CRY2 Gene

Name	cryptochrome circadian clock 2
Description	This gene encodes a flavin adenine dinucleotide-binding protein that is a key component of the circadian core oscillator complex, which regulates the circadian clock. This gene is upregulated by CLOCK/ARNTL heterodimers but then represses this upregulation in a feedback loop using PER/CRY heterodimers to interact with CLOCK/ARNTL. Polymorphisms in this gene have been associated with altered sleep patterns. The encoded protein is widely conserved across plants and animals. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2014]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n CRY2 is emerging as a multifunctional regulator that links the core circadian oscillator to diverse physiological processes. Genetic studies have identified variants in the CRY2 locus that associate with altered fasting glucose levels and beta‐cell function, implicating CRY2 in metabolic and glycemic regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " At the molecular level, CRY2 functions as a key repressor in the circadian transcription–translation feedback loop. It is subjected to precise posttranslational control via ubiquitination: for example, the F‐box protein FBXL3 promotes ubiquitin‐mediated degradation of CRY proteins, as demonstrated in mutant models where disruption of FBXL3 function leads to CRY stabilization."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Furthermore, CRY2 (together with CRY1) modulates cyclic AMP response element–binding protein (CREB) activity during fasting by interfering with G protein–coupled receptor signaling, thus contributing to the rhythmic regulation of hepatic gluconeogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, the abundance and stability of CRY2 are tightly regulated by opposing actions of ubiquitin ligases. Studies have shown that SCF complexes containing FBXL3 ubiquitinate CRY2, whereas a related complex involving FBXL21 counteracts this degradation by stabilizing CRY2 in the cytoplasm; the spatial compartmentalization of these antagonistic activities is critical for setting the circadian period."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its canonical role in timekeeping, CRY2 has been implicated in the regulation of cell proliferation. It functions as a component of an FBXL3-containing E3 ligase complex that specifically recruits T58-phosphorylated c-MYC for ubiquitylation, thereby linking circadian mechanisms to oncogenic protein turnover and suggesting an unexpected role in tumor suppression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, recent evidence in a transgenic Drosophila model reveals that human CRY2 can act as a light-dependent magnetosensor, indicating that CRY2 may have roles in magnetoreception in addition to circadian regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Together, these findings illustrate that CRY2 integrates circadian timing with metabolic control and cell proliferation, while also potentially mediating light-dependent magnetic sensitivity.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Josée Dupuis, Claudia Langenberg, Inga Prokopenko, et al. "}, {"type": "b", "children": [{"type": "t", "text": "New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng.520"}], "href": "https://doi.org/10.1038/ng.520"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20081858"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20081858"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Sandra M Siepka, Seung-Hee Yoo, Junghea Park, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Circadian mutant Overtime reveals F-box protein FBXL3 regulation of cryptochrome and period gene expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2007.04.030"}], "href": "https://doi.org/10.1016/j.cell.2007.04.030"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17462724"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17462724"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Masao Doi, Yukari Takahashi, Rie Komatsu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Salt-sensitive hypertension in circadian clock-deficient Cry-null mice involves dysregulated adrenal Hsd3b6."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Med (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nm.2061"}], "href": "https://doi.org/10.1038/nm.2061"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20023637"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20023637"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Luca Busino, Florian Bassermann, Alessio Maiolica, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.1141194"}], "href": "https://doi.org/10.1126/science.1141194"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17463251"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17463251"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Arisa Hirano, Kanae Yumimoto, Ryosuke Tsunematsu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "FBXL21 regulates oscillation of the circadian clock through ubiquitination and stabilization of cryptochromes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2013.01.054"}], "href": "https://doi.org/10.1016/j.cell.2013.01.054"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23452856"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23452856"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Anne-Laure Huber, Stephanie J Papp, Alanna B Chan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CRY2 and FBXL3 Cooperatively Degrade c-MYC."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2016.10.012"}], "href": "https://doi.org/10.1016/j.molcel.2016.10.012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27840026"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27840026"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Lauren E Foley, Robert J Gegear, Steven M Reppert "}, {"type": "b", "children": [{"type": "t", "text": "Human cryptochrome exhibits light-dependent magnetosensitivity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncomms1364"}], "href": "https://doi.org/10.1038/ncomms1364"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21694704"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21694704"}]}]}]}
Synonyms	PHLL2, HCRY2
Proteins	CRY2_HUMAN
NCBI Gene ID	1408
API
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Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

CRY2 has 7,421 functional associations with biological entities spanning 8 categories (molecular profile, organism, chemical, functional term, phrase or reference, disease, phenotype or trait, structural feature, cell line, cell type or tissue, gene, protein or microRNA) extracted from 120 datasets.

Click the + buttons to view associations for CRY2 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

CRY2 Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of CRY2 gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of CRY2 gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of CRY2 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of CRY2 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of CRY2 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of CRY2 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of CRY2 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of CRY2 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of CRY2 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of CRY2 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with CRY2 gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of CRY2 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of CRY2 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of CRY2 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of CRY2 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing CRY2 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing CRY2 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores	cellular components containing CRY2 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with CRY2 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with CRY2 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	CORUM Protein Complexes	protein complexs containing CRY2 protein from the CORUM Protein Complexes dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of CRY2 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with CRY2 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with CRY2 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with CRY2 gene/protein from the curated CTD Gene-Disease Associations dataset.
	dbGAP Gene-Trait Associations	traits associated with CRY2 gene in GWAS and other genetic association datasets from the dbGAP Gene-Trait Associations dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of CRY2 protein relative to other small molecule perturbations from the DeepCoverMOA Drug Mechanisms of Action dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by CRY2 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Curated Gene-Disease Association Evidence Scores 2025	diseases involving CRY2 gene from the DISEASES Curated Gene-Disease Association Evidence Scores 2025 dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores	diseases associated with CRY2 gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores 2025	diseases associated with CRY2 gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with CRY2 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with CRY2 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with CRY2 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with CRY2 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at CRY2 gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of CRY2 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of CRY2 gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing CRY2 from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GAD Gene-Disease Associations	diseases associated with CRY2 gene in GWAS and other genetic association datasets from the GAD Gene-Disease Associations dataset.