Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: UniProt-curated localization includes nuclear and cytoplasmic CRY1. Reason: Subcellular location annotations report cytoplasmic and nuclear CRY1. Supporting Evidence: UniProtKB:Q16526 SUBCELLULAR LOCATION: Cytoplasm. Nucleus {ECO:0000269\|PubMed:22798407,
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: UniProt-curated localization includes nuclear and cytoplasmic CRY1. Reason: Subcellular location annotations report cytoplasmic and nuclear CRY1. Supporting Evidence: UniProtKB:Q16526 SUBCELLULAR LOCATION: Cytoplasm. Nucleus {ECO:0000269\|PubMed:22798407,
GO:0045892 negative regulation of DNA-templated transcription	IBA GO_REF:0000033	ACCEPT	Summary: CRY proteins repress CLOCK:BMAL1-driven transcription in the circadian loop. Reason: CRY/PER repressors inhibit CLOCK:BMAL1 transcriptional activity. Supporting Evidence: PMID:21613214 repress their own transcription by suppressing the transactivator function of
GO:0003677 DNA binding	IBA GO_REF:0000033	MODIFY	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 Supporting Evidence: PMID:21613214 CRY binds stably to the CLOCK:BMAL1:E-box ternary
GO:0032922 circadian regulation of gene expression	IBA GO_REF:0000033	ACCEPT	Summary: CRY1 regulates circadian gene expression via the core transcriptional feedback loop. Reason: CRY represses CLOCK:BMAL1 activity, shaping circadian gene expression. Supporting Evidence: PMID:21613214 repress their own transcription by suppressing the transactivator function of
GO:0043153 entrainment of circadian clock by photoperiod	IBA GO_REF:0000033	REMOVE	Summary: Mammalian CRY is not required for photo-entrainment; photoperiod entrainment is unsupported. Reason: Evidence indicates mammalian CRY is not required for photo-entrainment. Supporting Evidence: PMID:23133559 Arabidopsis and Drosophila CRY is a major circadian photoreceptor for light entrainment, while mammalian CRY is not required for photo-entrainment.
GO:0071949 FAD binding	IBA GO_REF:0000033	ACCEPT	Summary: CRY1 binds FAD as a chromophore/cofactor. Reason: Purified hCRY1 contains FAD, supporting FAD binding. Supporting Evidence: PMID:8909283 were found to contain FAD and a pterin cofactor.
GO:0000166 nucleotide binding	IEA GO_REF:0000043	KEEP AS NON CORE	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. Supporting Evidence: UniProtKB:Q16526 Binds 1 FAD per subunit.
GO:0005634 nucleus	IEA GO_REF:0000120	ACCEPT	Summary: UniProt-curated localization includes nuclear and cytoplasmic CRY1. Reason: Subcellular location annotations report cytoplasmic and nuclear CRY1. Supporting Evidence: UniProtKB:Q16526 SUBCELLULAR LOCATION: Cytoplasm. Nucleus {ECO:0000269\|PubMed:22798407,
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: UniProt-curated localization includes nuclear and cytoplasmic CRY1. Reason: Subcellular location annotations report cytoplasmic and nuclear CRY1. Supporting Evidence: UniProtKB:Q16526 SUBCELLULAR LOCATION: Cytoplasm. Nucleus {ECO:0000269\|PubMed:22798407,
GO:0009881 photoreceptor activity	IEA GO_REF:0000043	REMOVE	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. Supporting Evidence: PMID:23133559 Arabidopsis and Drosophila CRY is a major circadian photoreceptor for light entrainment, while mammalian CRY is not required for photo-entrainment.
GO:0019902 phosphatase binding	IEA GO_REF:0000117	REMOVE	Summary: Phosphatase binding evidence is for hCRY2, not CRY1. Reason: The cited interaction involves hCRY2 rather than CRY1. Supporting Evidence: PMID:9383998 specifically interacted with hCRY2.
GO:0048511 rhythmic process	IEA GO_REF:0000043	ACCEPT	Summary: CRY1 participates in rhythmic processes as part of the circadian clock. Reason: CRY1 is a core circadian clock component regulating rhythmic gene expression. Supporting Evidence: UniProtKB:Q16526 Transcriptional repressor which forms a core component of the
GO:0005515 protein binding	IPI PMID:23133559 Role of type II protein arginine methyltransferase 5 in the ...	MARK AS OVER ANNOTATED	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. Supporting Evidence: PMID:23133559 interacting molecule of CRY1.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	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. Supporting Evidence: PMID:28514442 BioPlex 2.0 contains more than 29,000 previously unknown co-associations
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	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. Supporting Evidence: PMID:33961781 we have created two proteome-scale, cell-line-specific
GO:0000122 negative regulation of transcription by RNA polymerase II	IEA GO_REF:0000107	ACCEPT	Summary: CRY proteins repress CLOCK:BMAL1-driven transcription in the circadian loop. Reason: CRY/PER repressors inhibit CLOCK:BMAL1 transcriptional activity. Supporting Evidence: PMID:21613214 repress their own transcription by suppressing the transactivator function of
GO:0003690 double-stranded DNA binding	IEA GO_REF:0000107	MODIFY	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 Supporting Evidence: PMID:21613214 CRY binds stably to the CLOCK:BMAL1:E-box ternary
GO:0005739 mitochondrion	IEA GO_REF:0000107	REMOVE	Summary: Human CRY1 is primarily nuclear/cytoplasmic; mitochondrial localization is not established. Reason: Available human evidence supports cytoplasmic/nuclear localization; mitochondrial localization is from mouse CRY1. Supporting Evidence: UniProtKB:Q16526 SUBCELLULAR LOCATION: Cytoplasm. Nucleus {ECO:0000269\|PubMed:22798407, PMID:9801304 mCRY1 is localized in mitochondria
GO:0006094 gluconeogenesis	IEA GO_REF:0000107	MODIFY	Summary: CRY1 inhibits gluconeogenic gene expression rather than catalyzing gluconeogenesis. Reason: Evidence supports negative regulation of gluconeogenesis. Proposed replacements: negative regulation of gluconeogenesis Supporting Evidence: PMID:20852621 gluconeogenic gene expression by blocking glucagon-mediated increases in
GO:0006111 regulation of gluconeogenesis	IEA GO_REF:0000107	MODIFY	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 Supporting Evidence: PMID:20852621 gluconeogenic gene expression by blocking glucagon-mediated increases in
GO:0009416 response to light stimulus	IEA GO_REF:0000107	REMOVE	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. Supporting Evidence: PMID:23133559 Arabidopsis and Drosophila CRY is a major circadian photoreceptor for light entrainment, while mammalian CRY is not required for photo-entrainment.
GO:0014823 response to activity	IEA GO_REF:0000107	REMOVE	Summary: No evidence found linking CRY1 to response to activity. Reason: Accessible sources do not report CRY1 involvement in activity response. Supporting Evidence: UniProtKB:Q16526 Transcriptional repressor which forms a core component of the
GO:0016922 nuclear receptor binding	IEA GO_REF:0000120	ACCEPT	Summary: CRY1 interacts with nuclear receptors such as the glucocorticoid receptor. Reason: Cryptochromes bind the glucocorticoid receptor in a ligand-dependent manner. Supporting Evidence: PMID:22170608 cryptochromes 1 and 2, interact with the glucocorticoid receptor
GO:0019900 kinase binding	IEA GO_REF:0000107	UNDECIDED	Summary: Direct kinase binding evidence was not found in accessible sources. Reason: No direct kinase-binding assays were located in the available references.
GO:0019901 protein kinase binding	IEA GO_REF:0000107	UNDECIDED	Summary: Direct kinase binding evidence was not found in accessible sources. Reason: No direct kinase-binding assays were located in the available references.
GO:0019915 lipid storage	IEA GO_REF:0000107	REMOVE	Summary: No direct evidence found for CRY1 in lipid storage. Reason: Available references emphasize circadian regulation and gluconeogenesis rather than lipid storage. Supporting Evidence: UniProtKB:Q16526 Transcriptional repressor which forms a core component of the
GO:0031397 negative regulation of protein ubiquitination	IEA GO_REF:0000107	REMOVE	Summary: CRY1 is ubiquitinated by SCF(FBXL3), indicating it is a substrate not a regulator. Reason: Evidence shows CRY1 is ubiquitinated and degraded rather than regulating ubiquitination. Supporting Evidence: PMID:17463251 Cry1 and Cry2 proteins are ubiquitinated and degraded
GO:0031398 positive regulation of protein ubiquitination	IEA GO_REF:0000107	REMOVE	Summary: CRY1 is a ubiquitination substrate rather than a positive regulator. Reason: CRY1 is ubiquitinated and degraded via SCF(FBXL3). Supporting Evidence: PMID:17463251 Cry1 and Cry2 proteins are ubiquitinated and degraded
GO:0032868 response to insulin	IEA GO_REF:0000107	ACCEPT	Summary: CRY1 influences insulin sensitivity in metabolic settings. Reason: Cry1 overexpression improves insulin sensitivity in insulin-resistant mice. Supporting Evidence: PMID:20852621 improved insulin sensitivity in insulin-resistant db/db mice
GO:0032922 circadian regulation of gene expression	IEA GO_REF:0000107	ACCEPT	Summary: CRY1 regulates circadian gene expression via the core transcriptional feedback loop. Reason: CRY represses CLOCK:BMAL1 activity, shaping circadian gene expression. Supporting Evidence: PMID:21613214 repress their own transcription by suppressing the transactivator function of
GO:0033762 response to glucagon	IEA GO_REF:0000107	ACCEPT	Summary: CRY1 modulates glucagon-stimulated signaling during fasting. Reason: Cry1 reduces glucagon-mediated increases in cAMP. Supporting Evidence: PMID:20852621 gluconeogenic gene expression by blocking glucagon-mediated increases in
GO:0042593 glucose homeostasis	IEA GO_REF:0000107	ACCEPT	Summary: CRY1 contributes to glucose homeostasis. Reason: Loss of cryptochromes causes glucose intolerance and altered corticosterone levels. Supporting Evidence: PMID:22170608 results in glucose intolerance and constitutively
GO:0042752 regulation of circadian rhythm	IEA GO_REF:0000107	ACCEPT	Summary: CRY1 is a core circadian clock repressor. Reason: CRY1/2 encode inhibitors of CLOCK:BMAL1 in the feedback loop. Supporting Evidence: PMID:17463251 encode inhibitors of the Clock-Bmal1 complex
GO:0042754 negative regulation of circadian rhythm	IEA GO_REF:0000107	ACCEPT	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. Supporting Evidence: PMID:17463251 encode inhibitors of the Clock-Bmal1 complex
GO:0042770 signal transduction in response to DNA damage	IEA GO_REF:0000107	REMOVE	Summary: No direct evidence found for CRY1 in DNA damage response signaling. Reason: Accessible sources focus on circadian regulation and metabolism, not DNA damage signaling. Supporting Evidence: UniProtKB:Q16526 Transcriptional repressor which forms a core component of the
GO:0042826 histone deacetylase binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: CRY1 recruits histone deacetylases as part of transcriptional repression. Reason: CRY1 is reported to recruit HDACs during Per1 repression. Supporting Evidence: PMID:23133559 CRY1 negatively regulates Per1 gene expression by recruiting histone deacetylases (HDACs)
GO:0043153 entrainment of circadian clock by photoperiod	IEA GO_REF:0000107	REMOVE	Summary: Mammalian CRY is not required for photo-entrainment; photoperiod entrainment is unsupported. Reason: Evidence indicates mammalian CRY is not required for photo-entrainment. Supporting Evidence: PMID:23133559 Arabidopsis and Drosophila CRY is a major circadian photoreceptor for light entrainment, while mammalian CRY is not required for photo-entrainment.
GO:0045721 negative regulation of gluconeogenesis	IEA GO_REF:0000107	ACCEPT	Summary: CRY1 reduces gluconeogenic gene expression during fasting. Reason: Cry1 reduces fasting gluconeogenic gene expression by blocking glucagon-mediated cAMP increases. Supporting Evidence: PMID:20852621 gluconeogenic gene expression by blocking glucagon-mediated increases in
GO:0045722 positive regulation of gluconeogenesis	IEA GO_REF:0000107	REMOVE	Summary: CRY1 suppresses rather than promotes gluconeogenesis. Reason: Cry1 reduces gluconeogenic gene expression, supporting negative regulation instead. Supporting Evidence: PMID:20852621 gluconeogenic gene expression by blocking glucagon-mediated increases in
GO:0045744 negative regulation of G protein-coupled receptor signaling pathway	IEA GO_REF:0000107	ACCEPT	Summary: CRY1 dampens GPCR-driven cAMP signaling. Reason: Cry1 inhibits cAMP accumulation in response to GPCR activation. Supporting Evidence: PMID:20852621 Cry1 inhibited accumulation of cAMP in response to G protein-coupled receptor
GO:0045892 negative regulation of DNA-templated transcription	IEA GO_REF:0000107	ACCEPT	Summary: CRY proteins repress CLOCK:BMAL1-driven transcription in the circadian loop. Reason: CRY/PER repressors inhibit CLOCK:BMAL1 transcriptional activity. Supporting Evidence: PMID:21613214 repress their own transcription by suppressing the transactivator function of
GO:0070888 E-box binding	IEA GO_REF:0000107	MODIFY	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 Supporting Evidence: PMID:21613214 CRY binds stably to the CLOCK:BMAL1:E-box ternary
GO:0140297 DNA-binding transcription factor binding	IEA GO_REF:0000107	ACCEPT	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. Supporting Evidence: PMID:21613214 CRY binds stably to the CLOCK:BMAL1:E-box ternary
GO:2000001 regulation of DNA damage checkpoint	IEA GO_REF:0000107	REMOVE	Summary: No evidence found for CRY1 regulating the DNA damage checkpoint. Reason: Available references describe circadian transcriptional roles rather than checkpoint control. Supporting Evidence: UniProtKB:Q16526 Transcriptional repressor which forms a core component of the
GO:2000323 negative regulation of nuclear receptor-mediated glucocorticoid signaling pathway	IEA GO_REF:0000107	ACCEPT	Summary: CRY1 broadly represses glucocorticoid receptor activity. Reason: Cryptochromes oppose glucocorticoid receptor activation and promote repression. Supporting Evidence: PMID:22170608 cryptochromes broadly oppose
