CRY1 (cryptochrome circadian regulator 1)

Gene

• Entrez ID: 1407
• Gene name: Cryptochrome circadian regulator 1
• Gene symbol: CRY1
• Synonyms: DSPD, PHLL1
• Chromosome: 12
• Chromosome location: 12q23.3
• Summary: 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. Loss of the related gene in mouse results in a shortened circadian cycle in complete darkness. [provided by RefSeq, Jan 2014]

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs184039278	T>C,G	Risk-factor	Missense variant, intron variant, coding sequence variant

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT043195	hsa-miR-324-5p	CLASH	23622248

Transcription factors

Transcription factor	Regulation	Reference
ARNTL	Activation	22750052
ARNTL	Unknown	17660446
CLOCK	Activation	22750052
CLOCK	Unknown	17660446
NPAS2	Unknown	17660446

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0000122	Process	Negative regulation of transcription by RNA polymerase II	IDA	12397359, 14672706, 15147242
GO:0003677	Function	DNA binding	IBA	21873635
GO:0003690	Function	Double-stranded DNA binding	IDA	9801304
GO:0003904	Function	Deoxyribodipyrimidine photo-lyase activity	IDA	8909283
GO:0003914	Function	DNA (6-4) photolyase activity	IDA	8909283
GO:0005515	Function	Protein binding	IPI	9383998, 17463251, 20852621, 21613214, 21680841, 23133559, 26431207, 30530698
GO:0005634	Component	Nucleus	IBA	21873635
GO:0005634	Component	Nucleus	IDA	26431207
GO:0005634	Component	Nucleus	ISS
GO:0005737	Component	Cytoplasm	IBA	21873635
GO:0005739	Component	Mitochondrion	IEA
GO:0006094	Process	Gluconeogenesis	ISS
GO:0006975	Process	DNA damage induced protein phosphorylation	ISS
GO:0007623	Process	Circadian rhythm	ISS
GO:0009416	Process	Response to light stimulus	ISS
GO:0009785	Process	Blue light signaling pathway	NAS	8909283
GO:0009882	Function	Blue light photoreceptor activity	NAS	8909283
GO:0014823	Process	Response to activity	ISS
GO:0018298	Process	Protein-chromophore linkage	IEA
GO:0019901	Function	Protein kinase binding	IEA
GO:0019902	Function	Phosphatase binding	IPI	9383998
GO:0019915	Process	Lipid storage	IEA
GO:0031397	Process	Negative regulation of protein ubiquitination	ISS
GO:0031398	Process	Positive regulation of protein ubiquitination	ISS
GO:0032868	Process	Response to insulin	IEA
GO:0032922	Process	Circadian regulation of gene expression	IBA	21873635
GO:0032922	Process	Circadian regulation of gene expression	ISS
GO:0033762	Process	Response to glucagon	ISS
GO:0035257	Function	Nuclear hormone receptor binding	IPI	22170608
GO:0042593	Process	Glucose homeostasis	ISS
GO:0042752	Process	Regulation of circadian rhythm	ISS
GO:0042754	Process	Negative regulation of circadian rhythm	ISS
GO:0042826	Function	Histone deacetylase binding	IEA
GO:0043153	Process	Entrainment of circadian clock by photoperiod	IBA	21873635
GO:0043153	Process	Entrainment of circadian clock by photoperiod	ISS
GO:0045721	Process	Negative regulation of gluconeogenesis	ISS
GO:0045744	Process	Negative regulation of G protein-coupled receptor signaling pathway	ISS
GO:0045892	Process	Negative regulation of transcription, DNA-templated	IBA	21873635
GO:0045892	Process	Negative regulation of transcription, DNA-templated	IDA	12397359, 23133559
GO:0045892	Process	Negative regulation of transcription, DNA-templated	ISS
GO:0070888	Function	E-box binding	IEA
GO:0071949	Function	FAD binding	IBA	21873635
GO:2000001	Process	Regulation of DNA damage checkpoint	ISS
GO:2000323	Process	Negative regulation of glucocorticoid receptor signaling pathway	ISS
GO:2000850	Process	Negative regulation of glucocorticoid secretion	IEA

