COP1

Summary

COP1 (COP1 E3 ubiquitin ligase, HGNC:17440) is a protein-coding gene on chromosome 1q25.1-q25.2, encoding E3 ubiquitin-protein ligase COP1 (Q8NHY2). E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins. It is a selective cancer dependency (DepMap: 22.8% of cell lines).

Enables ubiquitin protein ligase activity. Involved in positive regulation of proteasomal ubiquitin-dependent protein catabolic process; proteasome-mediated ubiquitin-dependent protein catabolic process; and response to ionizing radiation. Part of Cul4A-RING E3 ubiquitin ligase complex.

Source: NCBI Gene 64326 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 117 total — 1 pathogenic
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 22.8% of screened cell lines
• MANE Select transcript: NM_022457

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17440
Approved symbol	COP1
Name	COP1 E3 ubiquitin ligase
Location	1q25.1-q25.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10416, RNF200, FAP78, CFAP78
Ensembl gene	ENSG00000143207
Ensembl biotype	protein_coding
OMIM	608067
Entrez	64326

Gene structure

Transcript identifiers

Ensembl transcripts: 47 — 41 protein_coding, 4 nonsense_mediated_decay, 2 retained_intron

ENST00000308769, ENST00000367666, ENST00000367667, ENST00000367669, ENST00000459744, ENST00000461830, ENST00000474194, ENST00000482305, ENST00000491600, ENST00000498306, ENST00000649803, ENST00000896356, ENST00000896357, ENST00000896358, ENST00000896359, ENST00000896360, ENST00000896361, ENST00000896362, ENST00000896363, ENST00000896364, ENST00000896365, ENST00000896366, ENST00000896367, ENST00000896368, ENST00000896369, ENST00000896370, ENST00000896371, ENST00000896372, ENST00000896373, ENST00000896374, ENST00000896375, ENST00000896376, ENST00000896377, ENST00000896378, ENST00000935466, ENST00000935467, ENST00000935468, ENST00000935469, ENST00000935470, ENST00000935471, ENST00000942104, ENST00000942105, ENST00000942106, ENST00000942107, ENST00000942108, ENST00000942109, ENST00000942110

RefSeq mRNA: 3 — MANE Select: NM_022457 NM_001001740, NM_001286644, NM_022457

CCDS: CCDS30944, CCDS44279

Canonical transcript exons

ENST00000367669 — 20 exons

Exon	Start	End
ENSE00001908512	176206572	176207286
ENSE00002414167	176175910	176176007
ENSE00003476117	176027572	176027688
ENSE00003478585	176085776	176085890
ENSE00003484352	175947195	175947239
ENSE00003507573	175988288	175988412
ENSE00003513292	175986943	175987103
ENSE00003516380	176043710	176043818
ENSE00003517966	176046181	176046324
ENSE00003584865	176135010	176135086
ENSE00003594921	176043186	176043267
ENSE00003611488	175989362	175989479
ENSE00003615626	176116624	176116681
ENSE00003616094	175944831	175945170
ENSE00003640752	176149006	176149074
ENSE00003644363	176081152	176081287
ENSE00003651015	176184633	176184692
ENSE00003651496	176162869	176162988
ENSE00003662433	176163815	176163891
ENSE00003674821	176136488	176136547

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 95.97.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.8486 / max 590.6847, expressed in 1817 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
16012	17.6503	1805
16010	3.2841	1461
16009	1.9567	712
16011	0.9576	525

