DegronMD - Q49AN0(CRY2)

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. Less potent transcriptional repressor in cerebellum and liver than CRY1, though less effective in lengthening the period of the SCN oscillator. Seems to play a critical role in tuning SCN circadian period by opposing the action of CRY1. With CRY1, dispensable for circadian rhythm generation but necessary for the development of intercellular networks for rhythm synchrony. May mediate circadian regulation of cAMP signaling and gluconeogenesis by blocking glucagon-mediated increases in intracellular cAMP concentrations and in CREB1 phosphorylation. Besides its role in the maintenance of the circadian clock, is also involved in the regulation of other processes. 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. Represses glucocorticoid receptor NR3C1/GR-induced transcriptional activity by binding to glucocorticoid response elements (GREs). Represses the CLOCK-ARNTL/BMAL1 induced transcription of BHLHE40/DEC1. Represses the CLOCK-ARNTL/BMAL1 induced transcription of NAMPT (By similarity). Represses PPARD and its target genes in the skeletal muscle and limits exercise capacity (By similarity). Represses the transcriptional activity of NR1I2 (By similarity). {ECO:0000250|UniProtKB:Q9R194, ECO:0000269|PubMed:10531061, ECO:0000269|PubMed:14672706, ECO:0000269|PubMed:16790549}. View more >>

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Mutation	Sample	Cancer	Dataset	Degron hit	Class	Location	Type	Impact score
p.R199H	TCGA-ND-A4WC	UCS	TCGA	DETYGVPSL	DEG_COP1_1	206:214	Mutation rewiring degron network	0.1389
p.E221D	TCGA-UE-A6QT	SARC	TCGA	DETYGVPSL	DEG_COP1_1	206:214	Mutation rewiring degron network	0.1389
p.S201F	DO220886	MELA	ICGC	DETYGVPSL	DEG_COP1_1	206:214	Mutation rewiring degron network	0.1944
p.R221C	DO42312	UCEC	ICGC	DETYGVPSL	DEG_COP1_1	206:214	Mutation rewiring degron network	0.1389
p.C218R	SIDM00572	Gastric Carcinoma	GDSC	DETYGVPSL	DEG_COP1_1	206:214	Mutation rewiring degron network	0.2222
p.C218R	ACH-000911	Gastric Cancer	CCLE	DETYGVPSL	DEG_COP1_1	206:214	Mutation rewiring degron network	0.2222
p.C218R	NUGC-3	stomach	COSMIC	DETYGVPSL	DEG_COP1_1	206:214	Mutation rewiring degron network	0.2222
p.I196L	SIDM00845	Burkitt's Lymphoma	GDSC	DETYGVPSL	DEG_COP1_1	206:214	Mutation blocking phosphorylation signal	0.5
p.I196L	SIDM00461	Acute Myeloid Leukemia	GDSC	DETYGVPSL	DEG_COP1_1	206:214	Mutation blocking phosphorylation signal	0.5
p.I196L	SIDM01519	Head and Neck Carcinoma	GDSC	DETYGVPSL	DEG_COP1_1	206:214	Mutation blocking phosphorylation signal	0.5
p.R219M	SIDM00498	Colorectal Carcinoma	GDSC	DETYGVPSL	DEG_COP1_1	206:214	Mutation rewiring degron network	0.1944
p.R219M	ACH-000970	Colon/Colorectal Cancer	CCLE	DETYGVPSL	DEG_COP1_1	206:214	Mutation rewiring degron network	0.1944
p.R219M	SNU-C5	large intestine	COSMIC	DETYGVPSL	DEG_COP1_1	206:214	Mutation rewiring degron network	0.1944
p.T211P	ACH-000491	Colon/Colorectal Cancer	CCLE	DETYGVPSL	DEG_COP1_1	206:214	Mutation altering degron motif	0.7031
p.C197R	NUGC-3	stomach	COSMIC	DETYGVPSL	DEG_COP1_1	206:214	Mutation rewiring degron network	0.0833
p.R198M	SNU-C5	large intestine	COSMIC	DETYGVPSL	DEG_COP1_1	206:214	Mutation rewiring degron network	0.1111

DegronMD: protein-targeted degradation, mutation and drug response to degrons

CRY2

UniProt ID: Q49AN0

Entrez ID: 1408

Protein name: Cryptochrome-2

External links: UniprotKB HGNC RefSeq COSMIC

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Kaplan plot for CRY2 in