GO:2000850 negative regulation of glucocorticoid secretion	IEA GO_REF:0000107	ACCEPT	Summary: Cryptochromes restrain glucocorticoid levels in vivo. Reason: Loss of cryptochromes leads to constitutively high corticosterone. Supporting Evidence: PMID:22170608 results in glucose intolerance and constitutively
GO:0005654 nucleoplasm	IDA GO_REF:0000052	MODIFY	Summary: CRY1 is nuclear, but nucleoplasm is more specific than supported. Reason: Evidence supports nuclear localization without nucleoplasm specificity. Proposed replacements: nucleus Supporting Evidence: UniProtKB:Q16526 SUBCELLULAR LOCATION: Cytoplasm. Nucleus {ECO:0000269\|PubMed:22798407,
GO:0007623 circadian rhythm	ISS GO_REF:0000024	ACCEPT	Summary: CRY1 functions in the core circadian clock. Reason: CRY1 is a core component of the circadian clock mechanism. Supporting Evidence: UniProtKB:Q16526 Transcriptional repressor which forms a core component of the
GO:0009416 response to light stimulus	ISS GO_REF:0000024	REMOVE	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. Supporting Evidence: PMID:23133559 Arabidopsis and Drosophila CRY is a major circadian photoreceptor for light entrainment, while mammalian CRY is not required for photo-entrainment.
GO:0014823 response to activity	ISS GO_REF:0000024	REMOVE	Summary: No evidence found linking CRY1 to response to activity. Reason: Accessible sources do not report CRY1 involvement in activity response. Supporting Evidence: UniProtKB:Q16526 Transcriptional repressor which forms a core component of the
GO:0005515 protein binding	IPI PMID:30530698 Nuclear receptor HNF4A transrepresses CLOCK:BMAL1 and modula...	MODIFY	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 Supporting Evidence: PMID:30530698 we noted a robust binding between core clock proteins and the HNF4A protein
GO:0005515 protein binding	IPI PMID:26431207 CUL4-DDB1-CDT2 E3 Ligase Regulates the Molecular Clock Activ...	MARK AS OVER ANNOTATED	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. Supporting Evidence: PMID:26431207 ubiquitinates CRY1 and promotes its
GO:0005634 nucleus	IDA PMID:26431207 CUL4-DDB1-CDT2 E3 Ligase Regulates the Molecular Clock Activ...	ACCEPT	Summary: UniProt-curated localization includes nuclear CRY1. Reason: Subcellular location annotations indicate nuclear localization; PMID:26431207 does not contradict this. Supporting Evidence: UniProtKB:Q16526 SUBCELLULAR LOCATION: Cytoplasm. Nucleus {ECO:0000269\|PubMed:22798407, PMID:26431207 ubiquitinates CRY1 and promotes its
GO:0031398 positive regulation of protein ubiquitination	ISS GO_REF:0000024	REMOVE	Summary: CRY1 is a ubiquitination substrate rather than a positive regulator. Reason: CRY1 is ubiquitinated and degraded via SCF(FBXL3). Supporting Evidence: PMID:17463251 Cry1 and Cry2 proteins are ubiquitinated and degraded
GO:0045721 negative regulation of gluconeogenesis	ISS GO_REF:0000024	ACCEPT	Summary: CRY1 reduces gluconeogenic gene expression during fasting. Reason: Cry1 reduces fasting gluconeogenic gene expression by blocking glucagon-mediated cAMP increases. Supporting Evidence: PMID:20852621 gluconeogenic gene expression by blocking glucagon-mediated increases in
GO:0045892 negative regulation of DNA-templated transcription	IDA PMID:23133559 Role of type II protein arginine methyltransferase 5 in the ...	ACCEPT	Summary: CRY1 participates in transcriptional repression within the circadian feedback loop. Reason: PER/CRY complexes inhibit CLOCK/BMAL1 transcriptional activity. Supporting Evidence: PMID:23133559 complexes inhibit the transcriptional activity of the CLOCK/BMAL1 heterodimer
GO:0043153 entrainment of circadian clock by photoperiod	ISS GO_REF:0000024	REMOVE	Summary: Mammalian CRY is not required for photo-entrainment; photoperiod entrainment is unsupported. Reason: Evidence indicates mammalian CRY is not required for photo-entrainment. Supporting Evidence: PMID:23133559 Arabidopsis and Drosophila CRY is a major circadian photoreceptor for light entrainment, while mammalian CRY is not required for photo-entrainment.
GO:0045892 negative regulation of DNA-templated transcription	IDA PMID:12397359 Dec1 and Dec2 are regulators of the mammalian molecular cloc...	ACCEPT	Summary: CRY proteins inhibit Per transcription in the circadian feedback loop. Reason: The study states Cry proteins inhibit Per transcription. Supporting Evidence: PMID:12397359 Cry proteins to inhibit Per transcription
GO:0031397 negative regulation of protein ubiquitination	ISS GO_REF:0000024	REMOVE	Summary: CRY1 is ubiquitinated by SCF(FBXL3), indicating it is a substrate not a regulator. Reason: Evidence shows CRY1 is ubiquitinated and degraded rather than regulating ubiquitination. Supporting Evidence: PMID:17463251 Cry1 and Cry2 proteins are ubiquitinated and degraded
GO:0005515 protein binding	IPI PMID:20852621 Cryptochrome mediates circadian regulation of cAMP signaling...	MARK AS OVER ANNOTATED	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. Supporting Evidence: PMID:20852621 modulate GPCR activity directly through interaction with
GO:0006094 gluconeogenesis	ISS GO_REF:0000024	MODIFY	Summary: CRY1 inhibits gluconeogenic gene expression rather than catalyzing gluconeogenesis. Reason: Evidence supports negative regulation of gluconeogenesis. Proposed replacements: negative regulation of gluconeogenesis Supporting Evidence: PMID:20852621 gluconeogenic gene expression by blocking glucagon-mediated increases in
GO:0033762 response to glucagon	ISS GO_REF:0000024	ACCEPT	Summary: CRY1 modulates glucagon-stimulated signaling during fasting. Reason: Cry1 reduces glucagon-mediated increases in cAMP. Supporting Evidence: PMID:20852621 gluconeogenic gene expression by blocking glucagon-mediated increases in
GO:0045744 negative regulation of G protein-coupled receptor signaling pathway	ISS GO_REF:0000024	ACCEPT	Summary: CRY1 dampens GPCR-driven cAMP signaling. Reason: Cry1 inhibits cAMP accumulation in response to GPCR activation. Supporting Evidence: PMID:20852621 Cry1 inhibited accumulation of cAMP in response to G protein-coupled receptor
GO:0005634 nucleus	ISS GO_REF:0000024	ACCEPT	Summary: UniProt-curated localization includes nuclear and cytoplasmic CRY1. Reason: Subcellular location annotations report cytoplasmic and nuclear CRY1. Supporting Evidence: UniProtKB:Q16526 SUBCELLULAR LOCATION: Cytoplasm. Nucleus {ECO:0000269\|PubMed:22798407,
GO:0042770 signal transduction in response to DNA damage	ISS GO_REF:0000024	REMOVE	Summary: No direct evidence found for CRY1 in DNA damage response signaling. Reason: Accessible sources focus on circadian regulation and metabolism, not DNA damage signaling. Supporting Evidence: UniProtKB:Q16526 Transcriptional repressor which forms a core component of the
GO:2000001 regulation of DNA damage checkpoint	ISS GO_REF:0000024	REMOVE	Summary: No evidence found for CRY1 regulating the DNA damage checkpoint. Reason: Available references describe circadian transcriptional roles rather than checkpoint control. Supporting Evidence: UniProtKB:Q16526 Transcriptional repressor which forms a core component of the
GO:0042593 glucose homeostasis	ISS GO_REF:0000024	ACCEPT	Summary: CRY1 contributes to glucose homeostasis. Reason: Loss of cryptochromes causes glucose intolerance and altered corticosterone levels. Supporting Evidence: PMID:22170608 results in glucose intolerance and constitutively
GO:2000323 negative regulation of nuclear receptor-mediated glucocorticoid signaling pathway	ISS GO_REF:0000024	ACCEPT	Summary: CRY1 broadly represses glucocorticoid receptor activity. Reason: Cryptochromes oppose glucocorticoid receptor activation and promote repression. Supporting Evidence: PMID:22170608 cryptochromes broadly oppose
GO:0016922 nuclear receptor binding	IPI PMID:22170608 Cryptochromes mediate rhythmic repression of the glucocortic...	ACCEPT	Summary: CRY1/2 interact with the glucocorticoid receptor in a ligand-dependent manner. Reason: The study reports cryptochromes binding the glucocorticoid receptor. Supporting Evidence: PMID:22170608 cryptochromes 1 and 2, interact with the glucocorticoid receptor
GO:0005515 protein binding	IPI PMID:21613214 Biochemical analysis of the canonical model for the mammalia...	MARK AS OVER ANNOTATED	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. Supporting Evidence: PMID:21613214 CRY binds stably to the CLOCK:BMAL1:E-box ternary
GO:0005515 protein binding	IPI PMID:21680841 A molecular mechanism for circadian clock negative feedback.	REMOVE	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. Supporting Evidence: PMID:21680841 PERIOD (PER) proteins, acting in a large complex, inhibit the transcriptional
GO:0042754 negative regulation of circadian rhythm	ISS GO_REF:0000024	ACCEPT	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. Supporting Evidence: PMID:17463251 encode inhibitors of the Clock-Bmal1 complex
GO:0032922 circadian regulation of gene expression	ISS GO_REF:0000024	ACCEPT	Summary: CRY1 regulates circadian gene expression via the core transcriptional feedback loop. Reason: CRY represses CLOCK:BMAL1 activity, shaping circadian gene expression. Supporting Evidence: PMID:21613214 repress their own transcription by suppressing the transactivator function of
GO:0045892 negative regulation of DNA-templated transcription	ISS GO_REF:0000024	ACCEPT	Summary: CRY proteins repress CLOCK:BMAL1-driven transcription in the circadian loop. Reason: CRY/PER repressors inhibit CLOCK:BMAL1 transcriptional activity. Supporting Evidence: PMID:21613214 repress their own transcription by suppressing the transactivator function of
GO:0005515 protein binding	IPI PMID:9383998 Human blue-light photoreceptor hCRY2 specifically interacts ...	REMOVE	Summary: The study reports PP5 interaction with hCRY2, not CRY1. Reason: Evidence is specific to CRY2, so it does not support CRY1 binding. Supporting Evidence: PMID:9383998 specifically interacted with hCRY2.
GO:0019902 phosphatase binding	IPI PMID:9383998 Human blue-light photoreceptor hCRY2 specifically interacts ...	REMOVE	Summary: Phosphatase binding evidence is for hCRY2, not CRY1. Reason: The study specifies PP5 interaction with hCRY2 rather than CRY1. Supporting Evidence: PMID:9383998 specifically interacted with hCRY2.
GO:0000122 negative regulation of transcription by RNA polymerase II	IDA PMID:12397359 Dec1 and Dec2 are regulators of the mammalian molecular cloc...	ACCEPT	Summary: Cry proteins inhibit Per transcription in the circadian feedback loop. Reason: Cry proteins are reported to inhibit Per transcription. Supporting Evidence: PMID:12397359 Cry proteins to inhibit Per transcription
GO:0000122 negative regulation of transcription by RNA polymerase II	IDA PMID:14672706 A novel autofeedback loop of Dec1 transcription involved in ...	ACCEPT	Summary: PER/CRY act as negative regulators of CLOCK/BMAL-driven transcription. Reason: PER/CRY suppress CLOCK/BMAL-induced expression in the feedback loop. Supporting Evidence: PMID:14672706 PERs and CRYs suppressed the induced expression.
GO:0000122 negative regulation of transcription by RNA polymerase II	IDA PMID:15147242 Expression of the gene for Dec2, a basic helix-loop-helix tr...	ACCEPT	Summary: Cry proteins suppress Clock/Bmal-induced transcription. Reason: Cry proteins are reported to suppress Clock/Bmal-induced transcription. Supporting Evidence: PMID:15147242 suppressed Clock/Bmal-induced transcription from the Dec2 promoter.
GO:0042752 regulation of circadian rhythm	ISS GO_REF:0000024	ACCEPT	Summary: CRY1 is a core circadian clock repressor. Reason: CRY1/2 encode inhibitors of CLOCK:BMAL1 in the feedback loop. Supporting Evidence: PMID:17463251 encode inhibitors of the Clock-Bmal1 complex
GO:0009785 blue light signaling pathway	NAS PMID:8909283 Putative human blue-light photoreceptors hCRY1 and hCRY2 are...	REMOVE	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. Supporting Evidence: PMID:23133559 Arabidopsis and Drosophila CRY is a major circadian photoreceptor for light entrainment, while mammalian CRY is not required for photo-entrainment.
GO:0009882 blue light photoreceptor activity	NAS PMID:8909283 Putative human blue-light photoreceptors hCRY1 and hCRY2 are...	MARK AS OVER ANNOTATED	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. Supporting Evidence: PMID:8909283 may function as blue-light photoreceptors in humans. PMID:23133559 Arabidopsis and Drosophila CRY is a major circadian photoreceptor for light entrainment, while mammalian CRY is not required for photo-entrainment.
GO:0003690 double-stranded DNA binding	IDA PMID:9801304 Characterization of photolyase/blue-light receptor homologs ...	MODIFY	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 Supporting Evidence: PMID:21613214 CRY binds stably to the CLOCK:BMAL1:E-box ternary
GO:0003904 deoxyribodipyrimidine photo-lyase activity	IDA NOT PMID:8909283 Putative human blue-light photoreceptors hCRY1 and hCRY2 are...	ACCEPT	Summary: CRY1 lacks cyclobutane pyrimidine dimer photolyase activity (negated). Reason: Purified hCRY1 lacks photolyase activity on cyclobutane pyrimidine dimers. Supporting Evidence: PMID:8909283 lacked photolyase activity on the
GO:0003914 DNA (6-4) photolyase activity	IDA NOT PMID:8909283 Putative human blue-light photoreceptors hCRY1 and hCRY2 are...	ACCEPT	Summary: CRY1 lacks (6-4) photolyase activity (negated). Reason: Purified hCRY1 lacks photolyase activity on (6-4) photoproducts. Supporting Evidence: PMID:8909283 lacked photolyase activity on the
GO:0005515 protein binding	IPI PMID:17463251 SCFFbxl3 controls the oscillation of the circadian clock by ...	MARK AS OVER ANNOTATED	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. Supporting Evidence: PMID:17463251 encode inhibitors of the Clock-Bmal1 complex
GO:0003677 DNA binding	TAS PMID:9801304 Characterization of photolyase/blue-light receptor homologs ...	MODIFY	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 Supporting Evidence: PMID:21613214 CRY binds stably to the CLOCK:BMAL1:E-box ternary

