CRY1

Summary: UniProt-curated localization includes nuclear and cytoplasmic CRY1.

Reason: Subcellular location annotations report cytoplasmic and nuclear CRY1.

Summary: UniProt-curated localization includes nuclear and cytoplasmic CRY1.

Reason: Subcellular location annotations report cytoplasmic and nuclear CRY1.

Summary: CRY proteins repress CLOCK:BMAL1-driven transcription in the circadian loop.

Reason: CRY/PER repressors inhibit CLOCK:BMAL1 transcriptional activity.

Summary: Evidence supports CRY1 binding to CLOCK:BMAL1 on E-boxes, not direct DNA binding.

Reason: CRY binds the CLOCK:BMAL1:E-box complex; DNA-binding TF binding is more accurate.

Proposed replacements: DNA-binding transcription factor binding

Summary: CRY1 regulates circadian gene expression via the core transcriptional feedback loop.

Reason: CRY represses CLOCK:BMAL1 activity, shaping circadian gene expression.

Summary: Mammalian CRY is not required for photo-entrainment; photoperiod entrainment is unsupported.

Reason: Evidence indicates mammalian CRY is not required for photo-entrainment.

Summary: CRY1 binds FAD as a chromophore/cofactor.

Reason: Purified hCRY1 contains FAD, supporting FAD binding.

Summary: CRY1 binds a nucleotide cofactor (FAD), consistent with nucleotide binding.

Reason: FAD is a nucleotide cofactor; the term is generic but compatible with FAD binding.

Summary: UniProt-curated localization includes nuclear and cytoplasmic CRY1.

Reason: Subcellular location annotations report cytoplasmic and nuclear CRY1.

Summary: UniProt-curated localization includes nuclear and cytoplasmic CRY1.

Reason: Subcellular location annotations report cytoplasmic and nuclear CRY1.

Summary: Mammalian CRY is not required for photo-entrainment; photoreceptor activity is not supported.

Reason: Evidence indicates mammalian CRY is not required for photo-entrainment.

Summary: Phosphatase binding from an automated rule; the same term has an IPI row citing the two-hybrid study of hCRY1 and hCRY2 interactors, whose full text is not available.

Reason: The same term carries an experimental (IPI) row citing the yeast two-hybrid study in which the two human cryptochromes were screened for interacting proteins and protein phosphatase 5 was recovered. That paper's title names hCRY2, but hCRY1 was also a bait and only the abstract is available, so whether CRY1 was shown to bind the phosphatase cannot be checked. This rule-based row asserts the same claim and is left undecided with it rather than removed.

Summary: CRY1 participates in rhythmic processes as part of the circadian clock.

Reason: CRY1 is a core circadian clock component regulating rhythmic gene expression.

Summary: CRY1 interacts with PRMT5, but the generic protein binding term is too broad.

Reason: The study reports a specific PRMT5 interaction rather than nonspecific binding.

Summary: High-throughput interactome study; generic protein binding term is not informative for CRY1.

Reason: Proteome-scale AP-MS reports many candidate interactions and does not validate a specific CRY1 binding partner.

Summary: Proteome-scale interactome mapping is too nonspecific for a generic protein-binding annotation.

Reason: The study reports large-scale interaction networks rather than a specific CRY1 binding partner.

Summary: CRY proteins repress CLOCK:BMAL1-driven transcription in the circadian loop.

Reason: CRY/PER repressors inhibit CLOCK:BMAL1 transcriptional activity.

Summary: Evidence supports CRY1 binding to CLOCK:BMAL1 on E-boxes, not direct DNA binding.

Reason: CRY binds the CLOCK:BMAL1:E-box complex; DNA-binding TF binding is more accurate.

Proposed replacements: DNA-binding transcription factor binding

Summary: Mitochondrion (IEA), transferred from mouse Cry1, which carries it from a direct assay and a mitochondrial proteome. Human CRY1 is established as nuclear and cytoplasmic.

Reason: The row is transferred from mouse Cry1, where mitochondrion rests on two experimental observations: a direct assay in an early localization study (IDA, PMID:9801304) and detection in the MitoCarta mitochondrial proteome (HDA, PMID:18614015). The transfer therefore has a real basis and is not an error of mapping. For the human protein there is no direct evidence, and the established sites of CRY1 action are the nucleus and cytoplasm, so a mitochondrial pool is unconfirmed rather than refuted; the organelle claim is treated as an over-annotation.

