DegronMD - P20393(NR1D1)

FUNCTION: Transcriptional repressor which coordinates circadian rhythm and metabolic pathways in a heme-dependent manner. Integral component of the complex transcription machinery that governs circadian rhythmicity and forms a critical negative limb of the circadian clock by directly repressing the expression of core clock components ARTNL/BMAL1, CLOCK and CRY1. Also regulates genes involved in metabolic functions, including lipid and bile acid metabolism, adipogenesis, gluconeogenesis and the macrophage inflammatory response. Acts as a receptor for heme which stimulates its interaction with the NCOR1/HDAC3 corepressor complex, enhancing transcriptional repression. Recognizes two classes of DNA response elements within the promoter of its target genes and can bind to DNA as either monomers or homodimers, depending on the nature of the response element. Binds as a monomer to a response element composed of the consensus half-site motif 5'-[A/G]GGTCA-3' preceded by an A/T-rich 5' sequence (RevRE), or as a homodimer to a direct repeat of the core motif spaced by two nucleotides (RevDR-2). Acts as a potent competitive repressor of ROR alpha (RORA) function and regulates the levels of its ligand heme by repressing the expression of PPARGC1A, a potent inducer of heme synthesis. Regulates lipid metabolism by repressing the expression of APOC3 and by influencing the activity of sterol response element binding proteins (SREBPs); represses INSIG2 which interferes with the proteolytic activation of SREBPs which in turn govern the rhythmic expression of enzymes with key functions in sterol and fatty acid synthesis. Regulates gluconeogenesis via repression of G6PC1 and PEPCK and adipocyte differentiation via repression of PPARG. Regulates glucagon release in pancreatic alpha-cells via the AMPK-NAMPT-SIRT1 pathway and the proliferation, glucose-induced insulin secretion and expression of key lipogenic genes in pancreatic-beta cells. Positively regulates bile acid synthesis by increasing hepatic expression of CYP7A1 via repression of NR0B2 and NFIL3 which are negative regulators of CYP7A1. Modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy; controls mitochondrial biogenesis and respiration by interfering with the STK11-PRKAA1/2-SIRT1-PPARGC1A signaling pathway. Represses the expression of SERPINE1/PAI1, an important modulator of cardiovascular disease and the expression of inflammatory cytokines and chemokines in macrophages. Represses gene expression at a distance in macrophages by inhibiting the transcription of enhancer-derived RNAs (eRNAs). Plays a role in the circadian regulation of body temperature and negatively regulates thermogenic transcriptional programs in brown adipose tissue (BAT); imposes a circadian oscillation in BAT activity, increasing body temperature when awake and depressing thermogenesis during sleep. In concert with NR2E3, regulates transcriptional networks critical for photoreceptor development and function. In addition to its activity as a repressor, can also act as a transcriptional activator. In the ovarian granulosa cells acts as a transcriptional activator of STAR which plays a role in steroid biosynthesis. In collaboration with SP1, activates GJA1 transcription in a heme-independent manner. Represses the transcription of CYP2B10, CYP4A10 and CYP4A14 (By similarity). Represses the transcription of CES2 (By similarity). Represses and regulates the circadian expression of TSHB in a NCOR1-dependent manner (By similarity). Negatively regulates the protein stability of NR3C1 and influences the time-dependent subcellular distribution of NR3C1, thereby affecting its transcriptional regulatory activity (By similarity). Plays a critical role in the circadian control of neutrophilic inflammation in the lung; under resting, non-stress conditions, acts as a rhythmic repressor to limit inflammatory activity whereas in the presence of inflammatory triggers undergoes ubiquitin-mediated degradation thereby relieving inhibition of the inflammatory response (By similarity). Plays a key role in the circadian regulation of microglial activation and neuroinflammation; suppresses microglial activation through the NF-kappaB pathway in the central nervous system (By similarity). Plays a role in the regulation of the diurnal rhythms of lipid and protein metabolism in the skeletal muscle via transcriptional repression of genes controlling lipid and amino acid metabolism in the muscle (By similarity). {ECO:0000250|UniProtKB:Q3UV55, ECO:0000269|PubMed:12021280, ECO:0000269|PubMed:15761026, ECO:0000269|PubMed:16968709, ECO:0000269|PubMed:18006707, ECO:0000269|PubMed:19710360, ECO:0000269|PubMed:1971514, ECO:0000269|PubMed:21479263, ECO:0000269|PubMed:22184247, ECO:0000269|PubMed:23398316, ECO:0000269|PubMed:2539258}. View more >>

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GO - Molecular function (MF): View more >>