Core Functions

Binds the CLOCK:BMAL1 E-box complex to repress circadian transcription.

Molecular Function:

DNA-binding transcription factor binding

Directly Involved In:

circadian regulation of gene expression negative regulation of transcription by RNA polymerase II

Cellular Locations:

nucleus

Supporting Evidence:

PMID:21613214
CRY binds stably to the CLOCK:BMAL1:E-box ternary
PMID:21613214
repress their own transcription by suppressing the transactivator function of

Binds FAD as a flavin cofactor.

Molecular Function:

FAD binding

Supporting Evidence:

PMID:8909283
were found to contain FAD and a pterin cofactor.

References

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:12397359

Dec1 and Dec2 are regulators of the mammalian molecular clock.

PMID:14672706

A novel autofeedback loop of Dec1 transcription involved in circadian rhythm regulation.

PMID:15147242

Expression of the gene for Dec2, a basic helix-loop-helix transcription factor, is regulated by a molecular clock system.

PMID:17463251

SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins.

PMID:20852621

Cryptochrome mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis.

PMID:21613214

Biochemical analysis of the canonical model for the mammalian circadian clock.

PMID:21680841

A molecular mechanism for circadian clock negative feedback.

PMID:22170608

Cryptochromes mediate rhythmic repression of the glucocorticoid receptor.

PMID:23133559

Role of type II protein arginine methyltransferase 5 in the regulation of Circadian Per1 gene.

PMID:26431207

CUL4-DDB1-CDT2 E3 Ligase Regulates the Molecular Clock Activity by Promoting Ubiquitination-Dependent Degradation of the Mammalian CRY1.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:30530698

Nuclear receptor HNF4A transrepresses CLOCK:BMAL1 and modulates tissue-specific circadian networks.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:8909283

Putative human blue-light photoreceptors hCRY1 and hCRY2 are flavoproteins.

PMID:9383998

Human blue-light photoreceptor hCRY2 specifically interacts with protein serine/threonine phosphatase 5 and modulates its activity.

PMID:9801304

Characterization of photolyase/blue-light receptor homologs in mouse and human cells.

📚 Additional Documentation

Deep Research Falcon

(CRY1-deep-research-falcon.md)

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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q16526
Protein Description: RecName: Full=Cryptochrome-1;
Gene Information: Name=CRY1; Synonyms=PHLL1;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the DNA photolyase class-1 family.
Key Domains: Crypto/Photolyase_FAD-like_sf. (IPR036134); Crypto/Photolyase_N_sf. (IPR036155); Cryptochr/Photolyase_FAD-bd. (IPR005101); Cryptochrome/DNA_photolyase_1. (IPR002081); DNA_photolyase_N. (IPR006050)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "CRY1" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'CRY1' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene CRY1 (gene ID: CRY1, UniProt: Q16526) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q16526
Protein Description: RecName: Full=Cryptochrome-1;
Gene Information: Name=CRY1; Synonyms=PHLL1;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the DNA photolyase class-1 family.
Key Domains: Crypto/Photolyase_FAD-like_sf. (IPR036134); Crypto/Photolyase_N_sf. (IPR036155); Cryptochr/Photolyase_FAD-bd. (IPR005101); Cryptochrome/DNA_photolyase_1. (IPR002081); DNA_photolyase_N. (IPR006050)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "CRY1" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene CRY1 (gene ID: CRY1, UniProt: Q16526) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Comprehensive Research Report: Human CRY1 (Cryptochrome-1) Functional Annotation (UniProt Q16526)

1) Identity verification (gene/protein, organism, domains)

The requested target is human cryptochrome-1 (CRY1), a mammalian member of the DNA photolyase/cryptochrome family whose core architecture is a conserved photolyase homology region (PHR) accompanied by a more divergent C-terminal extension (CCE) that confers circadian repressor function. Recent structural synthesis emphasizes that CRY proteins have a PHR composed of an α/β (Rossmann-like) domain and an α-helical domain that accommodate FAD in a conserved pocket (primary pocket), while additional pockets and loops (e.g., a secondary pocket and serine loop) are adapted for circadian protein–protein interactions rather than DNA repair catalysis. (deoliveira2024astructuraldecryption pages 4-5, deoliveira2024astructuraldecryption pages 5-6)

A current structural review provides a schematic domain anatomy consistent with the UniProt/domain expectations for CRY1 (PHR with FAD pocket; secondary pocket/serine loop; C-terminal lid/tail elements that regulate interactions and localization). (deoliveira2024astructuraldecryption media b0254006, deoliveira2024astructuraldecryption media 1547ad98)

2) Key concepts and definitions (current understanding)

2.1 CRY1 as a core negative limb component of the mammalian circadian clock

In the mammalian transcription–translation feedback loop, CLOCK:BMAL1 activates E-box genes, including negative regulators (PER/CRY). CRY1 functions as a core transcriptional repressor that shuts down CLOCK:BMAL1-driven transcription in a time-dependent fashion. (conrady2024identificationandevolution pages 22-26)

2.2 “Primary pocket” vs “secondary pocket” and the serine loop

Recent structure-focused work highlights two interaction “hotspots”:

Primary (FAD) pocket: ancestrally binds flavin; in mammalian CRYs it is repurposed as a regulatory interface recognized by E3 ubiquitin ligases (notably FBXL3/FBXL21) that control CRY stability. (conrady2024identificationandevolution pages 34-37, zhang2024thefunctionregulation pages 8-9)
Secondary pocket/serine loop region: supports interaction with the transcriptional activator complex (e.g., CLOCK PAS-B) and modulates repressor potency; dynamics of the serine loop are repeatedly implicated in tuning CRY affinity for CLOCK:BMAL1. (deoliveira2024astructuraldecryption pages 5-6, conrady2024identificationandevolution pages 22-26)

2.3 Late repression model: CRY1 vs PER–CRY complexes

Mechanistic synthesis in 2024 emphasizes that CRY1 can repress CLOCK:BMAL1 through direct binding to the BMAL1 transactivation domain (TAD), displacing coactivators such as CBP/p300 (functional definition: repression by coactivator exclusion). PER proteins can compete with or allosterically remodel CRY surfaces, shifting CRY1 between early PER-bound states and later CRY1-dominant repression states. (conrady2024identificationandevolution pages 117-121)

3) Molecular function, processes, and pathway placement

3.1 Primary molecular function: transcriptional repression of CLOCK:BMAL1

Mechanism (direct molecular contacts):

CRY1–CLOCK contact: A key mechanistic contact is mediated by a tryptophan residue in the CLOCK PAS-B HI-loop (W362). Mutation W362A abolishes CRY1 pulldown/co-elution, supporting a direct physical interface. (conrady2024identificationandevolution pages 22-26)
CRY1–BMAL1 TAD contact: CRY1 binds the BMAL1 transactivation domain, overlapping the site used by coactivators (CBP/p300 KIX domain), implying repression via competition and loss of coactivator recruitment. (conrady2024identificationandevolution pages 22-26)
Functional consequences: Altering CRY1:BMAL1-TAD affinity quantitatively shifts circadian period: an approximately 2-fold affinity increase lengthened period by ~1.5 h, while up to a 4-fold affinity decrease shortened period by up to ~3 h in assays summarized in the mechanistic synthesis. (conrady2024identificationandevolution pages 22-26)

Together these findings define CRY1 as a core protein–protein interaction (PPI) repressor rather than an enzyme catalyzing a substrate conversion.

3.2 Regulation of CRY1 activity by PER proteins (PER1/PER2)

PER proteins regulate CRY1’s repressor activity by direct binding (PER CBD to CRY) and competition with BMAL1-TAD binding. A 2024 synthesis reports that the PER2 CRY-binding domain reduces CRY1:CLOCK interaction ~3-fold, and that PER2 CBD and PER tails can compete with BMAL1 TAD binding to CRY1, supporting a phase-dependent handoff model from PER-bound repression to late CRY1-mediated TAD sequestration. (conrady2024identificationandevolution pages 117-121)

3.3 CRY1 turnover and post-translational regulation (protein stability as clock timing control)

CRY1 protein abundance and timing are regulated by ubiquitin-proteasome and lysosomal pathways:

SCF^FBXL3 ubiquitination: CRY1/CRY2 are substrates of SCF^FBXL3; their ubiquitination and proteasomal degradation are described as required to permit reactivation of CLOCK:BMAL1. Specific FBXL3 mutations (e.g., C358S, I364T) stabilize CRY1 and lengthen circadian period. (zhang2024thefunctionregulation pages 8-9)
FBXL21 competition/compartmentalization: FBXL3 and FBXL21 act as competing E3 ligases affecting period length; FBXL21 can protect CRY from FBXL3 in the nucleus while promoting CRY degradation in the cytoplasm (dual role described in the turnover review). (zhang2024thefunctionregulation pages 9-11)
Selective autophagy/CMA: CRY1 contains LC3-interacting region motifs (LIRs; 285SLYGQL290 and 492SRYRGL497) consistent with selective macroautophagy, and the same review notes chaperone-mediated autophagy involvement for clock proteins including CRY1. (zhang2024thefunctionregulation pages 9-11)
Redox-regulated interactions: A structural review highlights C-terminal lid cysteines (e.g., Cys412/Cys414) implicated in redox-dependent interactions with PER. (deoliveira2024astructuraldecryption pages 5-6)

3.4 Crosstalk pathways: Hippo signaling and DNA repair rhythms

Hippo pathway (YAP/TAZ) crosstalk: A 2023 primary study reported that CRY1 is a direct node in Hippo pathway interplay: YAP binds/enriches at the CRY1 promoter and regulates CRY1 transcription; CRY1, in turn, binds promoter regions and suppresses YAP promoter activity, with CRY1 depletion increasing YAP/TAZ activity. (azzi2023thecircadianclock pages 9-11, azzi2023thecircadianclock pages 7-9)

DNA repair/chronobiology: A 2024 PNAS study mapped strand-specific nucleotide excision repair rhythms (after cisplatin) and found that the normal rhythmic pattern of global/nontranscribed-strand repair (NTS) with a peak around ZT08 in wild-type mice was lost in core clock mutants including Cry1−/−Cry2−/−. Importantly, in Cry1−/−Cry2−/− liver, hundreds of genes retained rhythmic transcription-coupled repair, while the dominant NTS rhythm was abolished, linking CRY repressors to specific components of rhythmic DNA repair output. (yang2024mutationsofthe pages 2-4, yang2024mutationsofthe pages 7-8)

