COP1

UniProt ID: Q8NHY2
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

COP1 (also known as RFWD2; constitutive photomorphogenesis protein 1 homolog) is a RING-finger E3 ubiquitin-protein ligase (EC 2.3.2.27) that mediates ubiquitination and subsequent proteasomal degradation of substrate transcription factors and signaling proteins. Its domain architecture comprises an N-terminal C3HC4 RING-HC zinc finger (responsible for catalytic ubiquitin transfer and zinc binding), a central coiled-coil that mediates homodimerization, and a C-terminal seven-bladed WD40 beta-propeller that serves as the substrate-recognition module, binding short degron motifs in substrates. COP1 acts both as a stand-alone RING E3 and as the substrate-recognition subunit of a cullin-RING ligase (CRL4) module; in the DCX(DET1-COP1) complex (COP1, DET1, DDB1, CUL4A, RBX1) the catalytic RING is contributed by RBX1 while COP1 provides substrate recognition. Validated substrates include the AP-1 transcription factor c-Jun (JUN) and its relatives, the tumor suppressor p53 (TP53, with MTA1 co-regulation), the oncogenic ETS-family factors ETV1/ETV4/ETV5 and ETS1, the metastasis regulator MTA1, 14-3-3 sigma (SFN), C/EBPalpha (CEBPA, recruited via the pseudokinase adaptor TRIB1), and acetyl-CoA carboxylase 1 (ACACA). Substrate choice and ligase activity are regulated by the pseudokinase adaptors TRIB1/TRIB2, which bind the WD40 domain and compete with substrates. COP1 shuttles between nuclear speckles and the cytoplasm; ATM-dependent phosphorylation at Ser387 and 14-3-3 sigma binding drive its nuclear export and autoubiquitination upon DNA damage. Through degradation of these substrates, COP1 functions as a tumor suppressor in several contexts and contributes to control of lipogenesis. It autoubiquitinates and is stabilized by the COP9 signalosome subunit COPS6/CSN6.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic (IBA) transfer of the well-supported role of COP1 in targeting substrates for proteasomal degradation. This is directly experimentally established for COP1 (c-Jun, p53, MTA1, ETS factors, 14-3-3sigma), so the term is appropriate and core.
Reason: COP1 is an E3 ligase whose central function is to mediate ubiquitin-dependent proteasomal degradation of its substrates, demonstrated experimentally in multiple studies. The IBA annotation correctly captures this core biological process. The falcon deep research consolidates this across substrates, scoped correctly to the human protein.
Supporting Evidence:
PMID:14739464
Human De-etiolated-1 regulates c-Jun by assembling a CUL4A ubiquitin ligase.
file:human/COP1/COP1-deep-research-falcon.md
COP1 catalyzes the transfer of ubiquitin from E2 enzymes to specific substrate proteins, marking them for proteasomal degradation.
GO:0005737 cytoplasm
IEA
GO_REF:0000044 		KEEP AS NON CORE
Summary: Cytoplasmic localization derived from the UniProt subcellular location vocabulary. COP1 is documented to shuttle between nuclear speckles and the cytoplasm, so this localization is supported, though it is a general parent term.
Reason: Cytoplasmic localization is real (COP1 shuttles between nucleus and cytoplasm, and its nuclear export is regulated by 14-3-3 sigma after DNA damage), but the more informative location for its function is the nuclear speckle and the catalytic cytosol annotation; cytoplasm is a broad CC term retained as non-core.
GO:0016607 nuclear speck
IEA
GO_REF:0000044 		ACCEPT
Summary: Nuclear speckle localization from UniProt subcellular location mapping. COP1 forms nuclear speckles, supported by experimental characterization of the human protein, and this is a more specific and informative location than bare cytoplasm.
Reason: COP1 is documented to localize to nuclear speckles ("In the nucleus, it forms nuclear speckles"), consistent with its role in nuclear ubiquitination of transcription factors such as p53 and ETS factors. This is an accurate and informative CC term.
Supporting Evidence:
file:human/COP1/COP1-uniprot.txt
Nucleus speckle. Cytoplasm. Note=In the nucleus, it forms nuclear speckles.
GO:0061630 ubiquitin protein ligase activity
IEA
GO_REF:0000120 		ACCEPT
Summary: IEA assignment of ubiquitin protein ligase activity from InterPro/EC mapping (RING domain, EC 2.3.2.27). This is the core catalytic molecular function of COP1 and is independently supported by direct experimental evidence (EXP, IMP) in other annotations.
Reason: COP1 is a bona fide RING-finger E3 ubiquitin-protein ligase; the IEA inference from its RING domain and EC number is fully corroborated by experimental data. This is a core molecular function.
Supporting Evidence:
file:human/COP1/COP1-uniprot.txt
E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins.
GO:0005515 protein binding
IPI
PMID:20843328
Nuclear export regulation of COP1 by 14-3-3ฯƒ in response to ... 		MARK AS OVER ANNOTATED
Summary: Generic "protein binding" (GO:0005515) from an IntAct interaction with 14-3-3 sigma/SFN. The interaction is real (SFN binds phospho-Ser387 COP1 and drives its nuclear export), but the bare protein binding term is uninformative per curation guidelines.
Reason: GO:0005515 protein binding does not convey a specific molecular function. The underlying COP1-SFN interaction is captured more informatively elsewhere (SFN is both a COP1 substrate and a regulator of COP1 nuclear export); the catalytic ligase activity is the relevant MF.
GO:0005515 protein binding
IPI
PMID:21572435
COP1 is a tumour suppressor that causes degradation of ETS t... 		MARK AS OVER ANNOTATED
Summary: Generic "protein binding" from an IntAct interaction with ETV1, a substrate ETS transcription factor that COP1 ubiquitinates and degrades. The interaction is genuine but the bare term is uninformative. The COP1-ETV1 interaction reflects WD40-mediated degron recognition (VP/Val-Pro motif) rather than a non-specific binding event.
Reason: GO:0005515 is uninformative. The biologically meaningful relationship (COP1 recognizes and degrades ETV1/ETV4/ETV5) is better captured by the substrate-recognition and protein catabolic process annotations.
Supporting Evidence:
file:human/COP1/COP1-deep-research-falcon.md
Substrate selection is mediated by the WD40 domain, which recognizes a consensus VP (Val-Pro) degron motif present in many COP1 targets.
GO:0005515 protein binding
IPI
PMID:21625211
COP9 signalosome subunit 6 stabilizes COP1, which functions ... 		MARK AS OVER ANNOTATED
Summary: Generic "protein binding" from IntAct interactions reported in the COPS6/SFN study (interactors SFN and COPS6). COPS6/CSN6 binds and stabilizes COP1; SFN is a COP1 substrate. The interactions are real but the bare term is uninformative.
Reason: GO:0005515 protein binding conveys no specific function. The COP1-COPS6 and COP1-SFN interactions are better described by COP1's ligase activity (toward SFN) and its regulation/stabilization by the COP9 signalosome.
GO:0005515 protein binding
IPI
PMID:25117710
Phosphorylation of ETS1 by Src family kinases prevents its r... 		MARK AS OVER ANNOTATED
Summary: Generic "protein binding" from IntAct interactions with ETS1 and ETS2, substrate ETS transcription factors. COP1 recognizes a phospho-degron on ETS1 (blocked by Src-family kinase phosphorylation). Real interactions, uninformative term.
Reason: GO:0005515 is uninformative. The functional relationship (COP1 phospho-degron recognition and degradation of ETS1/ETS2) is captured by the substrate-recognition and catabolic process annotations.
GO:0005515 protein binding
IPI
PMID:26496610
A human interactome in three quantitative dimensions organiz... 		MARK AS OVER ANNOTATED
Summary: Generic "protein binding" from a high-throughput interactome study (interactor ETS2). Uninformative term derived from a proteome-scale screen.
Reason: GO:0005515 from a large-scale interactome screen does not convey a specific molecular function and provides no functional insight beyond what is already captured.
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		MARK AS OVER ANNOTATED
Summary: Generic "protein binding" from a high-throughput interactome study (interactors ETV5 and ETV1, both substrate ETS factors). Uninformative term.
Reason: GO:0005515 is uninformative. The ETV1/ETV5 interactions reflect COP1 substrate recognition, already captured by the catabolic-process and substrate-recognition annotations.
GO:0005515 protein binding
IPI
PMID:35140242
Human transcription factor protein interaction networks. 		MARK AS OVER ANNOTATED
Summary: Generic "protein binding" from a transcription-factor interaction network study (interactor ETV5, a substrate ETS factor). Uninformative term.
Reason: GO:0005515 conveys no specific molecular function; the ETV5 interaction reflects substrate recognition already captured elsewhere.
GO:0000139 Golgi membrane
IEA
GO_REF:0000107 		REMOVE
Summary: Golgi membrane localization transferred by Ensembl Compara from a rat ortholog. This is not supported by the human COP1 literature, which describes nuclear-speckle and cytoplasmic/cytosolic localization. Likely an erroneous ortholog transfer.
Reason: There is no experimental support in human (or convincing functional rationale) for COP1 acting at the Golgi membrane. The annotation derives solely from automatic transfer (GO_REF:0000107) from a rat protein and conflicts with the well-documented nuclear/cytoplasmic localization of COP1.
GO:0016567 protein ubiquitination
IEA
GO_REF:0000041 		ACCEPT
Summary: Protein ubiquitination assigned via UniPathway mapping. This is the core biological process catalyzed by COP1 as a RING E3 ligase and is well supported experimentally.
Reason: COP1 directly mediates ubiquitination of multiple substrates (JUN, p53, MTA1, SFN, ETS factors, ACC1); protein ubiquitination is a core BP for this gene.
Supporting Evidence:
file:human/COP1/COP1-uniprot.txt
PATHWAY: Protein modification; protein ubiquitination.
GO:0061630 ubiquitin protein ligase activity
EXP
PMID:12615916
Characterization of human constitutive photomorphogenesis pr... 		ACCEPT
Summary: Experimental (EXP) demonstration that the COP1 RING domain has ubiquitin ligase activity in an in vitro autoubiquitination assay. This is the strongest evidence for the core catalytic molecular function of COP1.
Reason: Direct in vitro demonstration of RING-dependent ubiquitin ligase activity firmly establishes GO:0061630 as a core molecular function of COP1.
Supporting Evidence:
PMID:12615916
The RING domain of huCOP1 displays ubiquitin ligase activity in an autoubiquitination assay in vitro
GO:0005737 cytoplasm
IC
PMID:39920308
Mutations in the kinesin KIF12 promote MASH in humans and mi... 		ACCEPT
Summary: Curator-inferred (IC) "is_active_in cytoplasm", from the KIF12/ACC1 study where COP1 ubiquitinates the cytoplasmic enzyme acetyl-CoA carboxylase 1. The is_active_in qualifier appropriately marks the cytoplasm as a site of COP1 catalytic activity.