Other IDs

• MIM: 601933
• HGNC: 2384
• e!Ensembl: ENSG00000008405

Protein

• UniProt ID: Q16526
• Protein name: Cryptochrome-1
• Protein function: Transcriptional repressor which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots 'circa' (about) and 'diem' (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for 'timegivers'). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, ARNTL/BMAL1, ARNTL2/BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and ARNTL/BMAL1 or ARNTL2/BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5'-CACGTG-3') within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-ARNTL/BMAL1|ARNTL2/BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress ARNTL/BMAL1 transcription, respectively. CRY1 and CRY2 have redundant functions but also differential and selective contributions at least in defining the pace of the SCN circadian clock and its circadian transcriptional outputs. More potent transcriptional repressor in cerebellum and liver than CRY2, though more effective in lengthening the period of the SCN oscillator. On its side, CRY2 seems to play a critical role in tuning SCN circadian period by opposing the action of CRY1. With CRY2, is dispensable for circadian rhythm generation but necessary for the development of intercellular networks for rhythm synchrony. Capable of translocating circadian clock core proteins such as PER proteins to the nucleus. Interacts with CLOCK-ARNTL/BMAL1 independently of PER proteins and is found at CLOCK-ARNTL/BMAL1-bound sites, suggesting that CRY may act as a molecular gatekeeper to maintain CLOCK-ARNTL/BMAL1 in a poised and repressed state until the proper time for transcriptional activation. Represses the CLOCK-ARNTL/BMAL1 induced transcription of BHLHE40/DEC1. Represses the CLOCK-ARNTL/BMAL1 induced transcription of ATF4, MTA1, KLF10 and NAMPT (By similarity). May repress circadian target genes expression in collaboration with HDAC1 and HDAC2 through histone deacetylation. Mediates the clock-control activation of ATR and modulates ATR-mediated DNA damage checkpoint. In liver, mediates circadian regulation of cAMP signaling and gluconeogenesis by binding to membrane-coupled G proteins and blocking glucagon-mediated increases in intracellular cAMP concentrations and CREB1 phosphorylation. Inhibits hepatic gluconeogenesis by decreasing nuclear FOXO1 levels that downregulates gluconeogenic gene expression (By similarity). Besides its role in the maintenance of the circadian clock, is also involved in the regulation of other processes. Represses glucocorticoid receptor NR3C1/GR-induced transcriptional activity by binding to glucocorticoid response elements (GREs). Plays a key role in glucose and lipid metabolism modulation, in part, through the transcriptional regulation of genes involved in these pathways, such as LEP or ACSL4 (By similarity). Represses PPARD and its target genes in the skeletal muscle and limits exercise capacity (By similarity). Plays an essential role in the generation of circadian rhythms in the retina (By similarity). Represses the transcriptional activity of NR1I2 (By similarity).
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF00875	DNA_photolyase	5 → 170	DNA photolyase	Domain
  PF03441	FAD_binding_7	286 → 486	FAD binding domain of DNA photolyase	Domain

• Sequence:

  MGVNAVHWFRKGLRLHDNPALKECIQGADTIRCVYILDPWFAGSSNVGINRWRFLLQCLE
  DLDANLRKLNSRLFVIRGQPADVFPRLFKEWNITKLSIEYDSEPFGKERDAAIKKLATEA
  GVEVIVRISHTLYDLDKIIELNGGQPPLTYKRFQTLISKMEPLEIPVETITSEVIEKCTT
  PLSDDHDEKYGVPSLEELGFDTDGLSSAVWPGGETEALTRLERHLERKAWVANFERPRMN
  ANSLLASPTGLSPYLRFGCLSCRLFYFKLTDLYKKVKKNSSPPLSLYGQLLWREFFYTAA
  TNNPRFDKMEGNPICVQIPWDKNPEALAKWAEGRTGFPWIDAIMTQLRQEGWIHHLARHA
  VACFLTRGDLWISWEEGMKVFEELLLDADWSINAGSWMWLSCSSFFQQFFHCYCPVGFGR
  RTDPNGDYIRRYLPVLRGFPAKYIYDPWNAPEGIQKVAKCLIGVNYPKPMVNHAEASRLN
  IERMKQIYQQLSRYRGLGLLASVPSNPNGNGGFMGYSAENIPGCSSSGSCSQGSGILHYA
  HGDSQQTHLLKQGRSSMGTGLSGGKRPSQEEDTQSIGPKVQRQSTN

• Sequence length: 586

Pathways

KEGG:

Circadian rhythm

Associated diseases

Disease name	Disease term	References
	Advanced Sleep Phase Syndrome
	Bipolar Disorder	20072116, 22538398, 15722957
	Delayed Sleep Phase Syndrome
	Mental Depression	23138696
	Depressive disorder	22538398, 23138696
	Myeloid Leukemia, Chronic	16999817
	Non-24 Hour Sleep-Wake Disorder
	Nonorganic Sleep Wake Cycle Disorders
	Seasonal Affective Disorder	22538398
	Shift-Work Sleep Disorder