4) Subcellular localization (where CRY1 acts)

CRY1’s circadian repression function is primarily nuclear/chromatin-associated, but its regulation depends on nucleocytoplasmic trafficking and compartment-specific turnover:

The C-terminal extension (CCE) is described as containing a nuclear import signal, and it directly participates in transcriptional repression complexes and interaction control. (deoliveira2024astructuraldecryption pages 5-6)
Evolution/mechanism synthesis emphasizes that mammalian CRYs shuttle with PER into the nucleus for repression, and that stability control by FBXL3/FBXL21 is integrated with these dynamics. (conrady2024identificationandevolution pages 34-37)

The retrieved 2023–2024 sources provide strong structural/motif-level evidence for nuclear import via the CCE, but do not provide time-resolved quantitative nuclear:cytoplasmic ratios across circadian phases in human tissues; the most detailed phase-dependent statements in this evidence set concern chromatin association states and partner competition rather than explicit microscopy-based trafficking curves. (conrady2024identificationandevolution pages 117-121, deoliveira2024astructuraldecryption pages 5-6)

5) Recent developments (2023–2024 prioritized)

5.1 Structural and mechanistic updates (2024)

A 2024 structural review synthesizes how conserved CRY architecture (PHR + variable CCE) supports diverse signaling roles and highlights: (i) the CCE as a regulatory module for partner accessibility and nuclear import; (ii) pocket/loop features such as the serine loop that tune CLOCK:BMAL1 interactions; and (iii) the reuse of the ancestral cofactor pocket as an interface for ligases and small molecules. (deoliveira2024astructuraldecryption pages 5-6, deoliveira2024astructuraldecryption pages 4-5)

A 2024 mechanistic synthesis further consolidates an updated “two-stage” repression view (PER-bound complexes vs late CRY1-mediated BMAL1-TAD sequestration) and provides quantitative comparisons of how PER2 CBD modulates CRY1:CLOCK binding. (conrady2024identificationandevolution pages 117-121)

5.2 Human genetics and disease links (2023–2024)

CRY1Δ11 (c.1657+3A>C; rs184039278): A 2023 JCI paper used genotype-first phenotyping across multigenerational families and reported this splice variant in CRY1 associated with combined circadian and psychiatric phenotypes. In one independent cohort, 8/62 patients with combined ADHD and insomnia carried CRY1Δ11, versus 0/369 controls. (onat2023humancry1variants pages 1-2)

The same work reports strong segregation statistics in family-based data: among mutation-positive individuals, 46/48 displayed ADHD symptoms plus DSPD, while 44/48 mutation-negative relatives/spouses did not (reported OR 281, P = 1.99×10−21). (onat2023humancry1variants pages 2-3)

Population frequency estimates in that study include gnomAD allele frequency ~0.0044 (approx. “1 in 103” European-derived individuals as stated in the paper) and higher MAFs in specific populations/biobanks (e.g., BioMe European subsample). (onat2023humancry1variants pages 5-9, onat2023humancry1variants pages 3-5)

A 2024 Annual Review article emphasizes CRY1 c.1657+3A>C as a gain-of-function splice variant that strengthens CLOCK–BMAL1 inhibition and lengthens the cellular period; it reports an allele prevalence estimate of 0.375%, and contextualizes DSP prevalence (~0.17–1.53% general population; 3.3–7.3% in adolescence). (zou2024thegeneticsof pages 7-9)

CRY1Δ6 (c.825+1G>A): The 2023 JCI study describes a splice variant that deletes 47 residues within the PHR/clock-binding domains, shows reduced affinity for BMAL1/CLOCK and an arrhythmic phenotype in functional assays, and segregates with ADHD/DSPD in an affected family. (onat2023humancry1variants pages 1-2, onat2023humancry1variants pages 10-11)

5.3 Circadian DNA repair and chronotherapy rationale (2024)

A 2024 PNAS study provides high-resolution repair mapping after cisplatin and explicitly frames implications for chronochemotherapy: the dominant NTS repair rhythm peaking at ZT08 is lost in Cry1−/−Cry2−/− mice, supporting the hypothesis that time-of-day dosing could exploit peak repair capacity to reduce toxicity. (yang2024mutationsofthe pages 2-4, yang2024mutationsofthe pages 7-8)

6) Current applications and real-world implementations

6.1 Diagnostic/precision medicine implications of CRY1 splice variants

CRY1Δ11 is proposed as a diagnostic/therapeutic marker candidate in the context of combined ADHD/insomnia/DSPD (“circiatric” framing) due to relatively high carrier frequency and strong genotype–phenotype association in the reported cohorts. (onat2023humancry1variants pages 1-2, onat2023humancry1variants pages 2-3)

6.2 Chronobiology-informed oncology and chronochemotherapy

Although direct clinical timing trials for cisplatin are not provided in the retrieved evidence, the 2024 DNA repair mapping study provides mechanistic justification for time-aware dosing strategies by demonstrating CRY-dependent repair rhythmicity and its disruption in clock mutants. (yang2024mutationsofthe pages 2-4, yang2024mutationsofthe pages 7-8)

6.3 Ongoing human studies measuring CRY1 expression (ClinicalTrials.gov)

Several registered studies include CRY1 mRNA/protein expression as an endpoint, reflecting real-world implementation of circadian gene readouts:

NCT07063303 (publication year in registry: 2025; completed): ICU feeding intervention comparing intermittent vs continuous enteral feeding; primary endpoints include BMAL1, CRY1, PER2 mRNA at 08:00/16:00/00:00 on Days 1 and 7 (n=24). (NCT07063303 chunk 1)
NCT07452783 (2024; completed observational case-control): periodontal disease vs control groups; gingival tissue RT-qPCR/Western blot targets include CRY1/CRY2 and other clock genes; standardized sampling window 09:00–11:00; enrollment 60 (20/group). (NCT07452783 chunk 1)
NCT01767181 (2013; completed): timed light therapy and timed exercise in night-shift workers; secondary molecular endpoints include PBMC expression of CRY1 and other clock genes after 12 weeks (n=154). (NCT01767181 chunk 1)
NCT02307747 (2015; completed): severe trauma patients; secondary endpoints include plasma expression of circadian genes including Cry1 sampled every 4 hours across 24 hours; enrollment 40. (NCT02307747 chunk 1)

These trials illustrate that CRY1 is already used as a molecular readout in interventions aimed at restoring or characterizing circadian physiology in clinical contexts.

7) Expert opinions and analysis (authoritative synthesis)

Recent authoritative reviews converge on several expert-level interpretations:

CRY1 is best viewed as a PPI-centric transcriptional repressor, where timing and output derive from regulated complex assembly/disassembly (PER competition), rather than from photochemistry or enzymatic DNA repair. (conrady2024identificationandevolution pages 22-26, conrady2024identificationandevolution pages 117-121)
Proteostasis is a timing mechanism: competition between E3 ligases (FBXL3/FBXL21), and additional lysosomal routes, provides tunable control of CRY abundance and thus the duration of repression. (zhang2024thefunctionregulation pages 9-11, zhang2024thefunctionregulation pages 8-9)
Structural plasticity matters: the CCE and loops (e.g., serine loop) are recurring explanatory elements for isoform-specific behaviors, small-molecule recognition, and variant effects (such as CRY1 exon-skipping variants that alter repression strength). (deoliveira2024astructuraldecryption pages 5-6)

8) Key statistics and recent data points (selected)

CRY1Δ11 in case/control cohort: 8/62 combined ADHD+insomnia cases vs 0/369 controls (2023 JCI). (onat2023humancry1variants pages 1-2)
Familial segregation (ADHD+DSPD phenotype): 46/48 mutation-positive individuals affected; 44/48 mutation-negative relatives/spouses unaffected; OR 281; P = 1.99×10−21 (2023 JCI). (onat2023humancry1variants pages 2-3)
Allele frequency estimates: gnomAD ~0.0044 (paper narrative) and Turkish MAF ~0.0124 (2023 JCI); Annual Review reports prevalence 0.375% (2024). (onat2023humancry1variants pages 5-9, zou2024thegeneticsof pages 7-9)
Circadian DNA repair timing: NTS repair peak at ZT08 in WT; dominant NTS rhythmicity lost in Cry1−/−Cry2−/− mice (2024 PNAS). (yang2024mutationsofthe pages 2-4, yang2024mutationsofthe pages 7-8)
Clock-controlled repair output: WT liver 762 genes rhythmic TS repair vs 19 in Bmal1−/−; >150 genes retain rhythmic TS repair in Cry1−/−Cry2−/− liver (2024 PNAS). (yang2024mutationsofthe pages 4-5)

Summary table (evidence-backed)

Topic	Key Functional Annotation Points	Key Sources (2023–2024)
Identity & Structure	• Domains: Conserved Photolyase Homology Region (PHR) containing α/β and α-helical domains; dynamic C-terminal Extension (CCE) with "lid," "clasp," and "tail" elements (deoliveira2024astructuraldecryption pages 4-5, deoliveira2024astructuraldecryption media b0254006). • Pockets: Primary pocket binds FAD (cofactor) or E3 ligase FBXL3 (tail insertion); Secondary pocket binds CLOCK PAS-B (W362) (conrady2024identificationandevolution pages 22-26, conrady2024identificationandevolution pages 34-37).	DeOliveira et al., 2024 (DOI); Conrady, 2024 (conrady2024identificationandevolution pages 117-121)
Circadian Mechanism	• Repression: CRY1 represses CLOCK:BMAL1 transcription by directly binding the BMAL1 Transactivation Domain (TAD), displacing coactivators CBP/p300 (conrady2024identificationandevolution pages 117-121, conrady2024identificationandevolution pages 22-26). • Phasing: A "late repression" phase occurs when CRY1 sequesters BMAL1 TAD after PER proteins (which compete for CRY binding) are degraded (conrady2024identificationandevolution pages 117-121).	Conrady, 2024 (conrady2024identificationandevolution pages 22-26); DeOliveira et al., 2024 (deoliveira2024astructuraldecryption pages 5-6)
Interactome	• Clock Partners: High-affinity binding to CLOCK (via W362) and BMAL1 (TAD); modulated by PER1/PER2 (PER2 CBD reduces CRY1:CLOCK affinity 3-fold) (conrady2024identificationandevolution pages 117-121, conrady2024identificationandevolution pages 22-26). • Regulators: SCF-FBXL3 (nuclear degradation) and SCF-FBXL21 (cytosolic degradation/nuclear stabilization) compete for the FAD pocket (zhang2024thefunctionregulation pages 9-11, conrady2024identificationandevolution pages 34-37).	Conrady, 2024 (conrady2024identificationandevolution pages 117-121); Zhang et al., 2024 (DOI)
Localization	• Nuclear Entry: C-terminal extension (CCE) contains a nuclear localization signal (NLS); associates with PER proteins for nuclear shuttling (deoliveira2024astructuraldecryption pages 5-6, conrady2024identificationandevolution pages 34-37). • Dynamics: Nucleo-cytoplasmic distribution is coupled to PER interaction and FBXL3-mediated turnover (conrady2024identificationandevolution pages 117-121).	DeOliveira et al., 2024 (deoliveira2024astructuraldecryption pages 5-6); Conrady, 2024 (conrady2024identificationandevolution pages 34-37)
Turnover & PTMs	• Ubiquitination: FBXL3 targets CRY1 for proteasomal degradation (required for clock reset); FBXL21 fine-tunes stability (zhang2024thefunctionregulation pages 8-9). • Autophagy: CRY1 contains LIR motifs (285–290, 492–497) for selective autophagic degradation (zhang2024thefunctionregulation pages 9-11). • Redox: C-terminal cysteines (C412, C414) implicated in redox sensing (deoliveira2024astructuraldecryption pages 5-6).	Zhang et al., 2024 (zhang2024thefunctionregulation pages 9-11); DeOliveira et al., 2024 (deoliveira2024astructuraldecryption pages 5-6)
Disease Variants	• CRY1Δ11 (c.1657+3A>C): Gain-of-function splice variant causing exon 11 skipping; lengthens period (~0.5h); linked to Delayed Sleep Phase Disorder (DSPD) and ADHD (OR 281 for combined phenotype) (onat2023humancry1variants pages 2-3, zou2024thegeneticsof pages 7-9). • CRY1Δ6: Associated with arrhythmia and reduced CLOCK:BMAL1 affinity (onat2023humancry1variants pages 1-2).	Onat et al., 2023 (DOI); Zou et al., 2024 (DOI)
Crosstalk & Repair	• DNA Repair: CRY1 modulates circadian timing of nucleotide excision repair (NER); loss of CRY1/2 abolishes rhythmic repair of nontranscribed strands (yang2024mutationsofthe pages 1-2, yang2024mutationsofthe pages 7-8). • Hippo Pathway: CRY1 directly binds YAP promoter and represses YAP transcription; reciprocal regulation exists (azzi2023thecircadianclock pages 9-11, azzi2023thecircadianclock pages 7-9).	Yang et al., 2024 (DOI); Azzi et al., 2023 (DOI)
Clinical Implications	• Chronotherapy: CRY-dependent repair rhythms suggest optimal dosing times for cisplatin to minimize toxicity (peak repair ~ZT08 in WT mice) (yang2024mutationsofthe pages 2-4, yang2024mutationsofthe pages 7-8). • Diagnostics: CRY1Δ11 screening proposed for "circiatric" (circadian-psychiatric) phenotypes (onat2023humancry1variants pages 1-2).	Yang et al., 2024 (yang2024mutationsofthe pages 2-4); Onat et al., 2023 (onat2023humancry1variants pages 1-2)

Table: Summary of molecular functions, interactions, and disease associations for human CRY1 based on 2023-2024 literature.