Reason: COP1 acts in the cytoplasm to ubiquitinate cytoplasmic substrates such as ACC1; the is_active_in qualifier captures functional cytoplasmic activity, which is more meaningful than the bare located_in cytoplasm annotation.
Supporting Evidence:
PMID:39920308
lipogenic enzyme turnover
GO:0006511 ubiquitin-dependent protein catabolic process
IMP
PMID:39920308
Mutations in the kinesin KIF12 promote MASH in humans and mi... 		ACCEPT
Summary: IMP evidence that COP1 drives ubiquitin-dependent turnover of the lipogenic enzyme ACC1/ACACA. Supports COP1's core role in ubiquitin-dependent protein catabolism.
Reason: COP1 mediates ubiquitin-dependent degradation of ACC1 (and many other substrates); this is a core biological process. The more specific proteasome-mediated term is also annotated and preferred for the core synthesis, but this parent term is correct.
Supporting Evidence:
PMID:39920308
lipogenic enzyme turnover
GO:0045717 negative regulation of fatty acid biosynthetic process
IMP
PMID:39920308
Mutations in the kinesin KIF12 promote MASH in humans and mi... 		KEEP AS NON CORE
Summary: IMP evidence that COP1-mediated degradation of acetyl-CoA carboxylase 1 (ACC1), enhanced by KIF12, suppresses lipogenesis; loss promotes MASH/steatohepatitis. This is a downstream physiological consequence of COP1's catalytic activity.
Reason: The link between COP1 and fatty acid biosynthesis is genuine but is a tissue-/ substrate-specific physiological outcome (ACC1 turnover in liver) rather than the core molecular/biological role of COP1, which is general substrate ubiquitination and degradation. Retained as a non-core process annotation.
Supporting Evidence:
PMID:39920308
lipogenic enzyme turnover
GO:0004842 ubiquitin-protein transferase activity
TAS
Reactome:R-HSA-264444 		ACCEPT
Summary: TAS (Reactome) assignment of ubiquitin-protein transferase activity, capturing COP1 autoubiquitination. This is a correct molecular-function term for COP1's E3 ligase activity (a parent/sibling of GO:0061630).
Reason: COP1's catalytic activity (EC 2.3.2.27) is ubiquitin-protein transferase activity; the term is accurate and supported by Reactome's modeling of COP1 autoubiquitination and by experimental data.
Supporting Evidence:
file:human/COP1/COP1-uniprot.txt
EC=2.3.2.27
GO:0005515 protein binding
IPI
PMID:14739464
Human De-etiolated-1 regulates c-Jun by assembling a CUL4A u... 		MARK AS OVER ANNOTATED
Summary: Generic "protein binding" from the DET1/CUL4A study (interactor DET1, UniProtKB Q7L5Y6). COP1 is a component of the DCX(DET1-COP1) complex; the DET1 interaction is real but the bare term is uninformative.
Reason: GO:0005515 conveys no specific function. The COP1-DET1 interaction is captured by the Cul4A-RING E3 ligase complex membership annotation, which is far more informative.
GO:0031464 Cul4A-RING E3 ubiquitin ligase complex
IDA
PMID:14739464
Human De-etiolated-1 regulates c-Jun by assembling a CUL4A u... 		ACCEPT
Summary: IDA evidence that COP1 is a component of the DCX(DET1-COP1) CUL4A-based E3 ligase complex (with DET1, DDB1, CUL4A, RBX1) that ubiquitinates c-Jun. Well-supported complex membership and a core cellular component for COP1's adaptor function.
Reason: COP1 is directly demonstrated to assemble into a CUL4A-RING ligase complex, where it serves as the substrate-recognition subunit. This is an accurate and informative CC annotation central to COP1 biology.
Supporting Evidence:
PMID:14739464
Human De-etiolated-1 regulates c-Jun by assembling a CUL4A ubiquitin ligase.
GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process
IMP
PMID:14739464
Human De-etiolated-1 regulates c-Jun by assembling a CUL4A u... 		ACCEPT
Summary: IMP evidence that the DET1-COP1 complex drives c-Jun ubiquitination and proteasomal degradation. Directly supports COP1's core role in proteasome-mediated protein catabolism.
Reason: Experimentally demonstrated that COP1 (within the CUL4A complex) targets c-Jun for proteasomal degradation; this is a core biological process for COP1.
Supporting Evidence:
PMID:14739464
Human De-etiolated-1 regulates c-Jun by assembling a CUL4A ubiquitin ligase.
GO:0005515 protein binding
IPI
PMID:19805145
E3 ubiquitin ligase COP1 regulates the stability and functio... 		MARK AS OVER ANNOTATED
Summary: Generic "protein binding" from the MTA1 study (interactor MTA1, UniProtKB Q13330), a COP1 substrate. The interaction is real but the bare term is uninformative.
Reason: GO:0005515 is uninformative. The COP1-MTA1 interaction (COP1 ubiquitinates MTA1; MTA1 reciprocally promotes COP1 autoubiquitination) is captured by the catalytic and regulatory annotations.
GO:0010212 response to ionizing radiation
IDA
PMID:19805145
E3 ubiquitin ligase COP1 regulates the stability and functio... 		KEEP AS NON CORE
Summary: IDA evidence that ionizing radiation modulates COP1-mediated MTA1 proteolysis (radiation stabilizes MTA1 by disrupting COP1 function). This is a contextual/stimulus response rather than a core function of COP1.
Reason: COP1's involvement in the ionizing-radiation/DNA-damage response (via MTA1 and p53 regulation) is a real but context-specific physiological role, not the core ligase function. Retained as a non-core process annotation.
GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process
IMP
PMID:19805145
E3 ubiquitin ligase COP1 regulates the stability and functio... 		ACCEPT
Summary: IMP evidence that COP1 promotes proteasomal degradation of MTA1 (and itself via autoubiquitination). Captures COP1's positive role in proteasomal protein catabolism.
Reason: As an E3 ligase, COP1 positively drives proteasomal degradation of its substrates; this is well supported and consistent with its core function.
Supporting Evidence:
PMID:19805145
E3 ubiquitin ligase COP1 regulates the stability and functions of MTA1.
GO:0061630 ubiquitin protein ligase activity
IMP
PMID:19805145
E3 ubiquitin ligase COP1 regulates the stability and functio... 		ACCEPT
Summary: IMP evidence for COP1 ubiquitin protein ligase activity toward MTA1, with RING mutants (C156S/C159S, C136S/C139S) abolishing MTA1 ubiquitination. Reinforces the core catalytic MF.
Reason: Mutagenesis-supported demonstration of RING-dependent ubiquitin ligase activity toward a substrate firmly supports GO:0061630 as a core molecular function.
Supporting Evidence:
PMID:19805145
E3 ubiquitin ligase COP1 regulates the stability and functions of MTA1.
GO:0005829 cytosol
TAS
Reactome:R-HSA-264418 		KEEP AS NON CORE
Summary: Cytosol localization from Reactome (TAS), modeling COP1 nucleus-to-cytoplasm translocation. Consistent with the documented cytoplasmic pool of COP1.
Reason: Cytosolic localization is supported and COP1 acts in the cytoplasm on substrates like ACC1, but cytosol is a general location captured non-core; the nuclear speckle and CUL4A complex annotations are more functionally informative.
GO:0005829 cytosol
TAS
Reactome:R-HSA-264444 		KEEP AS NON CORE
Summary: Cytosol localization from Reactome (TAS), modeling COP1 autoubiquitination of phospho-COP1(Ser387). Consistent with the cytoplasmic pool of COP1.
Reason: Supported general cytosolic localization; retained as non-core in favor of the more informative nuclear speckle and complex-membership annotations.
GO:0005829 cytosol
TAS
Reactome:R-HSA-264458 		KEEP AS NON CORE
Summary: Cytosol localization from Reactome (TAS), modeling proteasome-mediated degradation of COP1. Consistent with the cytoplasmic pool of COP1.
Reason: Supported general cytosolic localization; retained as non-core in favor of more functionally informative location annotations.
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-264418 		KEEP AS NON CORE
Summary: Nucleoplasm localization from Reactome (TAS), modeling COP1 nuclear-to-cytoplasmic translocation. Consistent with COP1's documented nuclear pool and nuclear-speckle localization.
Reason: COP1 is present in the nucleus; nucleoplasm is supported but is a general location. The nuclear speck annotation is the more specific and informative CC term for COP1.
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-264435 		KEEP AS NON CORE
Summary: Nucleoplasm localization from Reactome (TAS), modeling dissociation of the COP1-p53 complex. Consistent with COP1's nuclear pool where it regulates p53.
Reason: Supported nuclear localization; nucleoplasm is a general location retained as non-core, with nuclear speck preferred as the specific informative term.
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-349444 		KEEP AS NON CORE
Summary: Nucleoplasm localization from Reactome (TAS), modeling ATM phosphorylation of COP1 at Ser387 in the nucleus following DNA damage. Consistent with COP1's nuclear pool.
Reason: Supported nuclear localization; nucleoplasm is general and retained as non-core, with nuclear speck preferred as the specific informative term.
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-8952638 		KEEP AS NON CORE
Summary: Nucleoplasm localization from Reactome (TAS) within the CRL4 neddylation cycle (NEDD8 transfer to the CRL4 complex). Consistent with COP1's nuclear CRL4-associated pool.
Reason: Supported nuclear localization as part of the CRL4 complex; nucleoplasm is a general CC term retained as non-core, with nuclear speck preferred.
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-8952639 		KEEP AS NON CORE
Summary: Nucleoplasm localization from Reactome (TAS) within the CRL4 neddylation cycle (NEDD8:UBE2M binding the CRL4 complex). Consistent with COP1's nuclear CRL4 pool.
Reason: Supported nuclear localization as part of the CRL4 complex; nucleoplasm is general and retained as non-core, with nuclear speck preferred.
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-8955245 		KEEP AS NON CORE
Summary: Nucleoplasm localization from Reactome (TAS) within the CRL4 regulatory cycle (CAND1 binding the nuclear CRL4 complex). Consistent with COP1's nuclear CRL4 pool.
Reason: Supported nuclear localization as part of the CRL4 complex; nucleoplasm is general and retained as non-core, with nuclear speck preferred.
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-8955285 		KEEP AS NON CORE
Summary: Nucleoplasm localization from Reactome (TAS) within the CRL4 regulatory cycle (COMMDs displacing CAND1 from the CRL4 complex). Consistent with COP1's nuclear CRL4 pool.
Reason: Supported nuclear localization as part of the CRL4 complex; nucleoplasm is general and retained as non-core, with nuclear speck preferred.
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-8956045 		KEEP AS NON CORE
Summary: Nucleoplasm localization from Reactome (TAS) within the CRL4 regulatory cycle (COP9 signalosome deneddylation of the nuclear CRL4 complex). Consistent with COP1's nuclear CRL4 pool.
Reason: Supported nuclear localization as part of the CRL4 complex; nucleoplasm is general and retained as non-core, with nuclear speck preferred.