Top tissues by expression

259 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	95.97	gold quality
cortical plate	UBERON:0005343	95.61	gold quality
mucosa of transverse colon	UBERON:0004991	94.98	gold quality
embryo	UBERON:0000922	94.67	gold quality
ganglionic eminence	UBERON:0004023	94.67	gold quality
blood	UBERON:0000178	94.49	gold quality
ventricular zone	UBERON:0003053	94.41	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.86	gold quality
lower esophagus mucosa	UBERON:0035834	93.74	gold quality
leukocyte	CL:0000738	93.66	gold quality
monocyte	CL:0000576	93.61	gold quality
bone marrow cell	CL:0002092	93.57	gold quality
upper arm skin	UBERON:0004263	93.55	gold quality
colonic epithelium	UBERON:0000397	93.10	gold quality
rectum	UBERON:0001052	92.86	gold quality
right testis	UBERON:0004534	92.46	gold quality
granulocyte	CL:0000094	92.39	gold quality
calcaneal tendon	UBERON:0003701	92.24	gold quality
skin of leg	UBERON:0001511	92.01	gold quality
islet of Langerhans	UBERON:0000006	91.99	gold quality
nasal cavity epithelium	UBERON:0005384	91.99	gold quality
left testis	UBERON:0004533	91.80	gold quality
skin of abdomen	UBERON:0001416	91.79	gold quality
bone marrow	UBERON:0002371	91.64	gold quality
tonsil	UBERON:0002372	91.60	gold quality
testis	UBERON:0000473	91.56	gold quality
spleen	UBERON:0002106	91.52	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	91.35	gold quality
tendon	UBERON:0000043	91.31	gold quality
pancreatic ductal cell	CL:0002079	91.19	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.39

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
COP1	Repression
MMP1	Repression
PLAU	Repression

Upstream regulators (CollecTRI, top): CEBPA, COP1, CREB1, GATA2, JUN, KDM5D, MTA1, TP53

miRNA regulators (miRDB)

55 targeting COP1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-3158-5P	99.65	67.51	1763
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-186-3P	99.51	66.24	1685
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-942-5P	99.41	68.40	1977