Figures (structural schematics from 2024 review)

A 2024 structural review includes schematics depicting cryptochrome domain anatomy (PHR with primary FAD pocket, secondary pocket, serine loop; C-terminal lid/CCE/tail) and a pocket-focused depiction of FBXL3 binding in the cofactor pocket (illustrated for mammalian CRY2, structurally informative for the conserved mechanism). (deoliveira2024astructuraldecryption media b0254006, deoliveira2024astructuraldecryption media 1547ad98)

Limitations of this evidence set

The retrieved sources do not explicitly mention the UniProt accession Q16526 in-text; identity confirmation here relies on concordance of human CRY1 name, mammalian cryptochrome structure/function, and human genetic variant mapping within CRY1 described in primary literature. (deoliveira2024astructuraldecryption pages 5-6, onat2023humancry1variants pages 1-2)
Some mechanistic synthesis (e.g., Conrady 2024) appears to be a thesis/long-form review rather than a conventional journal review; it is used here to integrate mechanisms, while primary claims are also grounded in peer-reviewed reviews and primary studies. (conrady2024identificationandevolution pages 117-121, conrady2024identificationandevolution pages 22-26)

References

(deoliveira2024astructuraldecryption pages 4-5): Cristina C. DeOliveira and Brian R. Crane. A structural decryption of cryptochromes. Frontiers in Chemistry, Aug 2024. URL: https://doi.org/10.3389/fchem.2024.1436322, doi:10.3389/fchem.2024.1436322. This article has 14 citations.
(deoliveira2024astructuraldecryption pages 5-6): Cristina C. DeOliveira and Brian R. Crane. A structural decryption of cryptochromes. Frontiers in Chemistry, Aug 2024. URL: https://doi.org/10.3389/fchem.2024.1436322, doi:10.3389/fchem.2024.1436322. This article has 14 citations.
(deoliveira2024astructuraldecryption media b0254006): Cristina C. DeOliveira and Brian R. Crane. A structural decryption of cryptochromes. Frontiers in Chemistry, Aug 2024. URL: https://doi.org/10.3389/fchem.2024.1436322, doi:10.3389/fchem.2024.1436322. This article has 14 citations.
(deoliveira2024astructuraldecryption media 1547ad98): Cristina C. DeOliveira and Brian R. Crane. A structural decryption of cryptochromes. Frontiers in Chemistry, Aug 2024. URL: https://doi.org/10.3389/fchem.2024.1436322, doi:10.3389/fchem.2024.1436322. This article has 14 citations.
(conrady2024identificationandevolution pages 22-26): MC Conrady. Identification and evolution of protein-protein interactions in circadian gene regulation. Unknown journal, 2024.
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(zhang2024thefunctionregulation pages 8-9): Haoran Zhang, Zengxuan Zhou, and Jinhu Guo. The function, regulation, and mechanism of protein turnover in circadian systems in neurospora and other species. International Journal of Molecular Sciences, 25:2574, Feb 2024. URL: https://doi.org/10.3390/ijms25052574, doi:10.3390/ijms25052574. This article has 7 citations.
(conrady2024identificationandevolution pages 117-121): MC Conrady. Identification and evolution of protein-protein interactions in circadian gene regulation. Unknown journal, 2024.
(zhang2024thefunctionregulation pages 9-11): Haoran Zhang, Zengxuan Zhou, and Jinhu Guo. The function, regulation, and mechanism of protein turnover in circadian systems in neurospora and other species. International Journal of Molecular Sciences, 25:2574, Feb 2024. URL: https://doi.org/10.3390/ijms25052574, doi:10.3390/ijms25052574. This article has 7 citations.
(azzi2023thecircadianclock pages 9-11): Abdelhalim Azzi, Zhipeng Tao, Yang Sun, Hannah Erb, Carla Guarino, and Xu Wu. The circadian clock protein cryptochrome 1 is a direct target and feedback regulator of the hippo pathway. iScience, 26:107449, Aug 2023. URL: https://doi.org/10.1016/j.isci.2023.107449, doi:10.1016/j.isci.2023.107449. This article has 5 citations and is from a peer-reviewed journal.
(azzi2023thecircadianclock pages 7-9): Abdelhalim Azzi, Zhipeng Tao, Yang Sun, Hannah Erb, Carla Guarino, and Xu Wu. The circadian clock protein cryptochrome 1 is a direct target and feedback regulator of the hippo pathway. iScience, 26:107449, Aug 2023. URL: https://doi.org/10.1016/j.isci.2023.107449, doi:10.1016/j.isci.2023.107449. This article has 5 citations and is from a peer-reviewed journal.
(yang2024mutationsofthe pages 2-4): Yanyan Yang, Gang Wu, Aziz Sancar, and John B. Hogenesch. Mutations of the circadian clock genes cry, per, or bmal1 have different effects on the transcribed and nontranscribed strands of cycling genes. Proceedings of the National Academy of Sciences of the United States of America, Feb 2024. URL: https://doi.org/10.1073/pnas.2316731121, doi:10.1073/pnas.2316731121. This article has 11 citations and is from a highest quality peer-reviewed journal.
(yang2024mutationsofthe pages 7-8): Yanyan Yang, Gang Wu, Aziz Sancar, and John B. Hogenesch. Mutations of the circadian clock genes cry, per, or bmal1 have different effects on the transcribed and nontranscribed strands of cycling genes. Proceedings of the National Academy of Sciences of the United States of America, Feb 2024. URL: https://doi.org/10.1073/pnas.2316731121, doi:10.1073/pnas.2316731121. This article has 11 citations and is from a highest quality peer-reviewed journal.
(onat2023humancry1variants pages 1-2): O. Emre Onat, M. Ece Kars, Şeref Gül, Kaya Bilguvar, Yiming Wu, Ayşe Özhan, Cihan Aydın, A. Nazlı Başak, M. Allegra Trusso, Arianna Goracci, Chiara Fallerini, Alessandra Renieri, Jean-Laurent Casanova, Yuval Itan, Cem E. Atbaşoğlu, Meram C. Saka, İ. Halil Kavaklı, and Tayfun Özçelik. Human cry1 variants associate with attention deficit/hyperactivity disorder. The Journal of clinical investigation, 130:3885-3900, Jun 2023. URL: https://doi.org/10.1172/jci135500, doi:10.1172/jci135500. This article has 48 citations.
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(onat2023humancry1variants pages 5-9): O. Emre Onat, M. Ece Kars, Şeref Gül, Kaya Bilguvar, Yiming Wu, Ayşe Özhan, Cihan Aydın, A. Nazlı Başak, M. Allegra Trusso, Arianna Goracci, Chiara Fallerini, Alessandra Renieri, Jean-Laurent Casanova, Yuval Itan, Cem E. Atbaşoğlu, Meram C. Saka, İ. Halil Kavaklı, and Tayfun Özçelik. Human cry1 variants associate with attention deficit/hyperactivity disorder. The Journal of clinical investigation, 130:3885-3900, Jun 2023. URL: https://doi.org/10.1172/jci135500, doi:10.1172/jci135500. This article has 48 citations.
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(zou2024thegeneticsof pages 7-9): Xianlin Zou, Louis J. Ptáček, and Ying-Hui Fu. The genetics of human sleep and sleep disorders. Aug 2024. URL: https://doi.org/10.1146/annurev-genom-121222-120306, doi:10.1146/annurev-genom-121222-120306. This article has 15 citations and is from a domain leading peer-reviewed journal.
(onat2023humancry1variants pages 10-11): O. Emre Onat, M. Ece Kars, Şeref Gül, Kaya Bilguvar, Yiming Wu, Ayşe Özhan, Cihan Aydın, A. Nazlı Başak, M. Allegra Trusso, Arianna Goracci, Chiara Fallerini, Alessandra Renieri, Jean-Laurent Casanova, Yuval Itan, Cem E. Atbaşoğlu, Meram C. Saka, İ. Halil Kavaklı, and Tayfun Özçelik. Human cry1 variants associate with attention deficit/hyperactivity disorder. The Journal of clinical investigation, 130:3885-3900, Jun 2023. URL: https://doi.org/10.1172/jci135500, doi:10.1172/jci135500. This article has 48 citations.
(NCT07063303 chunk 1): Circadian Rhythm in Critical Illness. Atılım University. 2025. ClinicalTrials.gov Identifier: NCT07063303
(NCT07452783 chunk 1): Cuneyt Asim Aral. Circadian Clock Gene Expression in Periodontal Disease. Inonu University. 2024. ClinicalTrials.gov Identifier: NCT07452783
(NCT01767181 chunk 1): Light and Exercise in Night-shift Workers. Universitätsklinikum Hamburg-Eppendorf. 2013. ClinicalTrials.gov Identifier: NCT01767181
(NCT02307747 chunk 1): Disruption of Circadian Rhythm and Healthcare-related Infection in Patients With Severe Trauma. Assistance Publique Hopitaux De Marseille. 2015. ClinicalTrials.gov Identifier: NCT02307747
(yang2024mutationsofthe pages 4-5): Yanyan Yang, Gang Wu, Aziz Sancar, and John B. Hogenesch. Mutations of the circadian clock genes cry, per, or bmal1 have different effects on the transcribed and nontranscribed strands of cycling genes. Proceedings of the National Academy of Sciences of the United States of America, Feb 2024. URL: https://doi.org/10.1073/pnas.2316731121, doi:10.1073/pnas.2316731121. This article has 11 citations and is from a highest quality peer-reviewed journal.
(yang2024mutationsofthe pages 1-2): Yanyan Yang, Gang Wu, Aziz Sancar, and John B. Hogenesch. Mutations of the circadian clock genes cry, per, or bmal1 have different effects on the transcribed and nontranscribed strands of cycling genes. Proceedings of the National Academy of Sciences of the United States of America, Feb 2024. URL: https://doi.org/10.1073/pnas.2316731121, doi:10.1073/pnas.2316731121. This article has 11 citations and is from a highest quality peer-reviewed journal.

Citations

conrady2024identificationandevolution pages 22-26
conrady2024identificationandevolution pages 117-121
zhang2024thefunctionregulation pages 8-9
zhang2024thefunctionregulation pages 9-11
deoliveira2024astructuraldecryption pages 5-6
conrady2024identificationandevolution pages 34-37
zou2024thegeneticsof pages 7-9
yang2024mutationsofthe pages 4-5
yang2024mutationsofthe pages 2-4
deoliveira2024astructuraldecryption pages 4-5
azzi2023thecircadianclock pages 9-11
azzi2023thecircadianclock pages 7-9
yang2024mutationsofthe pages 7-8
yang2024mutationsofthe pages 1-2
DOI
https://doi.org/10.3389/fchem.2024.1436322
https://doi.org/10.3390/ijms25052574
https://doi.org/10.1172/jci135500
https://doi.org/10.1146/annurev-genom-121222-120306
https://doi.org/10.1073/pnas.2316731121
https://doi.org/10.1016/j.isci.2023.107449
https://doi.org/10.3389/fchem.2024.1436322,
https://doi.org/10.3390/ijms25052574,
https://doi.org/10.1016/j.isci.2023.107449,
https://doi.org/10.1073/pnas.2316731121,
https://doi.org/10.1172/jci135500,
https://doi.org/10.1146/annurev-genom-121222-120306,