Core Functions

RING-type E3 ubiquitin-protein ligase activity. COP1 transfers ubiquitin from an E2 conjugating enzyme to substrate lysines (EC 2.3.2.27), either as a stand-alone RING ligase or as part of a CUL4A-based cullin-RING ligase, driving substrate ubiquitination.

Molecular Function:
ubiquitin protein ligase activity
Directly Involved In:
protein ubiquitination
Cellular Locations:
nuclear speck cytosol
Supporting Evidence:
  • PMID:12615916
    The RING domain of huCOP1 displays ubiquitin ligase activity in an autoubiquitination assay in vitro

Substrate-recognition adaptor of a CUL4A-RING ubiquitin ligase. Via its C-terminal WD40 beta-propeller, COP1 binds degron motifs in substrate transcription factors and signaling proteins and recruits them to the DCX(DET1-COP1) CUL4A ligase for ubiquitination and proteasomal degradation; substrate selection is regulated by the pseudokinase adaptors TRIB1/TRIB2.

Molecular Function:
ubiquitin-like ligase-substrate adaptor activity
Directly Involved In:
proteasome-mediated ubiquitin-dependent protein catabolic process positive regulation of proteasomal ubiquitin-dependent protein catabolic process
Cellular Locations:
nuclear speck
In Complex:
Cul4A-RING E3 ubiquitin ligase complex
Substrates:
JUN TP53 ETV1 SFN
Supporting Evidence:
  • PMID:14739464
    Human De-etiolated-1 regulates c-Jun by assembling a CUL4A ubiquitin ligase.
  • PMID:21572435
    COP1 is a tumour suppressor that causes degradation of ETS transcription factors.
  • file:human/COP1/COP1-deep-research-falcon.md
    Substrate selection is mediated by the WD40 domain, which recognizes a consensus VP (Val-Pro) degron motif present in many COP1 targets.

References

GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000041
Gene Ontology annotation based on UniPathway vocabulary mapping
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:12615916
Characterization of human constitutive photomorphogenesis protein 1, a RING finger ubiquitin ligase that interacts with Jun transcription factors and modulates their transcriptional activity.
PMID:14739464
Human De-etiolated-1 regulates c-Jun by assembling a CUL4A ubiquitin ligase.
PMID:19805145
E3 ubiquitin ligase COP1 regulates the stability and functions of MTA1.
PMID:20843328
Nuclear export regulation of COP1 by 14-3-3ฯƒ in response to DNA damage.
PMID:21572435
COP1 is a tumour suppressor that causes degradation of ETS transcription factors.
PMID:21625211
COP9 signalosome subunit 6 stabilizes COP1, which functions as an E3 ubiquitin ligase for 14-3-3ฯƒ.
PMID:25117710
Phosphorylation of ETS1 by Src family kinases prevents its recognition by the COP1 tumor suppressor.
PMID:26496610
A human interactome in three quantitative dimensions organized by stoichiometries and abundances.
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
PMID:35140242
Human transcription factor protein interaction networks.
PMID:39920308
Mutations in the kinesin KIF12 promote MASH in humans and mice by disrupting lipogenic enzyme turnover.
Reactome:R-HSA-264418
Translocation of COP1 from the nucleus to the cytoplasm
Reactome:R-HSA-264435
Dissociation of the COP1-p53 complex
Reactome:R-HSA-264444
Autoubiquitination of phospho-COP1(Ser-387 )
Reactome:R-HSA-264458
Proteasome mediated degradation of COP1
Reactome:R-HSA-349444
Phosphorylation of COP1 at Ser-387 by ATM
Reactome:R-HSA-8952638
AcM-UBE2M transfers NEDD8 to CRL4 E3 ubiquitin ligase complex
Reactome:R-HSA-8952639
NEDD8:AcM-UBE2M binds CRL4 E3 ubiquitin ligase complex
Reactome:R-HSA-8955245
CAND1 binds CRL4 E3 ubiquitin ligase in the nucleus
Reactome:R-HSA-8955285
COMMDs displace CAND1 from CRL4 E3 ubiquitin ligase complex
Reactome:R-HSA-8956045
COP9 signalosome deneddylates nuclear CRL4 E3 ubiquitin ligase complex
file:human/COP1/COP1-deep-research-falcon.md
Falcon deep research report for COP1

Suggested Questions for Experts

Q: Does COP1 possess intrinsic, stand-alone E3 ligase activity toward all of its reported substrates, or is its physiological activity primarily channeled through the CUL4A-RING (DCX DET1-COP1) module in which RBX1 is the catalytic RING?

Q: How is COP1 substrate choice partitioned in vivo between its canonical WD40 degron binding and the TRIB1/TRIB2-mediated recruitment of non-canonical substrates such as C/EBPalpha?

Q: Which COP1 substrates are physiologically dominant in specific tissues (e.g., ETS factors in prostate, ACC1 in liver, c-Jun/p53 broadly), and does this explain its context-dependent tumor-suppressor versus other roles?

Suggested Experiments

Experiment: Define the COP1 ubiquitinome in cells with degron-binding-deficient WD40 mutants versus RING-catalytic mutants (e.g., quantitative diGly/ubiquitin-remnant proteomics) to separate substrate-recognition from catalytic contributions.

Experiment: Reconstitute the DCX(DET1-COP1) CUL4A-RBX1 complex in vitro and compare ubiquitination kinetics of c-Jun, p53, ETV1, SFN and ACC1 with and without TRIB1/TRIB2 to map the rules of substrate selectivity and adaptor competition.

Experiment: Use structure-guided degron mutagenesis of individual substrates (and the COP1 WD40 pocket) combined with cellular stability assays to validate which proteins are direct COP1 substrates versus indirect.