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 22.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• DET1 promotes ubiquitination and degradation of c-Jun by assembling a multisubunit ubiquitin ligase containing DNA Damage Binding Protein-1 (DDB1), cullin 4A (CUL4A), Regulator of Cullins-1 (ROC1), and constitutively photomorphogenic-1 (PMID:14739464)
• The ubiquitin ligase COP1 is a critical negative regulator of p53 and transcriptionally inducible by p53. (PMID:15103385)
• tumour-suppressor protein p53 is a COP1-interacting protein; COP1 is a critical negative regulator of p53 (PMID:15103385)
• Results suggest that overexpression of COP1 contributes to the accelerated degradation of p53 protein in cancers and attenuates the tumor suppressor function of p53. (PMID:15492238)
• in response to DNA damage, ATM phosphorylated COP1 on Ser(387) and stimulated a rapid autodegradation mechanism; ionizing radiation triggered an ATM-dependent movement of COP1 from the nucleus to the cytoplasm (PMID:16931761)
• dynamic changes of the COP1/COP1D ratio provide an additional level of regulation of the half-life of the substrates of this E3 ligase under homeostatic or pathological conditions (PMID:17968316)
• COP1 binds FoxO1, enhances its ubiquitination, and promotes its degradation via the ubiquitin-proteasome pathway. (PMID:18815134)
• COP1 contributes to UVB-induced signaling in human keratinocytes (PMID:19741714)
• Disruption of the COP1-mediated proteolysis by ionizing radiation leads to MTA1 stabilization. (PMID:19805145)
• MDM2, MDMX, Pirh2 and COP1 might inhibit p53 activity synergistically in vivo. (PMID:20333547)
• Data define the subcellular localization and regulation of COP1 after DNA damage and provide a mechanistic explanation for the notion that 14-3-3sigma’s impact on the inhibition of p53 E3 ligases is an important step for p53 stabilization after DNA damage. (PMID:20843328)
• Increased COP1 is associated with hepatocellular carcinoma. (PMID:20959491)
• RFWD2 is associated with acute lung injury in mice (PMID:21297076)
• the ubiquitin ligase COP1 (also known as RFWD2) is a tumour suppressor that negatively regulates ETV1, ETV4 and ETV5; ETV1, which is mutated in prostate cancer more often, was degraded after being ubiquitinated by COP1 (PMID:21572435)
• data suggest that the CSN6-COP1 axis is involved in 14-3-3sigma degradation, and that deregulation of this axis will promote cell growth and tumorigenicity (PMID:21625211)
• High level of COP1 expression is associated with poor prognosis in primary gastric cancer. (PMID:23091414)
• Modulation of fatty acid synthase degradation by concerted action of p38 MAP kinase, E3 ligase COP1, and SH2-tyrosine phosphatase Shp2. (PMID:23269672)
• COP1 physically interacted with PTP1B and suppressed PTP1B phosphatase activity as well as the association of PTP1B with IRbeta. (PMID:23439647)
• while the role of COP1 in malignancies is controversial, our current data support that COP1 acts as a tumor suppressor in gastric cancer. (PMID:23933908)
• co-expressing COP1 and active GSK3beta blocked in vitro cell growth/migration and in vivo metastasis of invasive breast cancer cells. (PMID:24027432)
• Phosphorylation of the ETS1 and ETS2 transcriptional oncoproteins at specific serine or threonine residues creates binding sites for the COP1 tumor suppressor protein. (PMID:25117710)
• changes in the expression of fast-responding early genes is modulated by huCOP1 in keratinocytes upon UVB irradiation (PMID:25169772)
• TRIB2 associated-ubiquitin E3 ligases beta-transducin repeat-containing E3 ubiquitin protein ligase (beta-TrCP), COP1 and Smad ubiquitination regulatory factor 1 (Smurf1) reduced TCF4/beta-Catenin expression, and these effects could be enhanced by TRIB2. (PMID:25311538)
• COP1 negatively regulates ETV1 in patients with triple-negative breast cancer. (PMID:25884720)
• COP1 overexpression leads to the cytoplasmic distribution of p27, thereby accelerating p27 degradation. (PMID:25945542)
• COP1 directly interacts with p27 through a VP motif on p27 and functions as an E3 ligase of p27 to accelerate the ubiquitin-mediated degradation of p27. COP1-p27 axis deregulation is involved in tumorigenesis. (PMID:26254224)
• the present study revealed that COP1 plays an important role in CLL cell proliferation and tumorigenicity, and may be a useful indicator of the chronic lymphocytic leukemia processes. (PMID:26717976)
• COP1 expression was an independent predictor of overall survival. (PMID:26753957)
• Authors demonstrate that mtp53 prevents the COP1/DET1 complex from ubiquitinating ETS2 and thereby marking it for destruction. Authors show that mtp53 destabilizes DET1 and also disrupts the DET1/ETS2 complex thereby preventing ETS2 degradation. (PMID:26871468)
• the reduced expression of COP1 and the upregulated expression of ETV1 in RCC tissue samples, which was associated with a high tumor-node-metastasis stage of RCC. Furthermore, the overexpression of COP1 in the RCC ACHN cells inhibited the migration and invasion of ACHN cells, and downregulated ETV1 and MMP7 expression levels. (PMID:27278120)
• In conclusion, miR-214 functions as a tumor suppressor by regulating the RFWD2-p53 cascade, thus delivery of miR-214 analogs could be a potential adjunct therapy in breast cancer harboring wild type p53. (PMID:27422604)
• that COP1 may play a role in promoting glioma cell proliferation by interacting with and downregulating tumor suppressor p53 rather than oncogenic protein c-JUN (PMID:27534417)
• protein level changes lead to increased sensitivity toward cisplatin treatment, implicating that huCOP1 plays a positive role in maintaining genome integrity in human keratinocytes. (PMID:27995412)
• STK40 binds the COP1 WD40 domain using a VPD/E motif in its C-terminal tail. (PMID:28089446)
• COP1/DET1/ETS axis regulates ERK transcriptome and sensitivity to MAPK inhibitors. (PMID:29360641)
• COP1 forms complex with p53 protein and plays a role in p53 down-regulation. (PMID:29379285)
• COP1 regulates human breast cancer cell proliferation and apoptosis in a p53-dependent manner.The COP1-mediated degradation of p53 regulates cancer cell growth and apoptosis. (PMID:29516369)
• COP1 overexpression inhibits p53 expression induced by fludarabine and promotes ubiquitin-mediated p53 degradation in chronic lymphocytic leukemia cells. (PMID:30423551)
• COP1 role in the proteasomal degradation of ATGL in hepatocytes. (PMID:30926171)
• Palmitate induces COP1 expression in hepG2 cells. COP1 functioned as an E3 Ub-ligase of SIRT1, responsible for its proteasomal degradation under lipotoxic conditions. TRB3 recruited COP1 to SIRT1 to promote its ubiquitination.The TRB3-COP1-SIRT1 pathway played an important role in lipotoxicity leading to insulin resistance in hepatocytes. (PMID:31125554)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cop1	ENSDARG00000079329
mus_musculus	Cop1	ENSMUSG00000040782
rattus_norvegicus	Cop1	ENSRNOG00000042492