📄 View Raw YAML

---
id: Q16526
gene_symbol: CRY1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: Cryptochrome-1 (CRY1) is a FAD-binding transcriptional repressor in the
  mammalian circadian clock that binds CLOCK:BMAL1 to inhibit E-box-driven transcription
  and regulate rhythmic gene expression; it also modulates metabolic and glucocorticoid
  signaling.
existing_annotations:
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: UniProt-curated localization includes nuclear and cytoplasmic CRY1.
      action: ACCEPT
      reason: Subcellular location annotations report cytoplasmic and nuclear CRY1.
      supported_by: &id001
        - reference_id: UniProtKB:Q16526
          supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm. Nucleus {ECO:0000269|PubMed:22798407,'
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: UniProt-curated localization includes nuclear and cytoplasmic CRY1.
      action: ACCEPT
      reason: Subcellular location annotations report cytoplasmic and nuclear CRY1.
      supported_by: *id001
  - term:
      id: GO:0045892
      label: negative regulation of DNA-templated transcription
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: CRY proteins repress CLOCK:BMAL1-driven transcription in the circadian
        loop.
      action: ACCEPT
      reason: CRY/PER repressors inhibit CLOCK:BMAL1 transcriptional activity.
      supported_by:
        - reference_id: PMID:21613214
          supporting_text: repress their own transcription by suppressing the transactivator
            function of
  - term:
      id: GO:0003677
      label: DNA binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Evidence supports CRY1 binding to CLOCK:BMAL1 on E-boxes, not direct
        DNA binding.
      action: MODIFY
      reason: CRY binds the CLOCK:BMAL1:E-box complex; DNA-binding TF binding is more
        accurate.
      proposed_replacement_terms:
        - id: GO:0140297
          label: DNA-binding transcription factor binding
      supported_by:
        - reference_id: PMID:21613214
          supporting_text: CRY binds stably to the CLOCK:BMAL1:E-box ternary
  - term:
      id: GO:0032922
      label: circadian regulation of gene expression
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: CRY1 regulates circadian gene expression via the core transcriptional
        feedback loop.
      action: ACCEPT
      reason: CRY represses CLOCK:BMAL1 activity, shaping circadian gene expression.
      supported_by:
        - reference_id: PMID:21613214
          supporting_text: repress their own transcription by suppressing the transactivator
            function of
  - term:
      id: GO:0043153
      label: entrainment of circadian clock by photoperiod
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Mammalian CRY is not required for photo-entrainment; photoperiod entrainment
        is unsupported.
      action: REMOVE
      reason: Evidence indicates mammalian CRY is not required for photo-entrainment.
      supported_by:
        - reference_id: PMID:23133559
          supporting_text: Arabidopsis and Drosophila CRY is a major circadian photoreceptor
            for light entrainment, while mammalian CRY is not required for photo-entrainment.
  - term:
      id: GO:0071949
      label: FAD binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: CRY1 binds FAD as a chromophore/cofactor.
      action: ACCEPT
      reason: Purified hCRY1 contains FAD, supporting FAD binding.
      supported_by:
        - reference_id: PMID:8909283
          supporting_text: were found to contain FAD and a pterin cofactor.
  - term:
      id: GO:0000166
      label: nucleotide binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: CRY1 binds a nucleotide cofactor (FAD), consistent with nucleotide
        binding.
      action: KEEP_AS_NON_CORE
      reason: FAD is a nucleotide cofactor; the term is generic but compatible with
        FAD binding.
      supported_by:
        - reference_id: UniProtKB:Q16526
          supporting_text: Binds 1 FAD per subunit.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: UniProt-curated localization includes nuclear and cytoplasmic CRY1.
      action: ACCEPT
      reason: Subcellular location annotations report cytoplasmic and nuclear CRY1.
      supported_by: *id001
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: UniProt-curated localization includes nuclear and cytoplasmic CRY1.
      action: ACCEPT
      reason: Subcellular location annotations report cytoplasmic and nuclear CRY1.
      supported_by: *id001
  - term:
      id: GO:0009881
      label: photoreceptor activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: Mammalian CRY is not required for photo-entrainment; photoreceptor
        activity is not supported.
      action: REMOVE
      reason: Evidence indicates mammalian CRY is not required for photo-entrainment.
      supported_by:
        - reference_id: PMID:23133559
          supporting_text: Arabidopsis and Drosophila CRY is a major circadian photoreceptor
            for light entrainment, while mammalian CRY is not required for photo-entrainment.
  - term:
      id: GO:0019902
      label: phosphatase binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: Phosphatase binding evidence is for hCRY2, not CRY1.
      action: REMOVE
      reason: The cited interaction involves hCRY2 rather than CRY1.
      additional_reference_ids: [PMID:9383998]
      supported_by:
        - reference_id: PMID:9383998
          supporting_text: specifically interacted with hCRY2.
  - term:
      id: GO:0048511
      label: rhythmic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: CRY1 participates in rhythmic processes as part of the circadian clock.
      action: ACCEPT
      reason: CRY1 is a core circadian clock component regulating rhythmic gene expression.
      supported_by: &id002
        - reference_id: UniProtKB:Q16526
          supporting_text: Transcriptional repressor which forms a core component
            of the
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23133559
    review:
      summary: CRY1 interacts with PRMT5, but the generic protein binding term is
        too broad.
      action: MARK_AS_OVER_ANNOTATED
      reason: The study reports a specific PRMT5 interaction rather than nonspecific
        binding.
      supported_by:
        - reference_id: PMID:23133559
          supporting_text: interacting molecule of CRY1.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28514442
    review:
      summary: High-throughput interactome study; generic protein binding term is
        not informative for CRY1.
      action: MARK_AS_OVER_ANNOTATED
      reason: Proteome-scale AP-MS reports many candidate interactions and does not
        validate a specific CRY1 binding partner.
      supported_by:
        - reference_id: PMID:28514442
          supporting_text: BioPlex 2.0 contains more than 29,000 previously unknown
            co-associations
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      summary: Proteome-scale interactome mapping is too nonspecific for a generic
        protein-binding annotation.
      action: MARK_AS_OVER_ANNOTATED
      reason: The study reports large-scale interaction networks rather than a specific
        CRY1 binding partner.
      supported_by:
        - reference_id: PMID:33961781
          supporting_text: we have created two proteome-scale, cell-line-specific
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: CRY proteins repress CLOCK:BMAL1-driven transcription in the circadian
        loop.
      action: ACCEPT
      reason: CRY/PER repressors inhibit CLOCK:BMAL1 transcriptional activity.
      supported_by:
        - reference_id: PMID:21613214
          supporting_text: repress their own transcription by suppressing the transactivator
            function of
  - term:
      id: GO:0003690
      label: double-stranded DNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: Evidence supports CRY1 binding to CLOCK:BMAL1 on E-boxes, not direct
        DNA binding.
      action: MODIFY
      reason: CRY binds the CLOCK:BMAL1:E-box complex; DNA-binding TF binding is more
        accurate.
      proposed_replacement_terms:
        - id: GO:0140297
          label: DNA-binding transcription factor binding
      supported_by:
        - reference_id: PMID:21613214
          supporting_text: CRY binds stably to the CLOCK:BMAL1:E-box ternary
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: Human CRY1 is primarily nuclear/cytoplasmic; mitochondrial localization
        is not established.
      action: REMOVE
      reason: Available human evidence supports cytoplasmic/nuclear localization;
        mitochondrial localization is from mouse CRY1.
      additional_reference_ids: [PMID:9801304]
      supported_by:
        - reference_id: UniProtKB:Q16526
          supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm. Nucleus {ECO:0000269|PubMed:22798407,'
        - reference_id: PMID:9801304
          supporting_text: mCRY1 is localized in mitochondria
  - term:
      id: GO:0006094
      label: gluconeogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: CRY1 inhibits gluconeogenic gene expression rather than catalyzing
        gluconeogenesis.
      action: MODIFY
      reason: Evidence supports negative regulation of gluconeogenesis.
      proposed_replacement_terms:
        - id: GO:0045721
          label: negative regulation of gluconeogenesis
      supported_by:
        - reference_id: PMID:20852621
          supporting_text: gluconeogenic gene expression by blocking glucagon-mediated
            increases in
  - term:
      id: GO:0006111
      label: regulation of gluconeogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: CRY1 represses gluconeogenic gene expression via glucagon/cAMP signaling.
      action: MODIFY
      reason: Evidence supports negative regulation rather than generic regulation.
      proposed_replacement_terms:
        - id: GO:0045721
          label: negative regulation of gluconeogenesis
      supported_by:
        - reference_id: PMID:20852621
          supporting_text: gluconeogenic gene expression by blocking glucagon-mediated
            increases in
  - term:
      id: GO:0009416
      label: response to light stimulus
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: Mammalian CRY is not required for photo-entrainment, so light response
        is unsupported.
      action: REMOVE
      reason: Evidence indicates mammalian CRY is not required for photo-entrainment.
      supported_by:
        - reference_id: PMID:23133559
          supporting_text: Arabidopsis and Drosophila CRY is a major circadian photoreceptor
            for light entrainment, while mammalian CRY is not required for photo-entrainment.
  - term:
      id: GO:0014823
      label: response to activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: No evidence found linking CRY1 to response to activity.
      action: REMOVE
      reason: Accessible sources do not report CRY1 involvement in activity response.
      supported_by: *id002
  - term:
      id: GO:0016922
      label: nuclear receptor binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: CRY1 interacts with nuclear receptors such as the glucocorticoid receptor.
      action: ACCEPT
      reason: Cryptochromes bind the glucocorticoid receptor in a ligand-dependent
        manner.
      supported_by:
        - reference_id: PMID:22170608
          supporting_text: cryptochromes 1 and 2, interact with the glucocorticoid
            receptor
  - term:
      id: GO:0019900
      label: kinase binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: Direct kinase binding evidence was not found in accessible sources.
      action: UNDECIDED
      reason: No direct kinase-binding assays were located in the available references.
  - term:
      id: GO:0019901
      label: protein kinase binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: Direct kinase binding evidence was not found in accessible sources.
      action: UNDECIDED
      reason: No direct kinase-binding assays were located in the available references.
  - term:
      id: GO:0019915
      label: lipid storage
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: No direct evidence found for CRY1 in lipid storage.
      action: REMOVE
      reason: Available references emphasize circadian regulation and gluconeogenesis
        rather than lipid storage.
      supported_by: *id002
  - term:
      id: GO:0031397
      label: negative regulation of protein ubiquitination
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: CRY1 is ubiquitinated by SCF(FBXL3), indicating it is a substrate not
        a regulator.
      action: REMOVE
      reason: Evidence shows CRY1 is ubiquitinated and degraded rather than regulating
        ubiquitination.
      supported_by:
        - reference_id: PMID:17463251
          supporting_text: Cry1 and Cry2 proteins are ubiquitinated and degraded
  - term:
      id: GO:0031398
      label: positive regulation of protein ubiquitination
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: CRY1 is a ubiquitination substrate rather than a positive regulator.
      action: REMOVE
      reason: CRY1 is ubiquitinated and degraded via SCF(FBXL3).
      supported_by:
        - reference_id: PMID:17463251
          supporting_text: Cry1 and Cry2 proteins are ubiquitinated and degraded
  - term:
      id: GO:0032868
      label: response to insulin
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: CRY1 influences insulin sensitivity in metabolic settings.
      action: ACCEPT
      reason: Cry1 overexpression improves insulin sensitivity in insulin-resistant
        mice.
      supported_by:
        - reference_id: PMID:20852621
          supporting_text: improved insulin sensitivity in insulin-resistant db/db
            mice
  - term:
      id: GO:0032922
      label: circadian regulation of gene expression
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: CRY1 regulates circadian gene expression via the core transcriptional
        feedback loop.
      action: ACCEPT
      reason: CRY represses CLOCK:BMAL1 activity, shaping circadian gene expression.
      supported_by:
        - reference_id: PMID:21613214
          supporting_text: repress their own transcription by suppressing the transactivator
            function of
  - term:
      id: GO:0033762
      label: response to glucagon
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: CRY1 modulates glucagon-stimulated signaling during fasting.
      action: ACCEPT
      reason: Cry1 reduces glucagon-mediated increases in cAMP.
      supported_by:
        - reference_id: PMID:20852621
          supporting_text: gluconeogenic gene expression by blocking glucagon-mediated
            increases in
  - term:
      id: GO:0042593
      label: glucose homeostasis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: CRY1 contributes to glucose homeostasis.
      action: ACCEPT
      reason: Loss of cryptochromes causes glucose intolerance and altered corticosterone
        levels.
      supported_by:
        - reference_id: PMID:22170608
          supporting_text: results in glucose intolerance and constitutively
  - term:
      id: GO:0042752
      label: regulation of circadian rhythm
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: CRY1 is a core circadian clock repressor.
      action: ACCEPT
      reason: CRY1/2 encode inhibitors of CLOCK:BMAL1 in the feedback loop.
      supported_by:
        - reference_id: PMID:17463251
          supporting_text: encode inhibitors of the Clock-Bmal1 complex
  - term:
      id: GO:0042754
      label: negative regulation of circadian rhythm
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: CRY1 represses CLOCK:BMAL1 as part of the negative limb of the clock.
      action: ACCEPT
      reason: CRY1/2 inhibit CLOCK:BMAL1 in a negative-feedback loop.
      supported_by:
        - reference_id: PMID:17463251
          supporting_text: encode inhibitors of the Clock-Bmal1 complex
  - term:
      id: GO:0042770
      label: signal transduction in response to DNA damage
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: No direct evidence found for CRY1 in DNA damage response signaling.
      action: REMOVE
      reason: Accessible sources focus on circadian regulation and metabolism, not
        DNA damage signaling.
      supported_by: *id002
  - term:
      id: GO:0042826
      label: histone deacetylase binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: CRY1 recruits histone deacetylases as part of transcriptional repression.
      action: KEEP_AS_NON_CORE
      reason: CRY1 is reported to recruit HDACs during Per1 repression.
      supported_by:
        - reference_id: PMID:23133559
          supporting_text: CRY1 negatively regulates Per1 gene expression by recruiting
            histone deacetylases (HDACs)
  - term:
      id: GO:0043153
      label: entrainment of circadian clock by photoperiod
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: Mammalian CRY is not required for photo-entrainment; photoperiod entrainment
        is unsupported.
      action: REMOVE
      reason: Evidence indicates mammalian CRY is not required for photo-entrainment.
      supported_by:
        - reference_id: PMID:23133559
          supporting_text: Arabidopsis and Drosophila CRY is a major circadian photoreceptor
            for light entrainment, while mammalian CRY is not required for photo-entrainment.
  - term:
      id: GO:0045721
      label: negative regulation of gluconeogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: CRY1 reduces gluconeogenic gene expression during fasting.
      action: ACCEPT
      reason: Cry1 reduces fasting gluconeogenic gene expression by blocking glucagon-mediated
        cAMP increases.
      supported_by:
        - reference_id: PMID:20852621
          supporting_text: gluconeogenic gene expression by blocking glucagon-mediated
            increases in
  - term:
      id: GO:0045722
      label: positive regulation of gluconeogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: CRY1 suppresses rather than promotes gluconeogenesis.
      action: REMOVE
      reason: Cry1 reduces gluconeogenic gene expression, supporting negative regulation
        instead.
      supported_by:
        - reference_id: PMID:20852621
          supporting_text: gluconeogenic gene expression by blocking glucagon-mediated
            increases in
  - term:
      id: GO:0045744
      label: negative regulation of G protein-coupled receptor signaling pathway
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: CRY1 dampens GPCR-driven cAMP signaling.
      action: ACCEPT
      reason: Cry1 inhibits cAMP accumulation in response to GPCR activation.
      supported_by:
        - reference_id: PMID:20852621
          supporting_text: Cry1 inhibited accumulation of cAMP in response to G protein-coupled
            receptor
  - term:
      id: GO:0045892
      label: negative regulation of DNA-templated transcription
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: CRY proteins repress CLOCK:BMAL1-driven transcription in the circadian
        loop.
      action: ACCEPT
      reason: CRY/PER repressors inhibit CLOCK:BMAL1 transcriptional activity.
      supported_by:
        - reference_id: PMID:21613214
          supporting_text: repress their own transcription by suppressing the transactivator
            function of
  - term:
      id: GO:0070888
      label: E-box binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: Evidence supports CRY1 binding to CLOCK:BMAL1 on E-boxes, not direct
        DNA binding.
      action: MODIFY
      reason: CRY binds the CLOCK:BMAL1:E-box complex; DNA-binding TF binding is more
        accurate.
      proposed_replacement_terms:
        - id: GO:0140297
          label: DNA-binding transcription factor binding
      supported_by:
        - reference_id: PMID:21613214
          supporting_text: CRY binds stably to the CLOCK:BMAL1:E-box ternary
  - term:
      id: GO:0140297
      label: DNA-binding transcription factor binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: CRY1 binds the CLOCK:BMAL1:E-box complex via protein-protein interactions.
      action: ACCEPT
      reason: CRY binds stably to the CLOCK:BMAL1:E-box ternary complex.
      supported_by:
        - reference_id: PMID:21613214
          supporting_text: CRY binds stably to the CLOCK:BMAL1:E-box ternary
  - term:
      id: GO:2000001
      label: regulation of DNA damage checkpoint
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: No evidence found for CRY1 regulating the DNA damage checkpoint.
      action: REMOVE
      reason: Available references describe circadian transcriptional roles rather
        than checkpoint control.
      supported_by: *id002
  - term:
      id: GO:2000323
      label: negative regulation of nuclear receptor-mediated glucocorticoid signaling
        pathway
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: CRY1 broadly represses glucocorticoid receptor activity.
      action: ACCEPT
      reason: Cryptochromes oppose glucocorticoid receptor activation and promote
        repression.
      supported_by:
        - reference_id: PMID:22170608
          supporting_text: cryptochromes broadly oppose
  - term:
      id: GO:2000850
      label: negative regulation of glucocorticoid secretion
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: Cryptochromes restrain glucocorticoid levels in vivo.
      action: ACCEPT
      reason: Loss of cryptochromes leads to constitutively high corticosterone.
      supported_by:
        - reference_id: PMID:22170608
          supporting_text: results in glucose intolerance and constitutively
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: CRY1 is nuclear, but nucleoplasm is more specific than supported.
      action: MODIFY
      reason: Evidence supports nuclear localization without nucleoplasm specificity.
      proposed_replacement_terms:
        - id: GO:0005634
          label: nucleus
      supported_by: *id001
  - term:
      id: GO:0007623
      label: circadian rhythm
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: CRY1 functions in the core circadian clock.
      action: ACCEPT
      reason: CRY1 is a core component of the circadian clock mechanism.
      supported_by: *id002
  - term:
      id: GO:0009416
      label: response to light stimulus