Summary: CRY1 inhibits gluconeogenic gene expression rather than catalyzing gluconeogenesis.

Reason: Evidence supports negative regulation of gluconeogenesis.

Proposed replacements: negative regulation of gluconeogenesis

Summary: CRY1 represses gluconeogenic gene expression via glucagon/cAMP signaling.

Reason: Evidence supports negative regulation rather than generic regulation.

Proposed replacements: negative regulation of gluconeogenesis

Summary: Mammalian CRY is not required for photo-entrainment, so light response is unsupported.

Reason: Evidence indicates mammalian CRY is not required for photo-entrainment.

Summary: Response to activity (IEA), transferred from mouse Cry1, annotated from a mutant phenotype in the study showing that CRY1/2 repress PPAR-delta and limit exercise capacity (PMID:28683290).

Reason: The row is transferred from mouse Cry1, annotated from a mutant phenotype in the study showing that CRY1 and CRY2 repress PPAR-delta and limit exercise capacity (PMID:28683290), so the claim has experimental support in the ortholog. The phenotype is altered exercise performance in cryptochrome-deficient animals, which is a consequence of CRY-dependent repression of a nuclear receptor rather than CRY1 taking part in a response to activity. The term over-reads the phenotype rather than being unsupported.

Summary: CRY1 interacts with nuclear receptors such as the glucocorticoid receptor.

Reason: Cryptochromes bind the glucocorticoid receptor in a ligand-dependent manner.

Summary: Direct kinase binding evidence was not found in accessible sources.

Reason: No direct kinase-binding assays were located in the available references.

Summary: Direct kinase binding evidence was not found in accessible sources.

Reason: No direct kinase-binding assays were located in the available references.

Summary: Lipid storage (IEA), transferred from mouse Cry1, annotated from a double-mutant experiment in a study of diet-induced metabolic changes in Cry-deficient mice (PMID:23531614).

Reason: The row is transferred from mouse Cry1, annotated from a genetic-interaction (double-mutant) experiment in a study of diet-induced hyperinsulinemia and insulin resistance in cryptochrome-deficient mice (PMID:23531614), so it has an experimental basis. Increased fat accumulation in Cry-deficient animals is, however, a systemic metabolic phenotype of losing clock-dependent regulation, not evidence that CRY1 carries out lipid storage. The term over-reads the phenotype rather than being unsupported.

Summary: Negative regulation of protein ubiquitination (IEA), transferred from mouse Cry1, where it is a direct assay showing that mCRY inhibits ubiquitylation of mPER2 (PMID:11889036).

Reason: The row is transferred from mouse Cry1, annotated by direct assay in the study that demonstrated mCRY-dependent inhibition of ubiquitylation of the clock protein mPER2 (PMID:11889036). The claim is therefore not a confusion of CRY1 as a ubiquitination substrate with a regulator: cryptochrome binding protects PER2 from ubiquitylation and degradation. CRY1 is itself also ubiquitinated through FBXL3, which is a separate fact. Stabilization of PER2 is part of how the repressor complex is assembled but is secondary to CRY1's role as a transcriptional repressor, so it is kept as non-core.

Summary: Positive regulation of protein ubiquitination (IEA), transferred from mouse Cry1, annotated from a mutant phenotype (PMID:28790135); the source paper is not available to check.

Reason: The row is transferred from mouse Cry1, annotated from a mutant phenotype in a study of DDB1-mediated CRY1 degradation and FOXO1-driven gluconeogenesis (PMID:28790135), which is not available here. CRY1 is itself ubiquitinated and degraded, but that does not exclude it promoting the ubiquitination of another protein, and the donor annotation is experimental; whether the paper shows such an effect cannot be checked. The row is left undecided rather than removed as a substrate/regulator confusion.

Summary: CRY1 influences insulin sensitivity in metabolic settings.

Reason: Cry1 overexpression improves insulin sensitivity in insulin-resistant mice.

Summary: CRY1 regulates circadian gene expression via the core transcriptional feedback loop.

Reason: CRY represses CLOCK:BMAL1 activity, shaping circadian gene expression.

Summary: CRY1 modulates glucagon-stimulated signaling during fasting.

Reason: Cry1 reduces glucagon-mediated increases in cAMP.

Summary: CRY1 contributes to glucose homeostasis.

Reason: Loss of cryptochromes causes glucose intolerance and altered corticosterone levels.

Summary: CRY1 is a core circadian clock repressor.

