Affinage

CRY1

Cryptochrome-1 · UniProt Q16526

Length
586 aa
Mass
66.4 kDa
Annotated
2026-06-09
100 papers in source corpus 35 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 27 steps
  1. 1999 High

    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

    PMID:10217146

    Open questions at the time
    • Did not resolve the molecular mechanism of repression
    • Redundancy with CRY2 obscures CRY1-specific roles
  2. 2002 Medium

    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

    PMID:11798163

    Open questions at the time
    • Cell-based reporters do not establish endogenous chromatin behavior
    • Mechanism of repression not defined
  3. 2001 Medium

    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

    PMID:11747820

    Open questions at the time
    • Ortholog (Xenopus) may not fully reflect mammalian CRY1
    • Does not address whether flavin acts catalytically or structurally
  4. 2006 High

    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

    PMID:16478995

    Open questions at the time
    • Did not define the structural basis of tail-mediated repression
    • Interplay with PHR not resolved at this stage
  5. 2012 High

    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

    PMID:22669941

    Open questions at the time
    • Did not identify the opposing E3 ligase in this context
    • Physiological role of TNF-α-driven stabilization unclear
  6. 2013 High

    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

    PMID:23223370 PMID:23616524

    Open questions at the time
    • Molecular basis of CRY1 vs CRY2 potency difference not fully resolved
    • Network-level coupling mechanism not identified
  7. 2014 High

    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

    PMID:24855952

    Open questions at the time
    • Did not capture the full-length tail or CLOCK:BMAL1-bound state
    • Functional role of disulfide/zinc interplay in vivo only partly defined
  8. 2015 High

    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

    PMID:25756610

    Open questions at the time
    • Kinase responsible for stress-induced phosphorylation not fully defined
    • Connection to repair-gene transcription addressed only later
  9. 2015 High

    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

    PMID:26431207

    Open questions at the time
    • Relationship to FBXL3-mediated degradation not reconciled
    • PCNA dependence mechanistically incomplete
  10. 2016 High

    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

    PMID:27412556

    Open questions at the time
    • Whether this is clock-dependent or independent not fully separated
    • MDM2 recruitment mechanism not structurally defined
  11. 2016 High

    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

    PMID:27721804 PMID:28017587

    Open questions at the time
    • Kinases for many sites not assigned
    • Mechanism of degradation-independent period control unclear
  12. 2017 High

    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

    PMID:28143926

    Open questions at the time
    • No high-resolution crystal structure of the ternary complex
    • Dynamics of pocket engagement not resolved
  13. 2017 High

    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

    PMID:28388406

    Open questions at the time
    • Did not establish in vivo human physiology beyond circadian period
    • Structural basis of enhanced affinity defined only later
  14. 2017 High

    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

    PMID:28683290 PMID:28751364

    Open questions at the time
    • How CRY1 is recruited to NR sites independent of CLOCK:BMAL1 not defined
    • Selectivity for subsets of target genes unexplained
  15. 2017 High

    Linked CRY1 to insulin-regulated gluconeogenesis via DDB1-CUL4A degradation controlling nuclear FOXO1.

    Evidence Hepatocyte-specific Ddb1 knockout mice, FOXO1 localization and gluconeogenesis assays

    PMID:28790135

    Open questions at the time
    • Reconciliation with MDM2-mediated FOXO1 degradation pathway incomplete
    • Diurnal timing of degradation not fully mapped
  16. 2018 High

    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

    PMID:29937374

    Open questions at the time
    • Relative contribution vs proteasomal degradation not quantified
    • Signal triggering diurnal autophagic window undefined
  17. 2018 High

    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

    PMID:30500822

    Open questions at the time
    • Enzymatic role of JMJD5 in this process unclear
    • Direct vs scaffolding contribution not separated
  18. 2019 High

    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

    PMID:30875610

    Open questions at the time
    • Mechanism by which CRY1 lowers HIF-1α half-life not defined
    • In vivo hypoxia relevance not established
  19. 2019 Medium

    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

    PMID:31258021

    Open questions at the time
    • Mechanism linking S71 to activity phenotype undefined
    • Single-site knock-in may be buffered by other sites
  20. 2020 High