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Mammalian CRY is not required for photo-entrainment, so light response
        is unsupported.
      action: REMOVE
      reason: Evidence indicates mammalian CRY is not required for photo-entrainment.
      supported_by:
        - reference_id: PMID:23133559
          supporting_text: Arabidopsis and Drosophila CRY is a major circadian photoreceptor
            for light entrainment, while mammalian CRY is not required for photo-entrainment.
  - term:
      id: GO:0014823
      label: response to activity
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: No evidence found linking CRY1 to response to activity.
      action: REMOVE
      reason: Accessible sources do not report CRY1 involvement in activity response.
      supported_by: *id002
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:30530698
    review:
      summary: CRY1 binds the nuclear receptor HNF4A; a nuclear receptor binding term
        is more appropriate.
      action: MODIFY
      reason: Evidence supports interaction with a nuclear receptor rather than generic
        protein binding.
      proposed_replacement_terms:
        - id: GO:0016922
          label: nuclear receptor binding
      supported_by:
        - reference_id: PMID:30530698
          supporting_text: we noted a robust binding between core clock proteins and
            the HNF4A protein
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26431207
    review:
      summary: CRY1 is ubiquitinated by the CUL4-DDB1-CDT2 ligase; generic protein
        binding is too broad.
      action: MARK_AS_OVER_ANNOTATED
      reason: The evidence describes CRY1 as a ubiquitination substrate rather than
        a general binding activity.
      supported_by:
        - reference_id: PMID:26431207
          supporting_text: ubiquitinates CRY1 and promotes its
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:26431207
    review:
      summary: UniProt-curated localization includes nuclear CRY1.
      action: ACCEPT
      reason: Subcellular location annotations indicate nuclear localization; PMID:26431207
        does not contradict this.
      supported_by:
        - reference_id: UniProtKB:Q16526
          supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm. Nucleus {ECO:0000269|PubMed:22798407,'
        - reference_id: PMID:26431207
          supporting_text: ubiquitinates CRY1 and promotes its
  - term:
      id: GO:0031398
      label: positive regulation of protein ubiquitination
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: CRY1 is a ubiquitination substrate rather than a positive regulator.
      action: REMOVE
      reason: CRY1 is ubiquitinated and degraded via SCF(FBXL3).
      supported_by:
        - reference_id: PMID:17463251
          supporting_text: Cry1 and Cry2 proteins are ubiquitinated and degraded
  - term:
      id: GO:0045721
      label: negative regulation of gluconeogenesis
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: CRY1 reduces gluconeogenic gene expression during fasting.
      action: ACCEPT
      reason: Cry1 reduces fasting gluconeogenic gene expression by blocking glucagon-mediated
        cAMP increases.
      supported_by:
        - reference_id: PMID:20852621
          supporting_text: gluconeogenic gene expression by blocking glucagon-mediated
            increases in
  - term:
      id: GO:0045892
      label: negative regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:23133559
    review:
      summary: CRY1 participates in transcriptional repression within the circadian
        feedback loop.
      action: ACCEPT
      reason: PER/CRY complexes inhibit CLOCK/BMAL1 transcriptional activity.
      supported_by:
        - reference_id: PMID:23133559
          supporting_text: complexes inhibit the transcriptional activity of the CLOCK/BMAL1
            heterodimer
  - term:
      id: GO:0043153
      label: entrainment of circadian clock by photoperiod
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Mammalian CRY is not required for photo-entrainment; photoperiod entrainment
        is unsupported.
      action: REMOVE
      reason: Evidence indicates mammalian CRY is not required for photo-entrainment.
      supported_by:
        - reference_id: PMID:23133559
          supporting_text: Arabidopsis and Drosophila CRY is a major circadian photoreceptor
            for light entrainment, while mammalian CRY is not required for photo-entrainment.
  - term:
      id: GO:0045892
      label: negative regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:12397359
    review:
      summary: CRY proteins inhibit Per transcription in the circadian feedback loop.
      action: ACCEPT
      reason: The study states Cry proteins inhibit Per transcription.
      supported_by:
        - reference_id: PMID:12397359
          supporting_text: Cry proteins to inhibit Per transcription
  - term:
      id: GO:0031397
      label: negative regulation of protein ubiquitination
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: CRY1 is ubiquitinated by SCF(FBXL3), indicating it is a substrate not
        a regulator.
      action: REMOVE
      reason: Evidence shows CRY1 is ubiquitinated and degraded rather than regulating
        ubiquitination.
      supported_by:
        - reference_id: PMID:17463251
          supporting_text: Cry1 and Cry2 proteins are ubiquitinated and degraded
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20852621
    review:
      summary: CRY1 interacts with G(s)α in GPCR signaling; generic protein binding
        is too broad.
      action: MARK_AS_OVER_ANNOTATED
      reason: Evidence supports a specific interaction with G(s)α rather than nonspecific
        binding.
      supported_by:
        - reference_id: PMID:20852621
          supporting_text: modulate GPCR activity directly through interaction with
  - term:
      id: GO:0006094
      label: gluconeogenesis
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: CRY1 inhibits gluconeogenic gene expression rather than catalyzing
        gluconeogenesis.
      action: MODIFY
      reason: Evidence supports negative regulation of gluconeogenesis.
      proposed_replacement_terms:
        - id: GO:0045721
          label: negative regulation of gluconeogenesis
      supported_by:
        - reference_id: PMID:20852621
          supporting_text: gluconeogenic gene expression by blocking glucagon-mediated
            increases in
  - term:
      id: GO:0033762
      label: response to glucagon
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: CRY1 modulates glucagon-stimulated signaling during fasting.
      action: ACCEPT
      reason: Cry1 reduces glucagon-mediated increases in cAMP.
      supported_by:
        - reference_id: PMID:20852621
          supporting_text: gluconeogenic gene expression by blocking glucagon-mediated
            increases in
  - term:
      id: GO:0045744
      label: negative regulation of G protein-coupled receptor signaling pathway
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: CRY1 dampens GPCR-driven cAMP signaling.
      action: ACCEPT
      reason: Cry1 inhibits cAMP accumulation in response to GPCR activation.
      supported_by:
        - reference_id: PMID:20852621
          supporting_text: Cry1 inhibited accumulation of cAMP in response to G protein-coupled
            receptor
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: UniProt-curated localization includes nuclear and cytoplasmic CRY1.
      action: ACCEPT
      reason: Subcellular location annotations report cytoplasmic and nuclear CRY1.
      supported_by: *id001
  - term:
      id: GO:0042770
      label: signal transduction in response to DNA damage
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: No direct evidence found for CRY1 in DNA damage response signaling.
      action: REMOVE
      reason: Accessible sources focus on circadian regulation and metabolism, not
        DNA damage signaling.
      supported_by: *id002
  - term:
      id: GO:2000001
      label: regulation of DNA damage checkpoint
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: No evidence found for CRY1 regulating the DNA damage checkpoint.
      action: REMOVE
      reason: Available references describe circadian transcriptional roles rather
        than checkpoint control.
      supported_by: *id002
  - term:
      id: GO:0042593
      label: glucose homeostasis
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: CRY1 contributes to glucose homeostasis.
      action: ACCEPT
      reason: Loss of cryptochromes causes glucose intolerance and altered corticosterone
        levels.
      supported_by:
        - reference_id: PMID:22170608
          supporting_text: results in glucose intolerance and constitutively
  - term:
      id: GO:2000323
      label: negative regulation of nuclear receptor-mediated glucocorticoid signaling
        pathway
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: CRY1 broadly represses glucocorticoid receptor activity.
      action: ACCEPT
      reason: Cryptochromes oppose glucocorticoid receptor activation and promote
        repression.
      supported_by:
        - reference_id: PMID:22170608
          supporting_text: cryptochromes broadly oppose
  - term:
      id: GO:0016922
      label: nuclear receptor binding
    evidence_type: IPI
    original_reference_id: PMID:22170608
    review:
      summary: CRY1/2 interact with the glucocorticoid receptor in a ligand-dependent
        manner.
      action: ACCEPT
      reason: The study reports cryptochromes binding the glucocorticoid receptor.
      supported_by:
        - reference_id: PMID:22170608
          supporting_text: cryptochromes 1 and 2, interact with the glucocorticoid
            receptor
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21613214
    review:
      summary: CRY binds to the CLOCK:BMAL1:E-box complex; generic protein binding
        is too broad.
      action: MARK_AS_OVER_ANNOTATED
      reason: Evidence describes specific interaction with CLOCK:BMAL1 on DNA.
      supported_by:
        - reference_id: PMID:21613214
          supporting_text: CRY binds stably to the CLOCK:BMAL1:E-box ternary
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21680841
    review:
      summary: The cited study focuses on PER complexes and does not present CRY1
        binding evidence.
      action: REMOVE
      reason: No CRY1 interaction evidence is provided in the abstract.
      supported_by:
        - reference_id: PMID:21680841
          supporting_text: PERIOD (PER) proteins, acting in a large complex, inhibit
            the transcriptional
  - term:
      id: GO:0042754
      label: negative regulation of circadian rhythm
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: CRY1 represses CLOCK:BMAL1 as part of the negative limb of the clock.
      action: ACCEPT
      reason: CRY1/2 inhibit CLOCK:BMAL1 in a negative-feedback loop.
      supported_by:
        - reference_id: PMID:17463251
          supporting_text: encode inhibitors of the Clock-Bmal1 complex
  - term:
      id: GO:0032922
      label: circadian regulation of gene expression
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: CRY1 regulates circadian gene expression via the core transcriptional
        feedback loop.
      action: ACCEPT
      reason: CRY represses CLOCK:BMAL1 activity, shaping circadian gene expression.
      supported_by:
        - reference_id: PMID:21613214
          supporting_text: repress their own transcription by suppressing the transactivator
            function of
  - term:
      id: GO:0045892
      label: negative regulation of DNA-templated transcription
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: CRY proteins repress CLOCK:BMAL1-driven transcription in the circadian
        loop.
      action: ACCEPT
      reason: CRY/PER repressors inhibit CLOCK:BMAL1 transcriptional activity.
      supported_by:
        - reference_id: PMID:21613214
          supporting_text: repress their own transcription by suppressing the transactivator
            function of
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:9383998
    review:
      summary: The study reports PP5 interaction with hCRY2, not CRY1.
      action: REMOVE
      reason: Evidence is specific to CRY2, so it does not support CRY1 binding.
      supported_by:
        - reference_id: PMID:9383998
          supporting_text: specifically interacted with hCRY2.
  - term:
      id: GO:0019902
      label: phosphatase binding
    evidence_type: IPI
    original_reference_id: PMID:9383998
    review:
      summary: Phosphatase binding evidence is for hCRY2, not CRY1.
      action: REMOVE
      reason: The study specifies PP5 interaction with hCRY2 rather than CRY1.
      supported_by:
        - reference_id: PMID:9383998
          supporting_text: specifically interacted with hCRY2.
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:12397359
    review:
      summary: Cry proteins inhibit Per transcription in the circadian feedback loop.
      action: ACCEPT
      reason: Cry proteins are reported to inhibit Per transcription.
      supported_by:
        - reference_id: PMID:12397359
          supporting_text: Cry proteins to inhibit Per transcription
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:14672706
    review:
      summary: PER/CRY act as negative regulators of CLOCK/BMAL-driven transcription.
      action: ACCEPT
      reason: PER/CRY suppress CLOCK/BMAL-induced expression in the feedback loop.
      supported_by:
        - reference_id: PMID:14672706
          supporting_text: PERs and CRYs suppressed the induced expression.
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:15147242
    review:
      summary: Cry proteins suppress Clock/Bmal-induced transcription.
      action: ACCEPT
      reason: Cry proteins are reported to suppress Clock/Bmal-induced transcription.
      supported_by:
        - reference_id: PMID:15147242
          supporting_text: suppressed Clock/Bmal-induced transcription from the Dec2
            promoter.
  - term:
      id: GO:0042752
      label: regulation of circadian rhythm
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: CRY1 is a core circadian clock repressor.
      action: ACCEPT
      reason: CRY1/2 encode inhibitors of CLOCK:BMAL1 in the feedback loop.
      supported_by:
        - reference_id: PMID:17463251
          supporting_text: encode inhibitors of the Clock-Bmal1 complex
  - term:
      id: GO:0009785
      label: blue light signaling pathway
    evidence_type: NAS
    original_reference_id: PMID:8909283
    review:
      summary: Human CRY1 is not required for photo-entrainment; blue-light signaling
        is not supported.
      action: REMOVE
      reason: Mammalian CRY is reported not to be required for photo-entrainment,
        so blue-light signaling is unsupported.
      additional_reference_ids: [PMID:23133559]
      supported_by:
        - reference_id: PMID:23133559
          supporting_text: Arabidopsis and Drosophila CRY is a major circadian photoreceptor
            for light entrainment, while mammalian CRY is not required for photo-entrainment.
  - term:
      id: GO:0009882
      label: blue light photoreceptor activity
    evidence_type: NAS
    original_reference_id: PMID:8909283
    review:
      summary: Early work suggested blue-light photoreceptor function, but mammalian
        CRY is not required for photo-entrainment.
      action: MARK_AS_OVER_ANNOTATED
      reason: The photoreceptor role is speculative for mammals; later evidence indicates
        CRY is not required for photo-entrainment.
      additional_reference_ids: [PMID:23133559]
      supported_by:
        - reference_id: PMID:8909283
          supporting_text: may function as blue-light photoreceptors in humans.
        - reference_id: PMID:23133559
          supporting_text: Arabidopsis and Drosophila CRY is a major circadian photoreceptor
            for light entrainment, while mammalian CRY is not required for photo-entrainment.
  - term:
      id: GO:0003690
      label: double-stranded DNA binding
    evidence_type: IDA
    original_reference_id: PMID:9801304
    review:
      summary: CRY1 binds CLOCK:BMAL1 on E-box DNA rather than directly binding DNA.
      action: MODIFY
      reason: Evidence supports association with the CLOCK:BMAL1:E-box complex, not
        direct DNA binding.
      proposed_replacement_terms:
        - id: GO:0140297
          label: DNA-binding transcription factor binding
      additional_reference_ids: [PMID:21613214]
      supported_by:
        - reference_id: PMID:21613214
          supporting_text: CRY binds stably to the CLOCK:BMAL1:E-box ternary
  - term:
      id: GO:0003904
      label: deoxyribodipyrimidine photo-lyase activity
    evidence_type: IDA
    original_reference_id: PMID:8909283
    negated: true
    review:
      summary: CRY1 lacks cyclobutane pyrimidine dimer photolyase activity (negated).
      action: ACCEPT
      reason: Purified hCRY1 lacks photolyase activity on cyclobutane pyrimidine dimers.
      supported_by:
        - reference_id: PMID:8909283
          supporting_text: lacked photolyase activity on the
  - term:
      id: GO:0003914
      label: DNA (6-4) photolyase activity
    evidence_type: IDA
    original_reference_id: PMID:8909283
    negated: true
    review:
      summary: CRY1 lacks (6-4) photolyase activity (negated).
      action: ACCEPT
      reason: Purified hCRY1 lacks photolyase activity on (6-4) photoproducts.
      supported_by:
        - reference_id: PMID:8909283
          supporting_text: lacked photolyase activity on the
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17463251
    review:
      summary: CRY1 is an inhibitor of CLOCK:BMAL1 but generic protein binding is
        too broad.
      action: MARK_AS_OVER_ANNOTATED
      reason: Evidence points to specific interactions in the clock feedback loop.
      supported_by:
        - reference_id: PMID:17463251
          supporting_text: encode inhibitors of the Clock-Bmal1 complex
  - term:
      id: GO:0003677
      label: DNA binding
    evidence_type: TAS
    original_reference_id: PMID:9801304
    review:
      summary: Evidence favors interaction with CLOCK:BMAL1 on E-boxes rather than
        direct DNA binding.
      action: MODIFY
      reason: CRY binds the CLOCK:BMAL1:E-box complex, so a TF-binding term is more
        accurate.
      proposed_replacement_terms:
        - id: GO:0140297
          label: DNA-binding transcription factor binding
      additional_reference_ids: [PMID:21613214]
      supported_by:
        - reference_id: PMID:21613214
          supporting_text: CRY binds stably to the CLOCK:BMAL1:E-box ternary
core_functions:
  - molecular_function:
      id: GO:0140297
      label: DNA-binding transcription factor binding
    directly_involved_in:
      - id: GO:0032922
        label: circadian regulation of gene expression
      - id: GO:0000122
        label: negative regulation of transcription by RNA polymerase II
    locations:
      - id: GO:0005634
        label: nucleus
    description: Binds the CLOCK:BMAL1 E-box complex to repress circadian transcription.
    supported_by:
      - reference_id: PMID:21613214
        supporting_text: CRY binds stably to the CLOCK:BMAL1:E-box ternary
      - reference_id: PMID:21613214
        supporting_text: repress their own transcription by suppressing the transactivator
          function of
  - molecular_function:
      id: GO:0071949
      label: FAD binding
    description: Binds FAD as a flavin cofactor.
    supported_by:
      - reference_id: PMID:8909283
        supporting_text: were found to contain FAD and a pterin cofactor.
references:
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data to
      orthologs by curator judgment of sequence similarity
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
      vocabulary mapping, accompanied by conservative changes to GO terms applied
      by UniProt
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation data
      to orthologs using Ensembl Compara
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning models
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:12397359
    title: Dec1 and Dec2 are regulators of the mammalian molecular clock.
    findings: []
  - id: PMID:14672706
    title: A novel autofeedback loop of Dec1 transcription involved in circadian rhythm
      regulation.
    findings: []
  - id: PMID:15147242
    title: Expression of the gene for Dec2, a basic helix-loop-helix transcription
      factor, is regulated by a molecular clock system.
    findings: []
  - id: PMID:17463251
    title: SCFFbxl3 controls the oscillation of the circadian clock by directing the
      degradation of cryptochrome proteins.
    findings: []
  - id: PMID:20852621
    title: Cryptochrome mediates circadian regulation of cAMP signaling and hepatic
      gluconeogenesis.
    findings: []
  - id: PMID:21613214
    title: Biochemical analysis of the canonical model for the mammalian circadian
      clock.
    findings: []
  - id: PMID:21680841
    title: A molecular mechanism for circadian clock negative feedback.
    findings: []
  - id: PMID:22170608
    title: Cryptochromes mediate rhythmic repression of the glucocorticoid receptor.
    findings: []
  - id: PMID:23133559
    title: Role of type II protein arginine methyltransferase 5 in the regulation
      of Circadian Per1 gene.
    findings: []
  - id: PMID:26431207
    title: CUL4-DDB1-CDT2 E3 Ligase Regulates the Molecular Clock Activity by Promoting
      Ubiquitination-Dependent Degradation of the Mammalian CRY1.
    findings: []
  - id: PMID:28514442
    title: Architecture of the human interactome defines protein communities and disease
      networks.
    findings: []
  - id: PMID:30530698
    title: Nuclear receptor HNF4A transrepresses CLOCK:BMAL1 and modulates tissue-specific
      circadian networks.
    findings: []
  - id: PMID:33961781
    title: Dual proteome-scale networks reveal cell-specific remodeling of the human
      interactome.
    findings: []
  - id: PMID:8909283
    title: Putative human blue-light photoreceptors hCRY1 and hCRY2 are flavoproteins.
    findings: []
  - id: PMID:9383998
    title: Human blue-light photoreceptor hCRY2 specifically interacts with protein
      serine/threonine phosphatase 5 and modulates its activity.
    findings: []
  - id: PMID:9801304
    title: Characterization of photolyase/blue-light receptor homologs in mouse and
      human cells.
    findings: []