Deep Research

Falcon

(COP1-deep-research-falcon.md)
Research Report: Functional Annotation of Human COP1 (RFWD2, UniProt Q8NHY2) Falcon Edison Scientific Literature 33 citations 1 artifacts 2026-06-20T07:06:59.455157
Edison artifact artifact-00 (text/markdown)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research Report: Functional Annotation of Human COP1 (RFWD2, UniProt Q8NHY2)

1. Key Concepts and Definitions

COP1 (Constitutive Photomorphogenesis Protein 1, gene symbol COP1, also known as RFWD2) is a highly conserved E3 ubiquitin-protein ligase in Homo sapiens (UniProt Q8NHY2). It has a verified structure featuring four major domains: an N-terminal glycine/serine-rich domain, a RING finger domain (crucial for E2 enzyme binding), a central coiled-coil domain (required for dimerization and oligomerization), and a C-terminal WD40-repeat domain (responsible for substrate recognition and binding, especially through Val-Pro motifs) (wang2026cryoemstructureof pages 1-2, wang2026cryoemstructureof pages 2-3, wang2026cryoemstructureof pages 4-5).

COP1 catalyzes the transfer of ubiquitin from E2 enzymes to specific substrate proteins, marking them for proteasomal degradation. It can act as a standalone E3 ligase, but more commonly operates as the substrate receptor in the CRL4 E3 ubiquitin ligase complex (CRL4COP1/DET1), which includes CUL4, DDB1, DET1, DDA1, RBX1, and associated E2 enzymes (wang2026cryoemstructureof pages 1-2, wang2026cryoemstructureof pages 2-3).

2. Molecular Function, Substrate Specificity, and Structure

COP1's E3 ligase activity is exerted through the RING finger domain, which recruits E2 ubiquitin-conjugating enzymes. Substrate selection is mediated by the WD40 domain, which recognizes a consensus VP (Val-Pro) degron motif present in many COP1 targets. COP1 also features two nuclear localization signals flanking the RING domain, supporting its functions within the nucleus (wang2026cryoemstructureof pages 1-2, wang2026cryoemstructureof pages 2-3).

Cryo-EM structures (Wang et al. 2026) have detailed the assembly of human COP1 within CUL4-based ligase complexes, highlighting conformational changes upon substrate engagement and identifying the dynamic states regulating substrate access (wang2026cryoemstructureof pages 1-2, wang2026cryoemstructureof pages 2-3, wang2026cryoemstructureof pages 4-5).

3. Subcellular Localization and Mechanism of Action

COP1 predominantly localizes to both the nucleus and cytoplasm, but at baseline is highly enriched at the nuclear envelope via interactions with the nuclear pore complex component TPR. In response to MAPK/ERK signaling inactivation, COP1 is rapidly released from the nuclear envelope into the nucleoplasm, where it mediates the degradation of nuclear protein substrates, such as transcription factors (ouyang2020erk12inactivationpromotes pages 1-3).

4. Substrate Spectrum and Biological Processes

A comprehensive substrate table, summarizing human COP1 targets, their biological roles, and supporting citations, is included below:
| Substrate name | Substrate type/function | Biological process regulated by COP1-mediated turnover | Evidence source (citation information) | Year |
|---|---|---|---|---|
| p53 (TP53) | Tumor suppressor transcription factor | Stress responses, cell-cycle arrest, apoptosis, tumor suppression; COP1-mediated ubiquitination/degradation reduces p53 stability | First mammalian COP1 substrate discussed in structural review; p53 described as a COP1 target whose disruption stabilizes p53 (wang2026cryoemstructureof pages 2-3, hu2023structuralbasisof pages 1-3, grigoreva2024p53themultifaceted pages 1-2) | 2023, 2024, 2026 |
| c-JUN | AP-1 family transcription factor | Cell proliferation, differentiation, survival; rapidly degraded after ERK1/2 inactivation via COP1 | CRL4^COP1/DET1 and COP1-dependent c-JUN degradation described in mechanistic and structural studies (wang2026cryoemstructureof pages 2-3, ouyang2020erk12inactivationpromotes pages 1-3) | 2020, 2026 |
| ETV1 | ETS family transcription factor | Developmental and oncogenic transcriptional programs; COP1 promotes degradation | Listed among established COP1 substrates in mammalian cells (ndoja2020ubiquitinligasecop1 pages 1-3, wang2026cryoemstructureof pages 2-3) | 2020, 2026 |
| ETV4 | ETS family transcription factor | Mitogen-responsive transcription, proliferation, cancer-associated programs; COP1-dependent degradation, especially after ERK1/2 inactivation | Listed as CRL4^COP1/DET1 substrate and experimentally restored by COP1 knockdown (ndoja2020ubiquitinligasecop1 pages 1-3, ouyang2020erk12inactivationpromotes pages 1-3) | 2020 |
| ETV5 | ETS family transcription factor | Mitogen-responsive transcription, proliferation, cancer-associated programs; COP1-dependent degradation | Listed as CRL4^COP1/DET1 substrate and experimentally restored by COP1 knockdown (ndoja2020ubiquitinligasecop1 pages 1-3, ouyang2020erk12inactivationpromotes pages 1-3) | 2020 |
| ETS1 | ETS family transcription factor | Immune/developmental transcription programs and oncogenic signaling; COP1-mediated turnover | Named among COP1 substrates in review/mechanistic discussion (ndoja2020ubiquitinligasecop1 pages 1-3, ducker2021ubiquitinmediatedcontrolof pages 1-2) | 2020, 2021 |
| ETS2 | ETS family transcription factor | Developmental signaling and oncogenic transcriptional regulation; recognized by COP1 WD40 substrate-binding interface | Named among COP1 substrates and used as substrate in structural work (ndoja2020ubiquitinligasecop1 pages 1-3, wang2026cryoemstructureof pages 1-2, wang2026cryoemstructureof pages 2-3) | 2020, 2026 |
| c/EBPฮฒ (CEBPB) | CCAAT/enhancer-binding transcription factor | Microglial inflammatory state, neuroinflammation, complement-dependent neurotoxicity; COP1 suppresses its accumulation | Direct biochemical and functional evidence showing COP1 promotes proteasomal degradation of c/EBPฮฒ (ndoja2020ubiquitinligasecop1 pages 1-3, ndoja2020ubiquitinligasecop1 pages 3-4) | 2020 |
| c/EBPฮฑ (CEBPA) | CCAAT/enhancer-binding transcription factor | Myeloid differentiation and growth control; known COP1 substrate via adaptor-mediated recruitment | Listed as established COP1 substrate in mammalian cells (ndoja2020ubiquitinligasecop1 pages 1-3, wang2026cryoemstructureof pages 4-5) | 2020, 2026 |
| UTX (KDM6A) | H3K27me2/3 histone demethylase; tumor suppressor | Chromatin regulation and colorectal tumor suppression; COP1-containing CRL4 complex promotes degradation, lowering UTX and favoring CRC progression | CRC study identifies CUL4B-DDB1-COP1 as functional E3 ligase for UTX degradation (luo2023cul4bddb1cop1mediatedutxdownregulation pages 1-2) | 2023 |
| P57Kip2 (CDKN1C) | Cyclin-dependent kinase inhibitor | Trophoblast cell-cycle exit and syncytiotrophoblast fusion; COP1-mediated degradation inhibits trophoblast fusion | STK40-dependent recruitment to COP1 reported in placental/trophoblast study (wang2026cryoemstructureof pages 1-2) | 2024 |
| ACSL4 | Acyl-CoA synthetase involved in lipid metabolism and ferroptosis sensitivity | Ferroptosis control in renal cell carcinoma; COP1-mediated K48-linked ubiquitination reduces ACSL4 and suppresses ferroptosis | RCC study identifies ACSL4 as direct COP1 substrate (wang2026cryoemstructureof pages 1-2) | 2025 |
| LUZP1 | Leucine zipper protein 1; cytoskeletal/signaling-associated protein | Colorectal cancer liver metastasis and oxaliplatin resistance; COP1-mediated degradation activates downstream MYL9 phosphorylation and EMT/JAK2-STAT3 signaling | Multi-omics organoid study identifies COP1-LUZP1 axis (wang2026cryoemstructureof pages 1-2) | 2026 |
| c/EBP family/Tribbles-recruited substrates (general) | Transcription factors recruited by pseudokinase adaptors such as STK40/TRIB proteins | Signal-dependent repression of differentiation or inflammatory programs through adaptor-assisted COP1 targeting | Structural and functional studies indicate COP1 substrate recognition via WD40 domain and adaptor-assisted recruitment (wang2026cryoemstructureof pages 2-3, ndoja2020ubiquitinligasecop1 pages 3-4, wang2026cryoemstructureof pages 4-5) | 2020, 2026 |

Table: This table summarizes human COP1/RFWD2 substrates identified or discussed in the collected literature, including their functions and the biological processes affected by COP1-mediated degradation. It is useful for organizing the functional annotation of COP1 around its substrate repertoire and pathway roles.