Paralogs (26): PAFAH1B1 (ENSG00000007168), SNRNP40 (ENSG00000060688), WDR62 (ENSG00000075702), WDR7 (ENSG00000091157), TBL2 (ENSG00000106638), PAK1IP1 (ENSG00000111845), WDR75 (ENSG00000115368), DCAF4 (ENSG00000119599), DAW1 (ENSG00000123977), TEP1 (ENSG00000129566), AHI1 (ENSG00000135541), WDR38 (ENSG00000136918), MAPKBP1 (ENSG00000137802), POC1B (ENSG00000139323), NEDD1 (ENSG00000139350), WDR17 (ENSG00000150627), WDR43 (ENSG00000163811), POC1A (ENSG00000164087), WDR88 (ENSG00000166359), WDR81 (ENSG00000167716), DCAF4L2 (ENSG00000176566), DCAF4L1 (ENSG00000182308), WDR27 (ENSG00000184465), NWD1 (ENSG00000188039), WDR5 (ENSG00000196363), WDR5B (ENSG00000196981)

Protein

Protein identifiers

E3 ubiquitin-protein ligase COP1 — Q8NHY2 (reviewed: Q8NHY2)

Alternative names: Constitutive photomorphogenesis protein 1 homolog, RING finger and WD repeat domain protein 2, RING finger protein 200, RING-type E3 ubiquitin transferase RFWD2

All UniProt accessions (8): Q8NHY2, A0A3B3ISQ9, E9PJB5, E9PMW8, H0Y339, H0Y340, H0YF49, X5DNY7

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Involved in JUN ubiquitination and degradation. Directly involved in p53 (TP53) ubiquitination and degradation, thereby abolishing p53-dependent transcription and apoptosis. Ubiquitinates p53 independently of MDM2 or RCHY1. Probably mediates E3 ubiquitin ligase activity by functioning as the essential RING domain subunit of larger E3 complexes. In contrast, it does not constitute the catalytic RING subunit in the DCX DET1-COP1 complex that negatively regulates JUN, the ubiquitin ligase activity being mediated by RBX1. Involved in 14-3-3 protein sigma/SFN ubiquitination and proteasomal degradation, leading to AKT activation and promotion of cell survival. Ubiquitinates MTA1 leading to its proteasomal degradation. Upon binding to TRIB1, ubiquitinates CEBPA, which lacks a canonical COP1-binding motif.

Subunit / interactions. Homodimer. Homodimerization is mediated by the coiled coil domain. Component of the DCX DET1-COP1 ubiquitin ligase complex at least composed of RBX1, DET1, DDB1, CUL4A and COP1. Isoform 2 does not interact with CUL4A but still binds to RBX1, suggesting that the interaction may be mediated by another cullin protein. Isoform 1 and isoform 2 interact with CUL5 but not with CUL1, CUL2 not CUL3. Interacts with bZIP transcription factors JUN, JUNB and JUND but not with FOS, ATF2 nor XBP1. Interacts with p53 (TP53). Interacts with COPS6; this interaction stabilizes RFWD2 through reducing its auto-ubiquitination and decelerating its turnover rate. Interacts with SFN; this interaction leads to SFN degradation. Isoform 4 forms heterodimers with isoform 1, preventing its association with DET1. Interacts with p53/TP53 and MTA1. Interacts with TRIB1 (via C-terminus) and TRIB2.

Subcellular location. Nucleus speckle. Cytoplasm.

Tissue specificity. Ubiquitously expressed at low level. Expressed at higher level in testis, placenta, skeletal muscle and heart.