    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

    PMID:33106415

    Open questions at the time
    • Full structural ensemble of tail-PHR states not captured
    • Quantitative coupling to in vivo period not complete
  21. 2020 Medium

    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

    PMID:33028638

    Open questions at the time
    • MD predictions of allostery not experimentally validated structurally
    • Single-lab functional data
  22. 2020 High

    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

    PMID:32383312

    Open questions at the time
    • Structural basis of mutual regulation unknown
    • Metabolic significance in vivo only partly defined
  23. 2020 Medium

    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

    PMID:33650658

    Open questions at the time
    • Single-lab Co-IP without reciprocal structural validation
    • Generality beyond bladder cancer cells untested
  24. 2020 Medium

    Identified MAGEL2 as a proximity partner modulating CRY1 ubiquitination, implicating MAGEL2-deubiquitinase complexes in CRY1 stability.

    Evidence BioID proximity labeling, immunofluorescence, ubiquitination assays

    PMID:32315313

    Open questions at the time
    • Functional consequence for circadian period not directly measured
    • Direct vs indirect interaction not resolved
  25. 2021 High

    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

    PMID:33452241

    Open questions at the time
    • Direct DNA-binding vs co-factor recruitment not distinguished
    • Relationship to canonical clock targets unclear
  26. 2022 Medium

    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

    PMID:35476750

    Open questions at the time
    • GSK3β phosphosite on CRY1 not mapped
    • Single-lab in vivo evidence
  27. 2023 High

    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

    PMID:37797722

    Open questions at the time
    • Mechanism of CRY1-E4BP4 repression not structurally defined
    • Generalization to other CYPs not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0098772 molecular function regulator activity 4 GO:0003677 DNA binding 2
Localization
GO:0005654 nucleoplasm 2 GO:0005634 nucleus 1
Pathway
R-HSA-392499 Metabolism of proteins 6 R-HSA-1430728 Metabolism 5 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-9909396 Circadian clock 4 R-HSA-73894 DNA Repair 2 R-HSA-9612973 Autophagy 1
Partners
BMAL1CLOCKFBXL3HIF1AJMJD5PER2USP2AUSP7