COP1 regulates a spectrum of substrates that control critical processes, including:
- Tumor suppression and cell cycle regulation: p53 (TP53), P57Kip2, UTX (KDM6A).
- Transcriptional programs and oncogenesis: c-Jun (AP-1), ETS family (ETV1, ETV4, ETV5, ETS1, ETS2), c/EBPฮฑ, c/EBPฮฒ.
- Metabolism and stress responses: ACSL4 (ferroptosis, lipid metabolism), LUZP1 (EMT, chemoresistance), CDH18 (PI3K/AKT pathway).

COP1 often acts as a signal transducer, quickly converting extracellular signals (such as MAPK/ERK inactivation and DNA damage) into rapid changes in substrate stability. For example, DNA damage inactivates COP1 via ATM-mediated phosphorylation and subsequent autoubiquitination (wang2026cryoemstructureof pages 2-3, ouyang2020erk12inactivationpromotes pages 1-3).

5. Pathways and Recent Developments (2023-2026)

  • MAPK/ERK Pathway: ERK inactivation mobilizes COP1 from the nuclear envelope into the nucleoplasm for substrate degradation (ouyang2020erk12inactivationpromotes pages 1-3).
  • p53 Pathway: COP1 is a major negative regulator of p53 stability and activity, acting alongside MDM2. COP1's role is particularly relevant in stress responses and tumor suppression (hu2023structuralbasisof pages 1-3, grigoreva2024p53themultifaceted pages 1-2).
  • AP-1/JNK Pathway: c-Jun, a major AP-1 family transcription factor, is tightly controlled by COP1, connecting to oncogenic and stress-signaling nodes (wang2026cryoemstructureof pages 2-3, ouyang2020erk12inactivationpromotes pages 1-3).
  • Chromatin Regulation (UTX/KDM6A axis): COP1-containing CRL4 complexes regulate the abundance of key chromatin regulators such as UTX, affecting differentiation, tumor progression, and development (luo2023cul4bddb1cop1mediatedutxdownregulation pages 1-2).
  • Metabolism and Cell Death: Recent studies have identified ACSL4 as a COP1 substrate, linking COP1 to ferroptosis and cancer cell survival (wang2026cryoemstructureof pages 1-2). LUZP1 is also a substrate, connecting COP1 activity to EMT and chemotherapy resistance (2026).

Recent high-impact studies (2023-2026):
- 2026 cryo-EM structure of human COP1-DET1 ligase complex, revealing new mechanistic insights (Nature Communications, Wang et al., 2026).
- 2025-2026: COP1's regulation of ACSL4 in renal cell carcinoma (Frontiers in Oncology), and LUZP1 in colorectal cancer metastasis (Exp Hematol Oncol).
- 2023: COP1-mediated UTX downregulation in colorectal cancer (Exp Hematol Oncol).
- 2024: COP1 and c/EBPฮฒ in Alzheimer's pathobiology (CNS Neurosci Ther).
- 2020-2023: Cross-disease evidence for COP1 in neuroinflammation, cell differentiation, and cell cycle regulation (ndoja2020ubiquitinligasecop1 pages 1-3, ndoja2020ubiquitinligasecop1 pages 3-4).

6. Expert Synthesis and Authoritative Perspectives

Leading reviews and mechanistic studies (2021-2026) repeatedly highlight COP1/RFWD2 as a central, multi-functional E3 ubiquitin ligase coordinating cellular fate through fast posttranslational control of transcription factors and chromatin regulators. Human molecular genetics, biochemistry, and translational disease research communities consider COP1-mediated protein degradation as a crucial lever in tumorigenesis, neuroinflammation, and development (ndoja2020ubiquitinligasecop1 pages 1-3, wang2026cryoemstructureof pages 2-3, ducker2021ubiquitinmediatedcontrolof pages 1-2, hu2023structuralbasisof pages 1-3, ndoja2020ubiquitinligasecop1 pages 3-4, grigoreva2024p53themultifaceted pages 1-2, wang2026cryoemstructureof pages 4-5, ouyang2020erk12inactivationpromotes pages 1-3).

7. Relevant Statistics and Data

  • COP1 is essential; biallelic deletion is embryonically lethal in mice, showing its fundamental biological role (ndoja2020ubiquitinligasecop1 pages 3-4).
  • High COP1 expression correlates with poor prognosis and therapy resistance in multiple cancers (luo2023cul4bddb1cop1mediatedutxdownregulation pages 1-2, wang2026cryoemstructureof pages 1-2).
  • Substrate-specific knockdown or mutation causes dramatic, context-dependent changes in inflammatory, differentiation, or tumorigenic phenotypes.

8. Conclusion

Human COP1 (RFWD2; Q8NHY2) is a modular, multi-domain E3 ubiquitin ligase that operates primarily at the nuclear envelope and within the nucleus to regulate protein stability of critical transcription factors, tumor suppressors, chromatin enzymes, and metabolic regulators. It acts through specific VP-motif substrate interactions and rapidly translates signaling inputs into graded or switch-like degradation of select protein targets, orchestrating numerous physiological and pathological outcomes. Its inclusion in CUL4 CRL4COP1/DET1 complexes expands its substrate repertoire and regulatory scope.

COP1 research is expanding rapidly, with frequent new substrate discoveries, disease links, and high-resolution structural elucidations. This keeps its annotation highly dynamic and underscores its translational relevance.

Key references include:
- Wang et al., Nature Communications 2026 [https://doi.org/10.1038/s41467-026-68375-7] (wang2026cryoemstructureof pages 1-2, wang2026cryoemstructureof pages 2-3, wang2026cryoemstructureof pages 4-5)
- Ndoja et al., Cell 2020 [https://doi.org/10.1016/j.cell.2020.07.011] (ndoja2020ubiquitinligasecop1 pages 1-3, ndoja2020ubiquitinligasecop1 pages 3-4)
- Ducker & Shaw, IJMS 2021 [https://doi.org/10.3390/ijms22105119] (ducker2021ubiquitinmediatedcontrolof pages 1-2)
- Luo et al., Exp Hematol Oncol 2023 [https://doi.org/10.1186/s40164-023-00440-z] (luo2023cul4bddb1cop1mediatedutxdownregulation pages 1-2)
- Ouyang et al., PNAS 2020 [https://doi.org/10.1073/pnas.1913698117] (ouyang2020erk12inactivationpromotes pages 1-3)
- Hu et al., Communications Biology 2023 [https://doi.org/10.1038/s42003-023-04458-1] (hu2023structuralbasisof pages 1-3)
- Grigoreva et al., Pharmaceuticals 2024 [https://doi.org/10.3390/ph17121682] (grigoreva2024p53themultifaceted pages 1-2)

References

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Artifacts

Citations

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๐Ÿ“š Additional Documentation

Notes

(COP1-notes.md)

COP1 (RFWD2) review notes

UniProt: Q8NHY2 (COP1_HUMAN). HGNC:17440, gene symbol COP1 (synonyms RFWD2, RNF200, RING finger protein 200).
731 aa. EC 2.3.2.27. NCBITaxon:9606.

Identity / domain architecture

  • E3 ubiquitin-protein ligase COP1, the human homolog of the Arabidopsis "constitutive
    photomorphogenesis protein 1" (atCOP1) light-signaling regulator [PMID:12615916, PMID:12466024].
  • Domain architecture (from UniProt Q8NHY2 feature table):
  • N-terminal RING-HC zinc finger (ZN_FING 136..174), C3HC4-type, mediating E3 ligase activity
    and zinc binding [file:human/COP1/COP1-uniprot.txt].
  • Coiled-coil (233..301) mediating homodimerization [file:human/COP1/COP1-uniprot.txt].
  • C-terminal 7-bladed WD40 beta-propeller (repeats ~419..729; domain 386-731) that is the
    substrate-recognition / adaptor module. The WD40 domain (386-731) is necessary and sufficient
    for TRIB1 binding [PMID:27041596 (UniProt-cited); file:human/COP1/COP1-uniprot.txt].
  • Crystal structures of the WD40 region alone and bound to a TRIB1 peptide: PDB 5HQG, 5IGQ.
  • Belongs to the COP1 family (UniProt SIMILARITY).
  • In the Proteostasis Network classification, COP1 is a Cul4A/Cul4B WD40 substrate adaptor /
    substrate-recognition subunit.

Catalytic activity / mechanism

  • RING-finger E3 ubiquitin-protein ligase: accepts ubiquitin from an E2 as a thioester and
    transfers it directly to substrate lysines (EC 2.3.2.27). Catalytic activity demonstrated in vitro
    in an autoubiquitination assay; RING mutations (C136A/C139A, C136S/C139S) abolish ligase function
    [PMID:12615916, PMID:19805145].
  • COP1 homodimerizes via its coiled-coil [PMID:12466024; file:human/COP1/COP1-uniprot.txt].
  • COP1 functions both as a stand-alone RING E3 and as the substrate-recognition subunit of a
    cullin-RING ligase (CRL4) module. In the DCX(DET1-COP1) complex (RBX1, DET1, DDB1, CUL4A, COP1),
    the catalytic RING is contributed by RBX1, not COP1; COP1 here acts as the substrate-recognition
    adaptor [PMID:14739464; file:human/COP1/COP1-uniprot.txt FUNCTION].
  • Substrate selectivity is governed by the WD40 domain recognizing a degron motif
    (D/E)-(D/E)-x-x-x-V-P-(D/E) in substrates; phosphorylation can create or destroy degrons
    [PMID:25117710, PMID:27041596].
  • Activity/substrate choice regulated by pseudokinase adaptors TRIB1/TRIB2, which bind the WD40
    domain and compete with substrates (TRIB1 competes with substrates for COP1 binding); TRIB1
    recruits non-canonical substrates such as C/EBPalpha (CEBPA) [PMID:27041596 (UniProt-cited),
    PMID:20410507 (UniProt-cited); file:human/COP1/COP1-uniprot.txt ACTIVITY REGULATION].