Reason: CRY1/2 encode inhibitors of CLOCK:BMAL1 in the feedback loop.

Summary: CRY1 represses CLOCK:BMAL1 as part of the negative limb of the clock.

Reason: CRY1/2 inhibit CLOCK:BMAL1 in a negative-feedback loop.

Summary: Signal transduction in response to DNA damage (IEA), transferred from mouse Cry1, annotated by direct assay in a study of CRY1 and the ATR-mediated checkpoint (PMID:24489120).

Reason: The row is transferred from mouse Cry1, annotated by direct assay in the study reporting modulation of the ATR-mediated DNA damage checkpoint response by cryptochrome 1 (PMID:24489120). The claim therefore has direct experimental support in the ortholog and is not merely absent from the circadian literature. A role in DNA damage signalling is secondary to CRY1's function as a circadian transcriptional repressor, so it is kept as non-core.

Summary: CRY1 recruits histone deacetylases as part of transcriptional repression.

Reason: CRY1 is reported to recruit HDACs during Per1 repression.

Summary: Mammalian CRY is not required for photo-entrainment; photoperiod entrainment is unsupported.

Reason: Evidence indicates mammalian CRY is not required for photo-entrainment.

Summary: CRY1 reduces gluconeogenic gene expression during fasting.

Reason: Cry1 reduces fasting gluconeogenic gene expression by blocking glucagon-mediated cAMP increases.

Summary: CRY1 suppresses rather than promotes gluconeogenesis.

Reason: Cry1 reduces gluconeogenic gene expression, supporting negative regulation instead.

Summary: CRY1 dampens GPCR-driven cAMP signaling.

Reason: Cry1 inhibits cAMP accumulation in response to GPCR activation.

Summary: CRY proteins repress CLOCK:BMAL1-driven transcription in the circadian loop.

Reason: CRY/PER repressors inhibit CLOCK:BMAL1 transcriptional activity.

Summary: Evidence supports CRY1 binding to CLOCK:BMAL1 on E-boxes, not direct DNA binding.

Reason: CRY binds the CLOCK:BMAL1:E-box complex; DNA-binding TF binding is more accurate.

Proposed replacements: DNA-binding transcription factor binding

Summary: CRY1 binds the CLOCK:BMAL1:E-box complex via protein-protein interactions.

Reason: CRY binds stably to the CLOCK:BMAL1:E-box ternary complex.

Summary: Regulation of DNA damage checkpoint (IEA), transferred from mouse Cry1, annotated by direct assay in a study of CRY1 and the ATR-mediated checkpoint (PMID:24489120).

Reason: The row is transferred from mouse Cry1, annotated by direct assay in the study reporting modulation of the ATR-mediated DNA damage checkpoint response by cryptochrome 1 (PMID:24489120), which is what the term states. The claim therefore has direct experimental support in the ortholog. Checkpoint modulation is secondary to CRY1's function as a circadian transcriptional repressor, so it is kept as non-core.

Summary: CRY1 broadly represses glucocorticoid receptor activity.

Reason: Cryptochromes oppose glucocorticoid receptor activation and promote repression.

Summary: Cryptochromes restrain glucocorticoid levels in vivo.

Reason: Loss of cryptochromes leads to constitutively high corticosterone.

Summary: CRY1 is nuclear, but nucleoplasm is more specific than supported.

Reason: Evidence supports nuclear localization without nucleoplasm specificity.

Proposed replacements: nucleus

Summary: CRY1 functions in the core circadian clock.

Reason: CRY1 is a core component of the circadian clock mechanism.

Summary: Mammalian CRY is not required for photo-entrainment, so light response is unsupported.

Reason: Evidence indicates mammalian CRY is not required for photo-entrainment.

Summary: Response to activity (ISS), inferred from mouse Cry1, annotated from a mutant phenotype in the study showing that CRY1/2 repress PPAR-delta and limit exercise capacity (PMID:28683290).

Reason: The row is inferred from mouse Cry1, annotated from a mutant phenotype in the study showing that CRY1 and CRY2 repress PPAR-delta and limit exercise capacity (PMID:28683290), so the claim has experimental support in the ortholog. The phenotype is altered exercise performance in cryptochrome-deficient animals, which is a consequence of CRY-dependent repression of a nuclear receptor rather than CRY1 taking part in a response to activity. The term over-reads the phenotype rather than being unsupported.

Summary: CRY1 binds the nuclear receptor HNF4A; a nuclear receptor binding term is more appropriate.