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 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. Genetic knockout (Cry1-/-, Cry2-/-, and double knockout mice), behavioral locomotor activity assays Nature High 10217146
2014 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. X-ray crystallography, in vivo interaction assays, mutagenesis Cell High 24855952
2017 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. Human genetics (family-based sequencing), functional cell-based circadian period assays, CLOCK/BMAL1 binding affinity measurements Cell High 28388406
2017 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. Biochemical binding assays, small-angle X-ray scattering (SAXS), integrative structural modeling, mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 28143926
2018 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. Mutational analysis of LIR motifs, lysosomal fractionation, co-immunoprecipitation with LC3, in vivo mouse studies Cell metabolism High 29937374
2015 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. Post-translational modification assays, deubiquitination assays, protein stability measurements, circadian phase-shift assays eLife High 25756610
2006 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. Deletion mutagenesis, nuclear localization assays, transcriptional repression assays, chimeric protein fusion experiments Molecular and cellular biology High 16478995
2012 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. Co-immunoprecipitation, shRNA knockdown, ubiquitination assays, luciferase reporter assays The Journal of biological chemistry High 22669941
2015 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. In vitro ubiquitination assay, site-directed mutagenesis (K585A), shRNA knockdown, luciferase reporter assay, in vivo mouse liver studies PloS one High 26431207
2017 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. Hepatocyte-specific knockout mice, Western blotting, gluconeogenesis assays, FOXO1 localization studies Diabetes High 28790135
2016 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. Knockout mice, adenovirus-mediated CRY1 overexpression, co-immunoprecipitation, glucose metabolism assays Nature communications High 27412556
2020 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. NMR, biochemical binding assays, mutagenesis, functional circadian period rescue assays Proceedings of the National Academy of Sciences of the United States of America High 33106415
2016 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. Knockout-rescue mouse system with phosphorylation-mimetic CRY1 mutants, circadian behavioral assays Molecular cell High 28017587
2017 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. Cell-based transcriptional assays, KO mouse muscle gene expression analysis, in vivo exercise performance testing Cell metabolism High 28683290
2017 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. ChIP-seq, transcriptional reporter assays, Co-IP Proceedings of the National Academy of Sciences of the United States of America High 28751364
2021 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. CRY1 cistrome (ChIP-seq) and transcriptome mapping, CRY1 knockdown/knockout, DNA damage assays, in vitro and in vivo tumor models Nature communications High 33452241
2019 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. Co-immunoprecipitation, protein stability assays, promoter-binding assays, CRISPR/Cas9 and shRNA knockouts iScience High 30875610
2020 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. Co-immunoprecipitation, circadian period assays, enzymatic activity assays, knockout mouse liver extracts, metabolomics The FEBS journal High 32383312
2018 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. Co-immunoprecipitation, JMJD5 knockout cell lines, protein stability assays, luciferase reporter assays PLoS biology High 30500822
2020 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. CRY1 knockdown, co-immunoprecipitation of p53-MDM2, SA-β-Gal senescence assay Oncology reports Medium 33650658
2002 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. Luciferase reporter assay, BMAL1 promoter characterization, transfection of clock components Biochemical and biophysical research communications Medium 11798163
2001 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. Site-directed mutagenesis, transcriptional repression assays (luciferase), cell transfection Current biology : CB Medium 11747820
2013 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. Genetic epistasis (Fbxl3Afh mutation in CRY1- and CRY2-deficient mice), SCN bioluminescence assays, behavioral wheel-running assays The Journal of neuroscience : the official journal of the Society for Neuroscience High 23616524
2012 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. Constant-light protocol to disrupt coupling, single-cell bioluminescence imaging of PER2::LUC in SCN slices Journal of biological rhythms High 23223370
2020 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. Rescue assay in Cry1-/-Cry2-/- MEFs, luciferase reporter assay, binding affinity measurements, molecular dynamics simulation The Journal of biological chemistry Medium 33028638
2008 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. RNAi knockdown in mouse oocytes, RT-PCR, maturation assays Biology of reproduction Medium 19020302
2009 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. Transgenic mouse generation, circadian locomotor activity assays Neuroscience letters Medium 19159659
2016 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. Phosphomimetic and non-phosphomimetic mutagenesis screen, CRY-deficient cell rescue assay, luciferase reporter assay, protein stability assay, subcellular localization assay Frontiers in neurology Medium 27721804
2019 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. Germline knock-in mouse (S71A), behavioral assays, protein level measurements Journal of biological rhythms Medium 31258021
2020 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. BioID proximity labeling, immunofluorescence, ubiquitination assays PloS one Medium 32315313
2022 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. In vivo mouse diabetes model, GSK3β inhibitor treatment, protein stability assays, glucose metabolism assays Diabetes Medium 35476750
2023 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. Cry1-null and Cry2-null mice, luciferase reporter assays, ChIP, Co-IP, enzymatic activity assays Biochemical pharmacology High 37797722
2013 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. Transcriptome sequencing, in situ hybridization, promoter-reporter assays with deletions and site-directed mutagenesis, in vivo melatonin treatment Molecular endocrinology (Baltimore, Md.) Medium 23598442
2018 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. shRNA knockdown in 3T3-L1 and C3H10T1/2 cells, Western blot for β-catenin localization, adipogenesis assays Biochemical and biophysical research communications Low 30384996
2009 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. Double knockout mice (C3H background), pineal melatonin measurements under LD and DD, light-pulse suppression assay Genes to cells : devoted to molecular & cellular mechanisms High 20825493
2009 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. Genetic epistasis (Fbxl3Afh in double KO SCN), bioluminescence recording The Journal of neuroscience : the official journal of the Society for Neuroscience High 23616524