Substrates (ubiquitination -> proteasomal degradation)

  • c-Jun / JUN (and JUNB, JUND family) [PMID:12615916, PMID:14739464]. In PMID:12615916, COP1
    bound Jun factors and repressed AP-1 transcription; in the early study the repression was seen
    without a change in c-Jun levels, but PMID:14739464 established COP1 (with DET1/DDB1/CUL4A/RBX1)
    drives c-Jun ubiquitination and degradation.
  • p53 / TP53: COP1 directly ubiquitinates p53 and targets it for proteasomal degradation
    independently of MDM2 or PIRH2/RCHY1, repressing p53-dependent transcription and apoptosis.
    COP1 is itself a p53-inducible gene (negative feedback) PMID:15103385. RING mutants C136A/C139A
    abolish p53 ubiquitination [file:human/COP1/COP1-uniprot.txt MUTAGEN].
  • p53 stability is co-regulated by MTA1 [PMID:19837670 (UniProt-cited)].
  • MTA1: COP1 ubiquitinates MTA1 for proteasomal degradation; MTA1 reciprocally destabilizes COP1 by
    promoting its autoubiquitination, forming a feedback loop. Ionizing radiation disrupts
    COP1-mediated MTA1 proteolysis, stabilizing MTA1 PMID:19805145.
  • ETS transcription factors ETV1, ETV4, ETV5 (and ETS2): COP1 ubiquitinates and degrades these
    proto-oncogenic ETS factors; this underlies its tumor-suppressor role in prostate cancer.
    TMPRSS2:ETV1 fusions delete the COP1 degron, escaping degradation PMID:21572435.
  • ETS1: COP1 recognizes a phospho-degron; Src/Yes-family-kinase phosphorylation of Tyr283 blocks
    COP1 binding and stabilizes ETS1 PMID:25117710.
  • 14-3-3 sigma / SFN: COP1 is an E3 ligase for 14-3-3sigma; degradation activates AKT and promotes
    survival. CSN6 (COPS6) stabilizes COP1 by reducing its autoubiquitination PMID:21625211.
  • ACC1 / ACACA (acetyl-CoA carboxylase 1): COP1 ubiquitinates ACC1; KIF12 enhances COP1-mediated
    ACC1 ubiquitination/turnover, suppressing lipogenesis (relevant to MASH). Loss of this turnover
    promotes steatohepatitis PMID:39920308. This is the basis for the IMP annotation to
    "negative regulation of fatty acid biosynthetic process" (GO:0045717).
  • Additional reported substrates (literature/UniProt, not all in GOA): C/EBPalpha (CEBPA, via TRIB1),
    FOXO1, TORC2/CRTC2, acetyl-CoA carboxylase [PMID:25117710 intro review].

Regulation / autoubiquitination

  • COP1 autoubiquitinates and turns over by the proteasome (Reactome "Autodegradation of the E3
    ubiquitin ligase COP1", R-HSA-349425) [file:human/COP1/COP1-uniprot.txt PTM].
  • COPS6/CSN6 (COP9 signalosome subunit 6) binds COP1, reduces self-ubiquitination, stabilizes it
    PMID:21625211.
  • DNA damage: ATM phosphorylates COP1 at Ser387; 14-3-3sigma binds phospho-Ser387 COP1 and drives
    its nuclear export and enhanced (auto)ubiquitination, relieving COP1 repression of p53
    [PMID:20843328; Reactome R-HSA-349444, R-HSA-264418].
  • COP9 signalosome deneddylates the nuclear CRL4 complex (Reactome neddylation/deneddylation cycle).

Subcellular localization

  • Nucleus (nuclear speckles) and cytoplasm; shuttles between the two. NLS motifs (109-113, 195-206)
    and an NES (235-245). The RING also acts as a structural scaffold mimicking a bipartite NLS
    [file:human/COP1/COP1-uniprot.txt SUBCELLULAR LOCATION, DOMAIN, MOTIF].
  • Reactome models place COP1/CRL4 activity in cytosol and nucleoplasm.
  • The Golgi membrane IEA annotation (GO:0000139) is an Ensembl Compara ortholog transfer from a rat
    protein; not supported by the human literature, which describes nuclear-speckle and cytoplasmic
    localization. Likely an over-annotation.

Isoforms

  • 5 isoforms. Isoform 4 (COP1D) is a dominant-negative that heterodimerizes with isoform 1 and
    blocks association with DET1, stabilizing UV-stress-induced c-Jun [PMID:17968316 (UniProt-cited)].
  • Isoform 2 (delta24) does not interact with CUL4A but still binds RBX1.

Disease / physiology

  • Tumor suppressor in prostate (ETV1/ETS axis), and Cop1 deletion in mice causes lymphoma; combined
    with Pten loss promotes invasive prostate cancer [PMID:21572435, PMID:25117710 intro].
  • Lipogenic enzyme turnover / MASH via ACC1 PMID:39920308.

Annotation review reasoning summary

  • Strong, well-supported core: RING-type ubiquitin-protein ligase activity (GO:0061630 /
    GO:0004842), protein ubiquitination (GO:0016567), proteasome-mediated ubiquitin-dependent
    protein catabolic process (GO:0043161), positive regulation of proteasomal degradation
    (GO:0032436), and membership of the Cul4A-RING E3 ligase complex (GO:0031464). All ACCEPT.
  • Substrate-recognition adaptor function (WD40 propeller) is a candidate core MF not currently
    captured: GO:1990756 (ubiquitin-like ligase-substrate adaptor activity) โ€” proposed new term.
  • The 9 generic "protein binding" (GO:0005515, IPI) annotations are uninformative per curation
    guidelines; most are interactions with substrates (SFN, ETV1/ETV5, ETS1/ETS2) or regulators
    (COPS6). MARK_AS_OVER_ANNOTATED (binding itself is real but the term is uninformative).
  • Localization: nuclear speck (GO:0016607), cytoplasm (GO:0005737), cytosol (GO:0005829),
    nucleoplasm (GO:0005654) are all supported. Golgi membrane (GO:0000139, IEA from rat ortholog)
    is unsupported -> MARK_AS_OVER_ANNOTATED.
  • GO:0045717 (neg. reg. fatty acid biosynthesis) supported by PMID:39920308 (ACC1) โ€” KEEP_AS_NON_CORE
    (downstream physiological consequence of catalytic activity, not the core MF).
  • GO:0010212 (response to ionizing radiation) supported by PMID:19805145 โ€” KEEP_AS_NON_CORE.

Review completion (2026-06-07)

  • Completed COP1-ai-review.yaml (status COMPLETE). All 40 existing_annotations reviewed.
  • ACCEPT (core): GO:0061630 (EXP/IMP/IEA ubiquitin protein ligase activity), GO:0004842
    (ubiquitin-protein transferase activity), GO:0016567 (protein ubiquitination), GO:0043161
    (proteasome-mediated ubiquitin-dependent protein catabolic process, IBA+IMP), GO:0006511,
    GO:0032436 (positive regulation of proteasomal catabolism), GO:0031464 (Cul4A-RING E3
    ligase complex), GO:0016607 (nuclear speck), GO:0005737 is_active_in cytoplasm (IC).
  • KEEP_AS_NON_CORE: GO:0005737 located_in cytoplasm (IEA), GO:0005829 cytosol (TAS x3),
    GO:0005654 nucleoplasm (TAS x8), GO:0045717 (neg reg fatty acid biosynthesis, ACC1),
    GO:0010212 (response to ionizing radiation).
  • MARK_AS_OVER_ANNOTATED: all 9 bare GO:0005515 protein binding (IPI) annotations.
  • REMOVE: GO:0000139 Golgi membrane (IEA Ensembl Compara from rat ortholog; unsupported in human).
  • Proposed (core_functions, not added to existing as NEW): GO:1990756 ubiquitin-like
    ligase-substrate adaptor activity (WD40 substrate-recognition adaptor function).
  • proposed_new_terms: [] (GO:1990756 already exists and is used in core_functions).
  • Validation: โœ“ Valid (3 advisory warnings: cytoplasm action consistency across qualifiers;
    novel adaptor MF and cytosol location not in existing block).