Reason: Evidence supports interaction with a nuclear receptor rather than generic protein binding.

Proposed replacements: nuclear receptor binding

Summary: CRY1 is ubiquitinated by the CUL4-DDB1-CDT2 ligase; generic protein binding is too broad.

Reason: The evidence describes CRY1 as a ubiquitination substrate rather than a general binding activity.

Summary: UniProt-curated localization includes nuclear CRY1.

Reason: Subcellular location annotations indicate nuclear localization; PMID:26431207 does not contradict this.

Summary: Positive regulation of protein ubiquitination (ISS), inferred from mouse Cry1, annotated from a mutant phenotype (PMID:28790135); the source paper is not available to check.

Reason: The row is inferred from mouse Cry1, annotated from a mutant phenotype in a study of DDB1-mediated CRY1 degradation and FOXO1-driven gluconeogenesis (PMID:28790135), which is not available here. CRY1 is itself ubiquitinated and degraded, but that does not exclude it promoting the ubiquitination of another protein, and the donor annotation is experimental; whether the paper shows such an effect cannot be checked. The row is left undecided rather than removed as a substrate/regulator confusion.

Summary: CRY1 reduces gluconeogenic gene expression during fasting.

Reason: Cry1 reduces fasting gluconeogenic gene expression by blocking glucagon-mediated cAMP increases.

Summary: CRY1 participates in transcriptional repression within the circadian feedback loop.

Reason: PER/CRY complexes inhibit CLOCK/BMAL1 transcriptional activity.

Summary: Mammalian CRY is not required for photo-entrainment; photoperiod entrainment is unsupported.

Reason: Evidence indicates mammalian CRY is not required for photo-entrainment.

Summary: CRY proteins inhibit Per transcription in the circadian feedback loop.

Reason: The study states Cry proteins inhibit Per transcription.

Summary: Negative regulation of protein ubiquitination (ISS), inferred from mouse Cry1, where it is a direct assay showing that mCRY inhibits ubiquitylation of mPER2 (PMID:11889036).

Reason: The row is inferred from mouse Cry1, annotated by direct assay in the study that demonstrated mCRY-dependent inhibition of ubiquitylation of the clock protein mPER2 (PMID:11889036). The claim is therefore not a confusion of CRY1 as a ubiquitination substrate with a regulator: cryptochrome binding protects PER2 from ubiquitylation and degradation. CRY1 is itself also ubiquitinated through FBXL3, which is a separate fact. Stabilization of PER2 is secondary to CRY1's role as a transcriptional repressor, so it is kept as non-core.

Summary: CRY1 interacts with G(s)α in GPCR signaling; generic protein binding is too broad.

Reason: Evidence supports a specific interaction with G(s)α rather than nonspecific binding.

Summary: CRY1 inhibits gluconeogenic gene expression rather than catalyzing gluconeogenesis.

Reason: Evidence supports negative regulation of gluconeogenesis.

Proposed replacements: negative regulation of gluconeogenesis

Summary: CRY1 modulates glucagon-stimulated signaling during fasting.

Reason: Cry1 reduces glucagon-mediated increases in cAMP.

Summary: CRY1 dampens GPCR-driven cAMP signaling.

Reason: Cry1 inhibits cAMP accumulation in response to GPCR activation.

Summary: UniProt-curated localization includes nuclear and cytoplasmic CRY1.

Reason: Subcellular location annotations report cytoplasmic and nuclear CRY1.

Summary: Signal transduction in response to DNA damage (ISS), inferred from mouse Cry1, annotated by direct assay in a study of CRY1 and the ATR-mediated checkpoint (PMID:24489120).

Reason: The row is inferred from mouse Cry1, annotated by direct assay in the study reporting modulation of the ATR-mediated DNA damage checkpoint response by cryptochrome 1 (PMID:24489120). The claim therefore has direct experimental support in the ortholog and is not merely absent from the circadian literature. A role in DNA damage signalling is secondary to CRY1's function as a circadian transcriptional repressor, so it is kept as non-core.

Summary: Regulation of DNA damage checkpoint (ISS), inferred from mouse Cry1, annotated by direct assay in a study of CRY1 and the ATR-mediated checkpoint (PMID:24489120).

Reason: The row is inferred from mouse Cry1, annotated by direct assay in the study reporting modulation of the ATR-mediated DNA damage checkpoint response by cryptochrome 1 (PMID:24489120), which is what the term states. The claim therefore has direct experimental support in the ortholog. Checkpoint modulation is secondary to CRY1's function as a circadian transcriptional repressor, so it is kept as non-core.