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms. Nature 1087 10217146
2017 Mutation of the Human Circadian Clock Gene CRY1 in Familial Delayed Sleep Phase Disorder. Cell 277 28388406
2010 Differential association of circadian genes with mood disorders: CRY1 and NPAS2 are associated with unipolar major depression and CLOCK and VIP with bipolar disorder. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 273 20072116
2014 Interaction of circadian clock proteins CRY1 and PER2 is modulated by zinc binding and disulfide bond formation. Cell 162 24855952
2018 Autophagy Regulates the Liver Clock and Glucose Metabolism by Degrading CRY1. Cell metabolism 138 29937374
2002 Interactivating feedback loops within the mammalian clock: BMAL1 is negatively autoregulated and upregulated by CRY1, CRY2, and PER2. Biochemical and biophysical research communications 117 11798163
2021 The circadian cryptochrome, CRY1, is a pro-tumorigenic factor that rhythmically modulates DNA repair. Nature communications 108 33452241
2003 Melatonin induces Cry1 expression in the pars tuberalis of the rat. Brain research. Molecular brain research 104 12829319
1994 The CRY1 gene in Chlamydomonas reinhardtii: structure and use as a dominant selectable marker for nuclear transformation. Molecular and cellular biology 99 8196640
2017 Formation of a repressive complex in the mammalian circadian clock is mediated by the secondary pocket of CRY1. Proceedings of the National Academy of Sciences of the United States of America 98 28143926
2015 DNA damage shifts circadian clock time via Hausp-dependent Cry1 stabilization. eLife 97 25756610
2017 CRY1/2 Selectively Repress PPARδ and Limit Exercise Capacity. Cell metabolism 95 28683290
2006 Functional evolution of the photolyase/cryptochrome protein family: importance of the C terminus of mammalian CRY1 for circadian core oscillator performance. Molecular and cellular biology 85 16478995
2015 Cross-Resistance between Cry1 Proteins in Fall Armyworm (Spodoptera frugiperda) May Affect the Durability of Current Pyramided Bt Maize Hybrids in Brazil. PloS one 83 26473961
2017 Circadian repressors CRY1 and CRY2 broadly interact with nuclear receptors and modulate transcriptional activity. Proceedings of the National Academy of Sciences of the United States of America 81 28751364
2016 SREBP1c-CRY1 signalling represses hepatic glucose production by promoting FOXO1 degradation during refeeding. Nature communications 80 27412556
2009 The circadian clock components CRY1 and CRY2 are necessary to sustain sex dimorphism in mouse liver metabolism. The Journal of biological chemistry 80 19211562
1983 Molecular cloning and analysis of the CRY1 gene: a yeast ribosomal protein gene. Nucleic acids research 77 6338478
2015 Overexpression of CRY1 protects against the development of atherosclerosis via the TLR/NF-κB pathway. International immunopharmacology 71 26218278
2016 Knockout-Rescue Embryonic Stem Cell-Derived Mouse Reveals Circadian-Period Control by Quality and Quantity of CRY1. Molecular cell 67 28017587
1987 Structure and expression of the Saccharomyces cerevisiae CRY1 gene: a highly conserved ribosomal protein gene. Molecular and cellular biology 63 3037334
2008 Expression and functional analyses of circadian genes in mouse oocytes and preimplantation embryos: Cry1 is involved in the meiotic process independently of circadian clock regulation. Biology of reproduction 61 19020302
2013 Cry1 and Tef gene polymorphisms are associated with major depressive disorder in the Chinese population. Journal of affective disorders 58 24581835
2019 The Circadian Clock Protein CRY1 Is a Negative Regulator of HIF-1α. iScience 55 30875610
2002 Altered Glycosylation of 63- and 68-kilodalton microvillar proteins in Heliothis virescens correlates with reduced Cry1 toxin binding, decreased pore formation, and increased resistance to Bacillus thuringiensis Cry1 toxins. Applied and environmental microbiology 55 12406769
2014 CRY1 circadian gene variant interacts with carbohydrate intake for insulin resistance in two independent populations: Mediterranean and North American. Chronobiology international 54 24548145