Post-translational modifications. Autoubiquitinated. MTA1 destabilizes it by promoting its autoubiquitination.

Activity regulation. TRIB1 competes with substrates for RFWD2 binding.

Domain organisation. The RING finger domain, in addition to its role in ubiquitination, functions as a structural scaffold to bring two clusters of positive-charged residues within spatial proximity to mimic a bipartite nuclear localization signal (NLS). The WD40 domain (386-731) is necessary and sufficient for TRIB1 binding.

Induction. By p53/TP53.

Pathway. Protein modification; protein ubiquitination.

Miscellaneous. Unable to associate with other components of the CRL complex. Acts as a dominant-negative.

Similarity. Belongs to the COP1 family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q8NHY2-1	1	yes
Q8NHY2-2	2, delta24
Q8NHY2-3	3
Q8NHY2-4	4, COP1D
Q8NHY2-5	5, E

RefSeq proteins (3): NP_001001740, NP_001273573, NP_071902* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001680	WD40_rpt	Repeat
IPR001841	Znf_RING	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR017907	Znf_RING_CS	Conserved_site
IPR019775	WD40_repeat_CS	Conserved_site
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR042755	COP1	Family

Pfam: PF00400, PF13923

UniProt features (64 total): strand 29, repeat 7, mutagenesis site 7, splice variant 6, region of interest 3, short sequence motif 3, site 2, helix 2, turn 2, chain 1, coiled-coil region 1, zinc finger region 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
5HQG	X-RAY DIFFRACTION	2
9LTR	ELECTRON MICROSCOPY	3.03
9LU1	ELECTRON MICROSCOPY	3.62
9W90	ELECTRON MICROSCOPY	3.7
5IGQ	X-RAY DIFFRACTION	3.9
9M0Y	ELECTRON MICROSCOPY	4.25
9LUL	ELECTRON MICROSCOPY	4.99

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NHY2-F1	75.64	0.43

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 472 (interaction with trib1); 491 (interaction with trib1)

Mutagenesis-validated functional residues (7):

Position	Phenotype
111–113	abolishes localization to the nucleus.
136	abolishes p53 ubiquitination and degradation but not that of jun; when associated with a-139.
136	loss of sfn and mta1 ubiquitination and degradation; when associated with s-139. loss of stabilization by cops6; when as
139	abolishes p53 ubiquitination and degradation but not that of jun; when associated with a-136.
139	loss of sfn and mta1 ubiquitination and degradation; when associated with s-136. loss of stabilization by cops6; when as
156	loss of mta1 ubiquitination and degradation; when associated with s-159.
159	loss of mta1 ubiquitination and degradation; when associated with s-156.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-349425	Autodegradation of the E3 ubiquitin ligase COP1
R-HSA-8951664	Neddylation

MSigDB gene sets: 182 (showing top): GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_LIPID_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_LIPID_BIOSYNTHETIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_KETONE_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_FATTY_ACID_METABOLIC_PROCESS, GOBP_REGULATION_OF_LIPID_BIOSYNTHETIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_LIPID_METABOLIC_PROCESS, MILI_PSEUDOPODIA_HAPTOTAXIS_UP

GO Biological Process (6): ubiquitin-dependent protein catabolic process (GO:0006511), response to ionizing radiation (GO:0010212), protein ubiquitination (GO:0016567), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), negative regulation of fatty acid biosynthetic process (GO:0045717)