Pn Notes

(COP1-pn-notes.md)

COP1 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q8NHY2
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-07
  • Batch change status: added

Source Files Checked

Deep Research Files

  • No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

  • Description: COP1 (also known as RFWD2; constitutive photomorphogenesis protein 1 homolog) is a RING-finger E3 ubiquitin-protein ligase (EC 2.3.2.27) that mediates ubiquitination and subsequent proteasomal degradation of substrate transcription factors and signaling proteins. Its domain architecture comprises an N-terminal C3HC4 RING-HC zinc finger (responsible for catalytic ubiquitin transfer and zinc binding), a central coiled-coil that mediates homodimerization, and a C-terminal seven-bladed WD40 beta-propeller that serves as the substrate-recognition module, binding short degron motifs in substrates. COP1 acts both as a stand-alone RING E3 and as the substrate-recognition subunit of a cullin-RING ligase (CRL4) module; in the DCX(DET1-COP1) complex (COP1, DET1, DDB1, CUL4A, RBX1) the catalytic RING is contributed by RBX1 while COP1 provides substrate recognition. Validated substrates include the AP-1 transcription factor c-Jun (JUN) and its relatives, the tumor suppressor p53 (TP53, with MTA1 co-regulation), the oncogenic ETS-family factors ETV1/ETV4/ETV5 and ETS1, the metastasis regulator MTA1, 14-3-3 sigma (SFN), C/EBPalpha (CEBPA, recruited via the pseudokinase adaptor TRIB1), and acetyl-CoA carboxylase 1 (ACACA). Substrate choice and ligase activity are regulated by the pseudokinase adaptors TRIB1/TRIB2, which bind the WD40 domain and compete with substrates. COP1 shuttles between nuclear speckles and the cytoplasm; ATM-dependent phosphorylation at Ser387 and 14-3-3 sigma binding drive its nuclear export and autoubiquitination upon DNA damage. Through degradation of these substrates, COP1 functions as a tumor suppressor in several contexts and contributes to control of lipogenesis. It autoubiquitinates and is stabilized by the COP9 signalosome subunit COPS6/CSN6.
  • Existing/core annotation action counts: ACCEPT: 12; KEEP_AS_NON_CORE: 14; MARK_AS_OVER_ANNOTATED: 9; REMOVE: 1

PN Consistency Summary

  • Consistency: Strong. The PN dual classification (catalytic RING E3 and CRL4 substrate adaptor) exactly matches the review's two core_functions: GO:0061630 ubiquitin protein ligase activity (EXP PMID:12615916, IMP PMID:19805145) and GO:1990756 substrate-adaptor activity (WD40 propeller; PMID:14739464, PMID:21572435). Deep-research notes, review YAML, and PN annotation agree COP1 is both stand-alone RING (catalytic) and the substrate-recognition subunit of DCX(DET1-COP1) CRL4 (RBX1 catalytic). No contradictions.
  • PN story / NEW pressure: No NEW pressure. Both projected terms are already present/captured: GO:0061630 is in existing_annotations (EXP/IMP/IEA, ACCEPT, core); GO:1990756 is asserted as a core_function (proposed_new_terms is empty because the term already exists and is used). PN's "new_to_goa" flag on GO:1990756 reflects that GOA lacks the explicit adaptor MF, but the review already proposes it. Already captured.
  • Evidence alignment: PN cites only review-stub PMIDs (17588513 = the DCAF discovery review for the Cul4 row; 19489725 = ER-RING-ligase screen for the RING row). Review's substantive evidence (PMID:12615916, 14739464, 19805145, 21572435, 39920308) does not overlap PN's two citations, but PN citations are family/architecture references, not gene-specific โ€” divergence is expected and benign.
  • Verdict: Consistent; mapping sound; no edits. COP1 correctly carries both catalytic and adaptor MFs.

Full Consistency Review

  • UniProt: Q8NHY2 (RFWD2) ยท batch: proteostasis-batch-2026-06-07 ยท review status: COMPLETE (40 annotations reviewed)
  • PN placement: two rows โ€” (1) UPS|E3 ubiquitin and UBL ligases|Cul4A/Cul4B substrate adaptor|WD40|other; (2) UPS|E3 ubiquitin and UBL ligases|RING|RFWD|WD40 ; PN-node mapping: group nodes mapped โ€” Cul4 adaptor group โ†’ GO:1990756 (substrate-adaptor MF); RING group โ†’ GO:0061630 (catalytic ligase MF); both ok_for_propagation.
  • Consistency: Strong. The PN dual classification (catalytic RING E3 and CRL4 substrate adaptor) exactly matches the review's two core_functions: GO:0061630 ubiquitin protein ligase activity (EXP PMID:12615916, IMP PMID:19805145) and GO:1990756 substrate-adaptor activity (WD40 propeller; PMID:14739464, PMID:21572435). Deep-research notes, review YAML, and PN annotation agree COP1 is both stand-alone RING (catalytic) and the substrate-recognition subunit of DCX(DET1-COP1) CRL4 (RBX1 catalytic). No contradictions.
  • PN story / NEW pressure: No NEW pressure. Both projected terms are already present/captured: GO:0061630 is in existing_annotations (EXP/IMP/IEA, ACCEPT, core); GO:1990756 is asserted as a core_function (proposed_new_terms is empty because the term already exists and is used). PN's "new_to_goa" flag on GO:1990756 reflects that GOA lacks the explicit adaptor MF, but the review already proposes it. Already captured.
  • Mapping strategy: Correct and well-calibrated. This gene is the precedent for distinguishing the two MFs: RING group โ†’ catalytic GO:0061630; Cul4 adaptor group โ†’ GO:1990756. Both group-level mappings fit COP1; class/branch correctly context_only/no_mapping. No change needed.
  • Evidence alignment: PN cites only review-stub PMIDs (17588513 = the DCAF discovery review for the Cul4 row; 19489725 = ER-RING-ligase screen for the RING row). Review's substantive evidence (PMID:12615916, 14739464, 19805145, 21572435, 39920308) does not overlap PN's two citations, but PN citations are family/architecture references, not gene-specific โ€” divergence is expected and benign.
  • Verdict: Consistent; mapping sound; no edits. COP1 correctly carries both catalytic and adaptor MFs.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07
  • review_yaml: genes/human/COP1/COP1-ai-review.yaml
  • PN workbook rows: 2

PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | Cul4A/Cul4B substrate adaptor | WD40 | other

  • UniProt: Q8NHY2
  • In branches: UPS
  • Signature domains: (none)
  • Auxiliary domains: IPR001680
  • PN references (titles):
    • 17588513 rev
  • PN-node mapping records (path + ancestors):
    • [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul4A/Cul4B substrate adaptor|WD40|other
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
    • [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul4A/Cul4B substrate adaptor|WD40
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower substrate-receptor, adaptor, domain, or family subdivision already covered by the curated parent adaptor/receptor mapping. No additional direct GO mapping is needed at this node.
    • [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul4A/Cul4B substrate adaptor
      status=mapped scope=ok_for_propagation_to_go GO=[GO:1990756 ubiquitin-like ligase-substrate adaptor activity]
      rationale: This PN group captures substrate receptors/adaptors for cullin/UBL ligase systems. The shared GO molecular-function target is ubiquitin-like ligase-substrate adaptor activity.
    • [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
      status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
      rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
    • [branch] Ubiquitin Proteasome System
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

PN row 2: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | RING | RFWD | WD40

  • UniProt: Q8NHY2
  • In branches: UPS
  • Signature domains: IPR001841
  • Auxiliary domains: IPR001680
  • PN references (titles):
    • 19489725 / rev
  • PN-node mapping records (path + ancestors):
    • [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING|RFWD|WD40
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower E3-ligase architecture, component, or domain subdivision already covered by the curated parent E3 mapping. No additional direct GO mapping is needed at this node.
    • [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING|RFWD
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower E3-ligase architecture, component, or domain subdivision already covered by the curated parent E3 mapping. No additional direct GO mapping is needed at this node.
    • [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0061630 ubiquitin protein ligase activity]
      rationale: This PN group is a catalytic ubiquitin E3 ligase bucket. The shared GO molecular-function target is ubiquitin protein ligase activity.
    • [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
      status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
      rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
    • [branch] Ubiquitin Proteasome System
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (2)

  • GO:1990756 ubiquitin-like ligase-substrate adaptor activity | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|Cul4A/Cul4B substrate adaptor
  • GO:0061630 ubiquitin protein ligase activity | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