Summary: CRY1 contributes to glucose homeostasis.

Reason: Loss of cryptochromes causes glucose intolerance and altered corticosterone levels.

Summary: CRY1 broadly represses glucocorticoid receptor activity.

Reason: Cryptochromes oppose glucocorticoid receptor activation and promote repression.

Summary: CRY1/2 interact with the glucocorticoid receptor in a ligand-dependent manner.

Reason: The study reports cryptochromes binding the glucocorticoid receptor.

Summary: CRY binds to the CLOCK:BMAL1:E-box complex; generic protein binding is too broad.

Reason: Evidence describes specific interaction with CLOCK:BMAL1 on DNA.

Summary: The cited study focuses on PER complexes and does not present CRY1 binding evidence.

Reason: No CRY1 interaction evidence is provided in the abstract.

Summary: CRY1 represses CLOCK:BMAL1 as part of the negative limb of the clock.

Reason: CRY1/2 inhibit CLOCK:BMAL1 in a negative-feedback loop.

Summary: CRY1 regulates circadian gene expression via the core transcriptional feedback loop.

Reason: CRY represses CLOCK:BMAL1 activity, shaping circadian gene expression.

Summary: CRY proteins repress CLOCK:BMAL1-driven transcription in the circadian loop.

Reason: CRY/PER repressors inhibit CLOCK:BMAL1 transcriptional activity.

Summary: The study reports PP5 interaction with hCRY2, not CRY1.

Reason: Evidence is specific to CRY2, so it does not support CRY1 binding.

Summary: IPI annotation from the two-hybrid study of hCRY1 and hCRY2 interactors; the title foregrounds the hCRY2-PP5 interaction and the full text is not available.

Reason: The cited study used the two human cryptochromes, hCRY1 and hCRY2, as baits in a yeast two-hybrid search and recovered the TPR-containing protein phosphatase 5. Its title singles out hCRY2, but only the abstract is available, so whether the full text also reports an hCRY1-PP5 interaction, which is what the curator's physical-interaction annotation asserts, cannot be checked. An experimental annotation is not treated as a paralog mis-attribution on the strength of a title, so the row is left undecided.

Summary: Cry proteins inhibit Per transcription in the circadian feedback loop.

Reason: Cry proteins are reported to inhibit Per transcription.

Summary: PER/CRY act as negative regulators of CLOCK/BMAL-driven transcription.

Reason: PER/CRY suppress CLOCK/BMAL-induced expression in the feedback loop.

Summary: Cry proteins suppress Clock/Bmal-induced transcription.

Reason: Cry proteins are reported to suppress Clock/Bmal-induced transcription.

Summary: CRY1 is a core circadian clock repressor.

Reason: CRY1/2 encode inhibitors of CLOCK:BMAL1 in the feedback loop.

Summary: Human CRY1 is not required for photo-entrainment; blue-light signaling is not supported.

Reason: Mammalian CRY is reported not to be required for photo-entrainment, so blue-light signaling is unsupported.

Summary: Early work suggested blue-light photoreceptor function, but mammalian CRY is not required for photo-entrainment.

Reason: The photoreceptor role is speculative for mammals; later evidence indicates CRY is not required for photo-entrainment.

Summary: CRY1 binds CLOCK:BMAL1 on E-box DNA rather than directly binding DNA.

Reason: Evidence supports association with the CLOCK:BMAL1:E-box complex, not direct DNA binding.

Proposed replacements: DNA-binding transcription factor binding

Summary: CRY1 lacks cyclobutane pyrimidine dimer photolyase activity (negated).

Reason: Purified hCRY1 lacks photolyase activity on cyclobutane pyrimidine dimers.

Summary: CRY1 lacks (6-4) photolyase activity (negated).

Reason: Purified hCRY1 lacks photolyase activity on (6-4) photoproducts.

Summary: CRY1 is an inhibitor of CLOCK:BMAL1 but generic protein binding is too broad.

Reason: Evidence points to specific interactions in the clock feedback loop.

Summary: Evidence favors interaction with CLOCK:BMAL1 on E-boxes rather than direct DNA binding.

Reason: CRY binds the CLOCK:BMAL1:E-box complex, so a TF-binding term is more accurate.

Proposed replacements: DNA-binding transcription factor binding