GO Molecular Function (6): ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (8): Golgi membrane (GO:0000139), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), nuclear speck (GO:0016607), Cul4A-RING E3 ubiquitin ligase complex (GO:0031464), nucleus (GO:0005634), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Stabilization of p53	1
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
protein ubiquitination	1
modification-dependent protein catabolic process	1
response to radiation	1
protein modification by small protein conjugation	1
regulation of proteasomal ubiquitin-dependent protein catabolic process	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
positive regulation of proteasomal protein catabolic process	1
positive regulation of ubiquitin-dependent protein catabolic process	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
fatty acid biosynthetic process	1
regulation of fatty acid biosynthetic process	1
negative regulation of fatty acid metabolic process	1
negative regulation of lipid biosynthetic process	1
ubiquitin-like protein transferase activity	1
transition metal ion binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
Golgi apparatus	1
bounding membrane of organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
nuclear ribonucleoprotein granule	1
Cul4-RING E3 ubiquitin ligase complex	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1361 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COP1	DET1	Q7L5Y6	850
COP1	FBXO40	Q9UH90	839
COP1	CORO2A	Q92828	750
COP1	DDB1	Q16531	729
COP1	ASTN2	O75129	722
COP1	CUL4A	Q13619	717
COP1	RIBC2	Q9H4K1	715
COP1	RBX1	P62877	710
COP1	NLGN1	Q8N2Q7	655
COP1	CNTN4	Q8IWV2	644
COP1	CDH9	Q9ULB4	630
COP1	UBE3A	P78355	619
COP1	NLGN3	Q9NZ94	603
COP1	NLGN4X	Q8N0W4	600
COP1	CDH10	Q9Y6N8	596

IntAct

110 interactions, top by confidence:

A	B	Type	Score
FOS	JUN	psi-mi:“MI:0914”(association)	0.980
FOSL2	JUN	psi-mi:“MI:0914”(association)	0.930
ATF6	ATF6	psi-mi:“MI:0914”(association)	0.790
SFN	TP53	psi-mi:“MI:0914”(association)	0.740
CUL4B	CUL4A	psi-mi:“MI:0914”(association)	0.730
PPP2R2D	YEATS4	psi-mi:“MI:0914”(association)	0.730
COP1	SFN	psi-mi:“MI:0915”(physical association)	0.720
SFN	COP1	psi-mi:“MI:0915”(physical association)	0.720
COP1	TP53	psi-mi:“MI:0914”(association)	0.720
TP53	COP1	psi-mi:“MI:0220”(ubiquitination reaction)	0.720
COP1	TP53	psi-mi:“MI:0915”(physical association)	0.720
TP53	COP1	psi-mi:“MI:0407”(direct interaction)	0.720
COP1	JUN	psi-mi:“MI:0915”(physical association)	0.710
FOSB	JUN	psi-mi:“MI:0914”(association)	0.690
SFN	COPS6	psi-mi:“MI:0915”(physical association)	0.650
CUL4A	COPS2	psi-mi:“MI:0914”(association)	0.640
TRIB1	DET1	psi-mi:“MI:0914”(association)	0.640
TRIB3	STK40	psi-mi:“MI:0914”(association)	0.640
ZNF397	ZNF213	psi-mi:“MI:0914”(association)	0.640
TRIB2	COP1	psi-mi:“MI:0403”(colocalization)	0.620
JUN	NFATC1	psi-mi:“MI:0914”(association)	0.610
ETV5	COP1	psi-mi:“MI:0915”(physical association)	0.600
COP1	ETV1	psi-mi:“MI:0915”(physical association)	0.560
ETS2	COP1	psi-mi:“MI:0915”(physical association)	0.560
COP1	DDB1	psi-mi:“MI:0914”(association)	0.530

BioGRID (866): RFWD2 (Affinity Capture-Western), RFWD2 (Affinity Capture-Western), RFWD2 (Affinity Capture-MS), RFWD2 (Affinity Capture-MS), RFWD2 (Affinity Capture-MS), RFWD2 (Affinity Capture-MS), RFWD2 (Affinity Capture-MS), RFWD2 (Affinity Capture-MS), RFWD2 (Affinity Capture-MS), RFWD2 (Affinity Capture-MS), RFWD2 (Affinity Capture-MS), RFWD2 (Affinity Capture-MS), RFWD2 (Affinity Capture-MS), CDKN1B (Co-fractionation), CDKN1B (Affinity Capture-Western)