CRY1

Gene Description

Existing Annotations Review

Core Functions

Binds the CLOCK:BMAL1 E-box complex to repress circadian transcription.

Binds FAD as a flavin cofactor.

References

📚 Additional Documentation

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Comprehensive Research Report: Human CRY1 (Cryptochrome-1) Functional Annotation (UniProt Q16526)

1) Identity verification (gene/protein, organism, domains)

2) Key concepts and definitions (current understanding)

2.1 CRY1 as a core negative limb component of the mammalian circadian clock

2.2 “Primary pocket” vs “secondary pocket” and the serine loop

2.3 Late repression model: CRY1 vs PER–CRY complexes

3) Molecular function, processes, and pathway placement

3.1 Primary molecular function: transcriptional repression of CLOCK:BMAL1

3.2 Regulation of CRY1 activity by PER proteins (PER1/PER2)

3.3 CRY1 turnover and post-translational regulation (protein stability as clock timing control)

3.4 Crosstalk pathways: Hippo signaling and DNA repair rhythms

4) Subcellular localization (where CRY1 acts)

5) Recent developments (2023–2024 prioritized)

5.1 Structural and mechanistic updates (2024)

5.2 Human genetics and disease links (2023–2024)

5.3 Circadian DNA repair and chronotherapy rationale (2024)

6) Current applications and real-world implementations

6.1 Diagnostic/precision medicine implications of CRY1 splice variants

6.2 Chronobiology-informed oncology and chronochemotherapy

6.3 Ongoing human studies measuring CRY1 expression (ClinicalTrials.gov)

7) Expert opinions and analysis (authoritative synthesis)

8) Key statistics and recent data points (selected)

Summary table (evidence-backed)

Figures (structural schematics from 2024 review)

Limitations of this evidence set

Citations

📄 View Raw YAML