GO - Cellular component (CC): View more >>

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Mutation	Sample	Cancer	Dataset	Degron hit	Class	Location	Type	Impact score
p.D78Y	TCGA-2H-A9GQ	ESCA	TCGA	PSSSS	DEG_SPOP_SBC_1	81:85	Mutation rewiring degron network	0.25
p.D78N	TCGA-A2-A04Q	BRCA	TCGA	PSSSS	DEG_SPOP_SBC_1	81:85	Mutation rewiring degron network	0.25
p.D78N	DO1678	BRCA	ICGC	PSSSS	DEG_SPOP_SBC_1	81:85	Mutation rewiring degron network	0.25
p.S88L	TCGA-AA-3510	COAD	TCGA	PSSSS	DEG_SPOP_SBC_1	81:85	Mutation rewiring degron network	0.25
p.S88L	DO7783	COAD	ICGC	PSSSS	DEG_SPOP_SBC_1	81:85	Mutation rewiring degron network	0.25
p.S87L	TCGA-AA-A02O	COAD	TCGA	PSSSS	DEG_SPOP_SBC_1	81:85	Mutation blocking phosphorylation signal	0.7222
p.S87L	DO9226	COAD	ICGC	PSSSS	DEG_SPOP_SBC_1	81:85	Mutation blocking phosphorylation signal	0.7222
p.E282Q	TCGA-C8-A8HP	BRCA	TCGA	LTPPRS	DEG_SCF_FBW7_1	273:278	Mutation rewiring degron network	0.2222
p.E282Q	DO219621	BRCA	ICGC	LTPPRS	DEG_SCF_FBW7_1	273:278	Mutation rewiring degron network	0.2222
p.F269V	TCGA-CD-8527	STAD	TCGA	LTPPRS	DEG_SCF_FBW7_1	273:278	Mutation rewiring degron network	0.2222
p.F269V	DO47739	STAD	ICGC	LTPPRS	DEG_SCF_FBW7_1	273:278	Mutation rewiring degron network	0.2222
p.S84L	TCGA-JW-A5VL	CESC	TCGA	PSSSS	DEG_SPOP_SBC_1	81:85	Mutation altering degron motif	0.8778
p.S84L	DO49976	CESC	ICGC	PSSSS	DEG_SPOP_SBC_1	81:85	Mutation altering degron motif	0.8778
p.P283A	DO50443	ESAD	ICGC	LTPPRS	DEG_SCF_FBW7_1	273:278	Mutation rewiring degron network	0.1944
p.P73H	DO229019	LICA	ICGC	PSSSS	DEG_SPOP_SBC_1	81:85	Mutation rewiring degron network	0.1111
p.S93F	SIDM00596	Endometrial Carcinoma	GDSC	PSSSS	DEG_SPOP_SBC_1	81:85	Mutation rewiring degron network	0.1111
p.S93F	ACH-001517	Endometrial/Uterine Cancer	CCLE	PSSSS	DEG_SPOP_SBC_1	81:85	Mutation rewiring degron network	0.1111
p.S93F	HEC-1	endometrium	COSMIC	PSSSS	DEG_SPOP_SBC_1	81:85	Mutation rewiring degron network	0.1111
p.V288M	SIDM00867	Glioblastoma	GDSC	LTPPRS	DEG_SCF_FBW7_1	273:278	Mutation rewiring degron network	0.0556
p.V288M	ACH-000863	Brain Cancer	CCLE	LTPPRS	DEG_SCF_FBW7_1	273:278	Mutation rewiring degron network	0.0556
p.V288M	DBTRG-05MG	central nervous system	COSMIC	LTPPRS	DEG_SCF_FBW7_1	273:278	Mutation rewiring degron network	0.0556
p.D77N	SIDM01378	Ovarian Carcinoma	GDSC	PSSSS	DEG_SPOP_SBC_1	81:85	Mutation rewiring degron network	0.2222
p.D77N	ACH-000646	Ovarian Cancer	CCLE	PSSSS	DEG_SPOP_SBC_1	81:85	Mutation rewiring degron network	0.2222
p.G79S	ACH-001484	Leukemia	CCLE	PSSSS	DEG_SPOP_SBC_1	81:85	Mutation rewiring degron network	0.2778
p.G79S	ACH-001485	Leukemia	CCLE	PSSSS	DEG_SPOP_SBC_1	81:85	Mutation rewiring degron network	0.2778

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

NR1D1

UniProt ID: P20393

Entrez ID: 9572

Protein name: Nuclear receptor subfamily 1 group D member 1 (Rev-erbA-alpha) (V-erbA-related protein 1) (EAR-1)

External links: UniprotKB HGNC RefSeq COSMIC

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Kaplan plot for NR1D1 in