ESM2 similar proteins: A2AKB9, A2RRH5, A2RRU4, A2SXS5, A6QM06, O60346, O88559, P30291, P97260, Q08BB3, Q0P5I0, Q12770, Q3B7L5, Q3MHH0, Q3UHE1, Q4R3J7, Q5E9I8, Q5FW06, Q5M9G8, Q5MNU5, Q5QP82, Q5R7H5, Q5T6F0, Q5VW00, Q5ZJL7, Q63ZP7, Q69Z89, Q6AX81, Q6GQT6, Q6NS60, Q6NWH1, Q6P809, Q6ZWB6, Q8AVS9, Q8BGW4, Q8BGZ3, Q8CHE4, Q8NHY2, Q8QZS3, Q8TEB1

Diamond homologs: A1CF18, A1CUD6, A1DP19, A2QP30, A4R3M4, A7EKM8, A7S338, A8NEG8, A9V790, B0LSW3, B0XM00, B2AEZ5, B2B766, B2VWG7, B3MEY6, B3NPW0, B3S4I5, B4GAJ1, B4HSL3, B4JWA1, B4KT48, B4LQ21, B4MY65, B4P6P9, B4QHG6, B5X3C4, B5X3Z6, B6GZD3, B6HP56, B6QC06, B6QC56, B7PS00, B8M0Q1, B8N9H4, B8P4B0, B8PD53, C0NRC6, C0S902, C1GB49, C3XVT5

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
MLF1	up-regulates	COP1
ATM	down-regulates	COP1	phosphorylation
COP1	“form complex”	“DCX DET1-COP1”	binding
Ub:E2	“up-regulates activity”	COP1	ubiquitination
COP1	“down-regulates quantity by destabilization”	ACACA	ubiquitination
COP1	“down-regulates quantity by destabilization”	ACACB	ubiquitination
TRIB3	“up-regulates activity”	COP1	binding
COP1	“down-regulates quantity by destabilization”	MTA1	polyubiquitination
MTA1	“down-regulates quantity by destabilization”	COP1	binding
COP1	“down-regulates quantity by destabilization”	COP1	polyubiquitination
COP1	“down-regulates quantity by destabilization”	CEBPB	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 112 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
NGF-stimulated transcription	6	25.6×	6e-05
DNA Damage Recognition in GG-NER	5	21.3×	9e-04
Formation of TC-NER Pre-Incision Complex	5	15.8×	3e-03
TP53 Regulates Transcription of DNA Repair Genes	5	13.5×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of miRNA transcription	5	14.5×	4e-03
transcription by RNA polymerase II	9	6.3×	2e-03
regulation of cell cycle	8	6.0×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

117 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	75
Likely benign	5
Benign	4

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
625613	GRCh37/hg19 1q24.2-25.3(chr1:169423492-180367623)	Pathogenic

SpliceAI

4872 predictions. Top by Δscore:

Variant	Effect	Δscore
1:175986936:AACTT:A	donor_loss	1.0000
1:175986937:ACTT:A	donor_loss	1.0000
1:175986938:CTT:C	donor_loss	1.0000
1:175986939:TTAC:T	donor_loss	1.0000
1:175986940:TAC:T	donor_loss	1.0000
1:175986941:A:AC	donor_gain	1.0000
1:175986941:AC:A	donor_gain	1.0000
1:175986941:ACC:A	donor_gain	1.0000
1:175986941:ACCC:A	donor_gain	1.0000
1:175986942:C:CA	donor_loss	1.0000
1:175986942:C:CC	donor_gain	1.0000
1:175986942:CC:C	donor_gain	1.0000
1:175986942:CCC:C	donor_gain	1.0000
1:175986942:CCCC:C	donor_gain	1.0000
1:175986942:CCCCA:C	donor_gain	1.0000
1:175987100:CTTC:C	acceptor_gain	1.0000
1:175987101:TTCC:T	acceptor_loss	1.0000
1:175987102:TCC:T	acceptor_loss	1.0000
1:175987104:CTGA:C	acceptor_loss	1.0000
1:175989360:A:AC	donor_gain	1.0000
1:175989361:C:CA	donor_gain	1.0000
1:175989361:CG:C	donor_gain	1.0000
1:175989387:CAAA:C	donor_gain	1.0000
1:175989475:GTGAT:G	acceptor_gain	1.0000
1:175989476:TGAT:T	acceptor_gain	1.0000
1:175989477:GAT:G	acceptor_gain	1.0000
1:175989478:ATC:A	acceptor_loss	1.0000
1:175989479:TCTA:T	acceptor_loss	1.0000
1:175989480:C:CC	acceptor_gain	1.0000
1:175989480:CTAA:C	acceptor_loss	1.0000