2020 The human CRY1 tail controls circadian timing by regulating its association with CLOCK:BMAL1. Proceedings of the National Academy of Sciences of the United States of America 53 33106415
2012 USP2a protein deubiquitinates and stabilizes the circadian protein CRY1 in response to inflammatory signals. The Journal of biological chemistry 53 22669941
2020 Two ABC transporters are differentially involved in the toxicity of two Bacillus thuringiensis Cry1 toxins to the invasive crop-pest Spodoptera frugiperda (J. E. Smith). Pest management science 52 33145907
2013 Distinct and separable roles for endogenous CRY1 and CRY2 within the circadian molecular clockwork of the suprachiasmatic nucleus, as revealed by the Fbxl3(Afh) mutation. The Journal of neuroscience : the official journal of the Society for Neuroscience 51 23616524
2019 Resveratrol Prevents Acrylamide-Induced Mitochondrial Dysfunction and Inflammatory Responses via Targeting Circadian Regulator Bmal1 and Cry1 in Hepatocytes. Journal of agricultural and food chemistry 47 31294559
2014 Mice deficient in cryptochrome 1 (cry1 (-/-)) exhibit resistance to obesity induced by a high-fat diet. Frontiers in endocrinology 47 24782829
2012 Epigenetic silencing of the circadian clock gene CRY1 is associated with an indolent clinical course in chronic lymphocytic leukemia. PloS one 43 22470559
2001 Effect of estrogen on the expression of Cry1 and Cry2 mRNAs in the suprachiasmatic nucleus of female rats. Neuroscience research 42 11672838
2009 Combined PER2 and CRY1 expression predicts outcome in chronic lymphocytic leukemia. European journal of haematology 41 19500131
2009 Unusual circadian locomotor activity and pathophysiology in mutant CRY1 transgenic mice. Neuroscience letters 40 19159659
2003 Characterization of cry1, cry2, and cry9 genes in Bacillus thuringiensis isolates from China. Journal of invertebrate pathology 40 12581721
2018 Over-expressed microRNA-181a reduces glomerular sclerosis and renal tubular epithelial injury in rats with chronic kidney disease via down-regulation of the TLR/NF-κB pathway by binding to CRY1. Molecular medicine (Cambridge, Mass.) 38 30241461
2014 Synergism and antagonism between Bacillus thuringiensis Vip3A and Cry1 proteins in Heliothis virescens, Diatraea saccharalis and Spodoptera frugiperda. PloS one 38 25275646
2003 Photoinducible phase-specific light induction of Cry1 gene in the pars tuberalis of Japanese quail. Endocrinology 38 14684603
2020 Human CRY1 variants associate with attention deficit/hyperactivity disorder. The Journal of clinical investigation 35 32538895
2009 Cry1 circadian phase in vitro: wrapped up with an E-box. Journal of biological rhythms 34 19150926
2021 The blue light receptor CRY1 interacts with GID1 and DELLA proteins to repress gibberellin signaling and plant growth. Plant communications 33 34778751
2020 CRY1-CBS binding regulates circadian clock function and metabolism. The FEBS journal 33 32383312
2014 CRY1, CRY2 and PRKCDBP genetic variants in metabolic syndrome. Hypertension research : official journal of the Japanese Society of Hypertension 32 25391456
2012 Cry1-/- circadian rhythmicity depends on SCN intercellular coupling. Journal of biological rhythms 32 23223370
2020 Circadian clock protein CRY1 prevents paclitaxel‑induced senescence of bladder cancer cells by promoting p53 degradation. Oncology reports 31 33650658
2019 Synergism of the Bacillus thuringiensis Cry1, Cry2, and Vip3 Proteins in Spodoptera frugiperda Control. Applied biochemistry and biotechnology 31 30706415
2022 Resistance of Spodoptera frugiperda to Cry1, Cry2, and Vip3Aa Proteins in Bt Corn and Cotton in the Americas: Implications for the Rest of the World. Journal of economic entomology 30 36515105
2012 Deregulated expression of cry1 and cry2 in human gliomas. Asian Pacific journal of cancer prevention : APJCP 29 23317246
2017 DDB1-Mediated CRY1 Degradation Promotes FOXO1-Driven Gluconeogenesis in Liver. Diabetes 28 28790135
2013 Npas4 is activated by melatonin, and drives the clock gene Cry1 in the ovine pars tuberalis. Molecular endocrinology (Baltimore, Md.) 28 23598442
