\": [\"33106415\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full structural ensemble of tail-PHR states not captured\", \"Quantitative coupling to in vivo period not complete\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined an allosteric route (Arg-293 to the serine-rich loop) controlling CLOCK-CRY1 affinity and explaining a short-period human variant.\",\n      \"evidence\": \"Cry-deficient MEF rescue, reporter and binding assays, molecular dynamics simulation\",\n      \"pmids\": [\"33028638\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MD predictions of allostery not experimentally validated structurally\", \"Single-lab functional data\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Uncovered a bidirectional CRY1-CBS interaction connecting the clock to one-carbon metabolism, where CBS augments CRY1 repression and CRY1 modulates CBS activity.\",\n      \"evidence\": \"Co-IP, period and enzymatic assays, KO mouse liver extracts, metabolomics\",\n      \"pmids\": [\"32383312\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of mutual regulation unknown\", \"Metabolic significance in vivo only partly defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Implicated CRY1 in p53 turnover via MDM2, linking it to chemotherapy-induced senescence in cancer cells.\",\n      \"evidence\": \"CRY1 knockdown, p53-MDM2 Co-IP, senescence assay\",\n      \"pmids\": [\"33650658\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab Co-IP without reciprocal structural validation\", \"Generality beyond bladder cancer cells untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified MAGEL2 as a proximity partner modulating CRY1 ubiquitination, implicating MAGEL2-deubiquitinase complexes in CRY1 stability.\",\n      \"evidence\": \"BioID proximity labeling, immunofluorescence, ubiquitination assays\",\n      \"pmids\": [\"32315313\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence for circadian period not directly measured\", \"Direct vs indirect interaction not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established a chromatin-level role for CRY1 in the DNA-damage response, where androgen- and damage-stabilized CRY1 temporally controls homologous-recombination gene expression and supports cancer-cell survival.\",\n      \"evidence\": \"CRY1 cistrome and transcriptome mapping, loss-of-function, DNA-damage and tumor models\",\n      \"pmids\": [\"33452241\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct DNA-binding vs co-factor recruitment not distinguished\", \"Relationship to canonical clock targets unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected GSK3\\u03b2 phosphorylation to FBXL3-dependent CRY1 degradation in liver, defining a druggable node for hepatic glucose production.\",\n      \"evidence\": \"In vivo diabetic mouse model, GSK3\\u03b2 inhibitor treatment, stability and glucose assays\",\n      \"pmids\": [\"35476750\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GSK3\\u03b2 phosphosite on CRY1 not mapped\", \"Single-lab in vivo evidence\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended CRY1's diurnal control of xenobiotic metabolism, showing it represses E4BP4 to drive rhythmic hepatic CYP2A5 expression.\",\n      \"evidence\": \"Cry1/Cry2-null mice, reporter assays, ChIP, Co-IP, enzymatic activity assays\",\n      \"pmids\": [\"37797722\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of CRY1-E4BP4 repression not structurally defined\", \"Generalization to other CYPs not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the many parallel CRY1 degradation routes (FBXL3, CUL4-DDB1-CDT2, autophagy, USP7/USP2a) and phosphorylation sites are integrated into a single coherent period-setting and tissue-specific metabolic program remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified model reconciling competing E3 ligases and DUBs\", \"Tissue-specific selection of CRY1's clock vs non-clock functions unexplained\", \"No full-length ternary CLOCK:BMAL1:CRY1:PER2 structure\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 3, 6, 14, 20, 22, 31]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 10, 16, 19]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [14, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [6, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [0, 3, 22, 34]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 14, 20, 31]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [9, 10, 13, 17, 31]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 5, 7, 8, 18, 30]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [5, 15]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PER2\", \"CLOCK\", \"BMAL1\", \"FBXL3\", \"USP7\", \"USP2a\", \"JMJD5\", \"HIF1A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}