AlphaMissense

4836 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:175945166:A:G	L728P	1.000
1:175947205:C:A	G723V	1.000
1:175947205:C:T	G723D	1.000
1:175947206:C:A	G723C	1.000
1:175947206:C:G	G723R	1.000
1:175947206:C:T	G723S	1.000
1:175947213:G:C	N720K	1.000
1:175947213:G:T	N720K	1.000
1:175947214:T:A	N720I	1.000
1:175947217:G:A	A719V	1.000
1:175947217:G:T	A719D	1.000
1:175947218:C:G	A719P	1.000
1:175947220:G:T	A718D	1.000
1:175947221:C:G	A718P	1.000
1:175947226:A:G	L716P	1.000
1:175986963:A:G	W705R	1.000
1:175986963:A:T	W705R	1.000
1:175986968:A:T	V703E	1.000
1:175986971:G:T	A702D	1.000
1:175986972:C:G	A702P	1.000
1:175986973:A:C	S701R	1.000
1:175986973:A:T	S701R	1.000
1:175986974:C:A	S701I	1.000
1:175986974:C:T	S701N	1.000
1:175986975:T:A	S701C	1.000
1:175986975:T:G	S701R	1.000
1:175986977:A:T	V700D	1.000
1:175986978:C:A	V700F	1.000
1:175986979:A:C	F699L	1.000
1:175986979:A:T	F699L	1.000

dbSNP variants (sampled 300 via entrez): RS1000017122 (1:176090804 A>C), RS1000019723 (1:176053061 T>A), RS1000019936 (1:176050029 T>C), RS1000072284 (1:176086664 T>C), RS1000075685 (1:176171613 T>A,G), RS1000085523 (1:175972757 C>A), RS1000089411 (1:176097126 A>G), RS1000092133 (1:176092418 C>G,T), RS1000093784 (1:176136914 C>A), RS1000104656 (1:176008119 G>A), RS1000109312 (1:176062075 C>T), RS1000146410 (1:175965368 A>G), RS1000177953 (1:176108296 T>C), RS1000178831 (1:176009521 A>G), RS1000189622 (1:175976450 G>A,T)

Disease associations

OMIM: gene MIM:608067 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST004029_19	Angiotensin-converting enzyme inhibitor intolerance	6.000000e-07
GCST009306_22	Spatial processing	3.000000e-07
GCST012227_1167	Hip circumference adjusted for BMI	2.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005325	response to angiotensin-converting enzyme inhibitor
EFO:0008354	cognitive function measurement
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL5465335 (SINGLE PROTEIN), CHEMBL5483085 (PROTEIN-PROTEIN INTERACTION)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression	3
sodium arsenite	decreases expression, increases abundance, increases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
3,3’-dimethylbisphenol A	increases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
bisphenol Z	increases expression	1
bisphenol S	increases expression	1
Sunitinib	increases expression	1
Acetaminophen	decreases expression	1
Arsenic	decreases expression, increases abundance	1
Atrazine	decreases expression	1
Cadmium	increases abundance, increases expression	1
Ketoconazole	decreases expression	1
Valproic Acid	decreases methylation	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5379920	Binding	Inhibition of COP1 auto-ubiquitination in human HepG2 cells preincubated for 20 hrs followed by MG132 addition and measured after 4 hrs by immunoprecipitation method	Discovery and Development of Quinazolinones and Quinazolinediones for Ameliorating Nonalcoholic Fatty Liver Disease (NAFLD) by Modulating COP1-ATGL Axis. — J Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1P2	Abcam HeLa COP1 KO	Cancer cell line	Female
CVCL_D7MR	Ubigene A-549 COP1 KO	Cancer cell line	Male
CVCL_E0AR	Ubigene HeLa COP1 KO	Cancer cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.