2002 Role of Bacillus thuringiensis Cry1 delta endotoxin binding in determining potency during lepidopteran larval development. Applied and environmental microbiology 27 11916662
2020 Toxicological and molecular profiling of insecticide resistance in a Brazilian strain of fall armyworm resistant to Bt Cry1 proteins. Pest management science 26 32841530
2018 Screening for single-chain variable fragment antibodies against multiple Cry1 toxins from an immunized mouse phage display antibody library. Applied microbiology and biotechnology 26 29484477
2019 Generation of Human CRY1 and CRY2 Knockout Cells Using Duplex CRISPR/Cas9 Technology. Frontiers in physiology 25 31143130
2016 Production and Characterization of Monoclonal Antibody Broadly Recognizing Cry1 Toxins by Use of Designed Polypeptide as Hapten. Analytical chemistry 25 27341419
2018 Cry1 deficiency leads to testicular dysfunction and altered expression of genes involved in cell communication, chromatin reorganization, spermatogenesis, and immune response in mouse testis. Molecular reproduction and development 24 29411926
2010 Loss of circadian rhythm and light-induced suppression of pineal melatonin levels in Cry1 and Cry2 double-deficient mice. Genes to cells : devoted to molecular & cellular mechanisms 24 20825493
2018 Cry1 Bt Susceptibilities of Fall Armyworm (Lepidoptera: Noctuidae) Host Strains. Journal of economic entomology 23 29240921
2018 Knocking down clock control gene CRY1 decreases adipogenesis via canonical Wnt/β-catenin signaling pathway. Biochemical and biophysical research communications 23 30384996
2015 CUL4-DDB1-CDT2 E3 Ligase Regulates the Molecular Clock Activity by Promoting Ubiquitination-Dependent Degradation of the Mammalian CRY1. PloS one 22 26431207
1990 A Neurospora crassa ribosomal protein gene, homologous to yeast CRY1, contains sequences potentially coordinating its transcription with rRNA genes. Nucleic acids research 22 1977135
1984 Molecular cloning and biosynthetic regulation of cry1 gene of Saccharomyces cerevisiae. Molecular & general genetics : MGG 21 6088947
2020 A MAGEL2-deubiquitinase complex modulates the ubiquitination of circadian rhythm protein CRY1. PloS one 20 32315313
2008 Identification of coding polymorphisms in human circadian rhythm genes PER1, PER2, PER3, CLOCK, ARNTL, CRY1, CRY2 and TIMELESS in a multi-ethnic screening panel. DNA sequence : the journal of DNA sequencing and mapping 20 17852344
2012 Molecular cloning, tissue distribution and daily expression of cry1 and cry2 clock genes in European seabass (Dicentrarchus labrax). Comparative biochemistry and physiology. Part A, Molecular & integrative physiology 19 22841604
2016 Phosphorylation Regulating the Ratio of Intracellular CRY1 Protein Determines the Circadian Period. Frontiers in neurology 18 27721804
2002 Polydispersity of Bacillus thuringiensis Cry1 toxins in solution and its effect on receptor binding kinetics. Biochimica et biophysica acta 18 11904222
2001 A putative flavin electron transport pathway is differentially utilized in Xenopus CRY1 and CRY2. Current biology : CB 18 11747820
2023 Blue light receptor CRY1 regulates HSFA1d nuclear localization to promote plant thermotolerance. Cell reports 17 37703177
2021 The molecular clock gene cryptochrome 1 (CRY1) and its role in cluster headache. Cephalalgia : an international journal of headache 17 34256648
2013 Altered phase-relationship between peripheral oscillators and environmental time in Cry1 or Cry2 deficient mouse models for early and late chronotypes. PloS one 17 24386234
2011 Hypertension due to loss of clock: novel insight from the molecular analysis of Cry1/Cry2-deleted mice. Current hypertension reports 17 21286865
2017 Genetic Environment of cry1 Genes Indicates Their Common Origin. Genome biology and evolution 16 29617829
1991 Altered response to growth rate changes in Kluyveromyces lactis versus Saccharomyces cerevisiae as demonstrated by heterologous expression of ribosomal protein 59 (CRY1). Nucleic acids research 16 1891361
2021 CRY1 Regulates Chemoresistance in Association With NANOG by Inhibiting Apoptosis via STAT3 Pathway in Patients With Cervical Cancer. Cancer genomics & proteomics 15 34697063
2020 The Arg-293 of Cryptochrome1 is responsible for the allosteric regulation of CLOCK-CRY1 binding in circadian rhythm. The Journal of biological chemistry 15 33028638
2014 The Trichoderma reesei Cry1 protein is a member of the cryptochrome/photolyase family with 6-4 photoproduct repair activity. PloS one 15 24964051
2021 ATP-binding cassette transporter subfamily C members 2, 3 and cadherin protein are susceptibility-determining factors in Bombyx mori for multiple Bacillus thuringiensis Cry1 toxins. Insect biochemistry and molecular biology 14 34560243
2016 Role and expression of cry1 in the adductor muscle of the oyster Crassostrea gigas during daily and tidal valve activity rhythms. Chronobiology international 14 27246263
2015 The induction of Per1 expression by the combined treatment with glutamate, 5-hydroxytriptamine and dopamine initiates a ripple effect on Bmal1 and Cry1 mRNA expression via the ERK signaling pathway in cultured rat spinal astrocytes. Neurochemistry international 14 26151099
2024 Bevacizumab increases the sensitivity of olaparib to homologous recombination-proficient ovarian cancer by suppressing CRY1 via PI3K/AKT pathway. Frontiers in oncology 13 38420012
2022 Hepatic GSK3β-Dependent CRY1 Degradation Contributes to Diabetic Hyperglycemia. Diabetes 13 35476750
2018 The expression of clock genes cry1 and cry2 in human colorectal cancer and tumor adjacent tissues correlates differently dependent on tumor location. Neoplasma 13 29940771
2007 Cry1 expression in the chicken pineal gland: effects of changes in the light/dark conditions. General and comparative endocrinology 13 17324421
2023 The circadian clock CRY1 regulates pluripotent stem cell identity and somatic cell reprogramming. Cell reports 12 37261952
2021 Restoration of H3k27me3 Modification Epigenetically Silences Cry1 Expression and Sensitizes Leptin Signaling to Reduce Obesity-Related Properties. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 12 34306972
2021 CHRONO and DEC1/DEC2 compensate for lack of CRY1/CRY2 in expression of coherent circadian rhythm but not in generation of circadian oscillation in the neonatal mouse SCN. Scientific reports 12 34584158
2018 JMJD5 links CRY1 function and proteasomal degradation. PLoS biology 12 30500822
2015 CRY1 Variations Impacts on the Depressive Relapse Rate in a Sample of Bipolar Patients. Psychiatry investigation 12 25670954
2023 CRY1/2 regulate rhythmic CYP2A5 in mouse liver through repression of E4BP4. Biochemical pharmacology 11 37797722
2022 Knockout of ABC Transporter ABCG4 Gene Confers Resistance to Cry1 Proteins in Ostrinia furnacalis. Toxins 11 35051029
2021 Variants in Circadian Rhythm Gene Cry1 Interacts with Healthy Dietary Pattern for Serum Leptin Levels: a Cross-sectional Study. Clinical nutrition research 11 33564652
2005 Identification of cry-type genes on 20-kb DNA associated with Cry1 crystal proteins from Bacillus thuringiensis. Current microbiology 11 15942699
2023 Screening for resistance alleles to Cry1 proteins through targeted sequencing in the native and invasive range of Spodoptera frugiperda (Lepidoptera: Noctuidae). Journal of economic entomology 10 37311017
2022 Comparison of in vitro and in vivo binding site competition of Bacillus thuringiensis Cry1 proteins in two important maize pests. Pest management science 10 34951106
2019 Phosphorylation of CRY1 Serine 71 Alters Voluntary Activity but Not Circadian Rhythms In Vivo. Journal of biological rhythms 10 31258021
2005 Assessment of cry1 gene contents of Bacillus thuringiensis strains by use of DNA microarrays. Applied and environmental microbiology 10 16151129
1992 The complete sequence of K3B, a 7.9 kb fragment between PGK1 and CRY1 on chromosome III, reveals the presence of seven open reading frames. Yeast (Chichester, England) 10 1574926

Missed literature

Know a paper Affinage missed for CRY1? Flag it for the maintainers and the community.

No submissions yet.