๐Ÿ“„ View Raw YAML

 
id: Q8NHY2
gene_symbol: COP1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: COP1 (also known as RFWD2; constitutive photomorphogenesis protein 1 homolog)
  is a RING-finger E3 ubiquitin-protein ligase (EC 2.3.2.27) that mediates ubiquitination
  and subsequent proteasomal degradation of substrate transcription factors and signaling
  proteins. Its domain architecture comprises an N-terminal C3HC4 RING-HC zinc finger
  (responsible for catalytic ubiquitin transfer and zinc binding), a central coiled-coil
  that mediates homodimerization, and a C-terminal seven-bladed WD40 beta-propeller that
  serves as the substrate-recognition module, binding short degron motifs in substrates.
  COP1 acts both as a stand-alone RING E3 and as the substrate-recognition subunit of a
  cullin-RING ligase (CRL4) module; in the DCX(DET1-COP1) complex (COP1, DET1, DDB1, CUL4A,
  RBX1) the catalytic RING is contributed by RBX1 while COP1 provides substrate recognition.
  Validated substrates include the AP-1 transcription factor c-Jun (JUN) and its relatives,
  the tumor suppressor p53 (TP53, with MTA1 co-regulation), the oncogenic ETS-family factors
  ETV1/ETV4/ETV5 and ETS1, the metastasis regulator MTA1, 14-3-3 sigma (SFN), C/EBPalpha
  (CEBPA, recruited via the pseudokinase adaptor TRIB1), and acetyl-CoA carboxylase 1 (ACACA).
  Substrate choice and ligase activity are regulated by the pseudokinase adaptors TRIB1/TRIB2,
  which bind the WD40 domain and compete with substrates. COP1 shuttles between nuclear speckles
  and the cytoplasm; ATM-dependent phosphorylation at Ser387 and 14-3-3 sigma binding drive its
  nuclear export and autoubiquitination upon DNA damage. Through degradation of these substrates,
  COP1 functions as a tumor suppressor in several contexts and contributes to control of
  lipogenesis. It autoubiquitinates and is stabilized by the COP9 signalosome subunit COPS6/CSN6.
alternative_products:
- name: '1'
  id: Q8NHY2-1
- name: 2 (delta24)
  id: Q8NHY2-2
  sequence_note: VSP_012024, VSP_012025
- name: '3'
  id: Q8NHY2-3
  sequence_note: VSP_012026, VSP_012027
- name: 4 (COP1D)
  id: Q8NHY2-4
  sequence_note: VSP_012025
- name: 5 (E)
  id: Q8NHY2-5
  sequence_note: VSP_055894, VSP_055895
existing_annotations:
- term:
    id: GO:0043161
    label: proteasome-mediated ubiquitin-dependent protein catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic (IBA) transfer of the well-supported role of COP1 in targeting
      substrates for proteasomal degradation. This is directly experimentally established
      for COP1 (c-Jun, p53, MTA1, ETS factors, 14-3-3sigma), so the term is appropriate
      and core.
    action: ACCEPT
    reason: COP1 is an E3 ligase whose central function is to mediate ubiquitin-dependent
      proteasomal degradation of its substrates, demonstrated experimentally in multiple
      studies. The IBA annotation correctly captures this core biological process.
      The falcon deep research consolidates this across substrates, scoped correctly
      to the human protein.
    supported_by:
    - reference_id: PMID:14739464
      supporting_text: Human De-etiolated-1 regulates c-Jun by assembling a CUL4A ubiquitin
        ligase.
    - reference_id: file:human/COP1/COP1-deep-research-falcon.md
      supporting_text: COP1 catalyzes the transfer of ubiquitin from E2 enzymes to specific
        substrate proteins, marking them for proteasomal degradation.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Cytoplasmic localization derived from the UniProt subcellular location vocabulary.
      COP1 is documented to shuttle between nuclear speckles and the cytoplasm, so this
      localization is supported, though it is a general parent term.
    action: KEEP_AS_NON_CORE
    reason: Cytoplasmic localization is real (COP1 shuttles between nucleus and cytoplasm,
      and its nuclear export is regulated by 14-3-3 sigma after DNA damage), but the more
      informative location for its function is the nuclear speckle and the catalytic cytosol
      annotation; cytoplasm is a broad CC term retained as non-core.
- term:
    id: GO:0016607
    label: nuclear speck
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Nuclear speckle localization from UniProt subcellular location mapping.
      COP1 forms nuclear speckles, supported by experimental characterization of the
      human protein, and this is a more specific and informative location than bare cytoplasm.
    action: ACCEPT
    reason: COP1 is documented to localize to nuclear speckles ("In the nucleus, it forms
      nuclear speckles"), consistent with its role in nuclear ubiquitination of transcription
      factors such as p53 and ETS factors. This is an accurate and informative CC term.
    supported_by:
    - reference_id: file:human/COP1/COP1-uniprot.txt
      supporting_text: 'Nucleus speckle. Cytoplasm. Note=In the nucleus, it forms nuclear
        speckles.'
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: IEA assignment of ubiquitin protein ligase activity from InterPro/EC mapping
      (RING domain, EC 2.3.2.27). This is the core catalytic molecular function of COP1
      and is independently supported by direct experimental evidence (EXP, IMP) in other
      annotations.
    action: ACCEPT
    reason: COP1 is a bona fide RING-finger E3 ubiquitin-protein ligase; the IEA inference
      from its RING domain and EC number is fully corroborated by experimental data. This
      is a core molecular function.
    supported_by:
    - reference_id: file:human/COP1/COP1-uniprot.txt
      supporting_text: E3 ubiquitin-protein ligase that mediates ubiquitination and
        subsequent proteasomal degradation of target proteins.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20843328
  qualifier: enables
  review:
    summary: Generic "protein binding" (GO:0005515) from an IntAct interaction with 14-3-3
      sigma/SFN. The interaction is real (SFN binds phospho-Ser387 COP1 and drives its
      nuclear export), but the bare protein binding term is uninformative per curation
      guidelines.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 protein binding does not convey a specific molecular function. The
      underlying COP1-SFN interaction is captured more informatively elsewhere (SFN is both
      a COP1 substrate and a regulator of COP1 nuclear export); the catalytic ligase activity
      is the relevant MF.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21572435
  qualifier: enables
  review:
    summary: Generic "protein binding" from an IntAct interaction with ETV1, a substrate
      ETS transcription factor that COP1 ubiquitinates and degrades. The interaction is
      genuine but the bare term is uninformative. The COP1-ETV1 interaction reflects
      WD40-mediated degron recognition (VP/Val-Pro motif) rather than a non-specific
      binding event.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is uninformative. The biologically meaningful relationship (COP1
      recognizes and degrades ETV1/ETV4/ETV5) is better captured by the substrate-recognition
      and protein catabolic process annotations.
    supported_by:
    - reference_id: file:human/COP1/COP1-deep-research-falcon.md
      supporting_text: Substrate selection is mediated by the WD40 domain, which recognizes
        a consensus VP (Val-Pro) degron motif present in many COP1 targets.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21625211
  qualifier: enables
  review:
    summary: Generic "protein binding" from IntAct interactions reported in the COPS6/SFN
      study (interactors SFN and COPS6). COPS6/CSN6 binds and stabilizes COP1; SFN is a
      COP1 substrate. The interactions are real but the bare term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 protein binding conveys no specific function. The COP1-COPS6 and
      COP1-SFN interactions are better described by COP1's ligase activity (toward SFN) and
      its regulation/stabilization by the COP9 signalosome.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25117710
  qualifier: enables
  review:
    summary: Generic "protein binding" from IntAct interactions with ETS1 and ETS2, substrate
      ETS transcription factors. COP1 recognizes a phospho-degron on ETS1 (blocked by
      Src-family kinase phosphorylation). Real interactions, uninformative term.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is uninformative. The functional relationship (COP1 phospho-degron
      recognition and degradation of ETS1/ETS2) is captured by the substrate-recognition
      and catabolic process annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26496610
  qualifier: enables
  review:
    summary: Generic "protein binding" from a high-throughput interactome study (interactor
      ETS2). Uninformative term derived from a proteome-scale screen.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 from a large-scale interactome screen does not convey a specific
      molecular function and provides no functional insight beyond what is already captured.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Generic "protein binding" from a high-throughput interactome study (interactors
      ETV5 and ETV1, both substrate ETS factors). Uninformative term.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is uninformative. The ETV1/ETV5 interactions reflect COP1 substrate
      recognition, already captured by the catabolic-process and substrate-recognition
      annotations.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35140242
  qualifier: enables
  review:
    summary: Generic "protein binding" from a transcription-factor interaction network study
      (interactor ETV5, a substrate ETS factor). Uninformative term.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 conveys no specific molecular function; the ETV5 interaction reflects
      substrate recognition already captured elsewhere.
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Golgi membrane localization transferred by Ensembl Compara from a rat ortholog.
      This is not supported by the human COP1 literature, which describes nuclear-speckle and
      cytoplasmic/cytosolic localization. Likely an erroneous ortholog transfer.
    action: REMOVE
    reason: There is no experimental support in human (or convincing functional rationale)
      for COP1 acting at the Golgi membrane. The annotation derives solely from automatic
      transfer (GO_REF:0000107) from a rat protein and conflicts with the well-documented
      nuclear/cytoplasmic localization of COP1.
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: Protein ubiquitination assigned via UniPathway mapping. This is the core
      biological process catalyzed by COP1 as a RING E3 ligase and is well supported
      experimentally.
    action: ACCEPT
    reason: COP1 directly mediates ubiquitination of multiple substrates (JUN, p53, MTA1,
      SFN, ETS factors, ACC1); protein ubiquitination is a core BP for this gene.
    supported_by:
    - reference_id: file:human/COP1/COP1-uniprot.txt
      supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.'
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: EXP
  original_reference_id: PMID:12615916
  qualifier: enables
  review:
    summary: Experimental (EXP) demonstration that the COP1 RING domain has ubiquitin ligase
      activity in an in vitro autoubiquitination assay. This is the strongest evidence for
      the core catalytic molecular function of COP1.
    action: ACCEPT
    reason: Direct in vitro demonstration of RING-dependent ubiquitin ligase activity firmly
      establishes GO:0061630 as a core molecular function of COP1.
    supported_by:
    - reference_id: PMID:12615916
      supporting_text: The RING domain of huCOP1 displays ubiquitin ligase activity in an
        autoubiquitination assay in vitro
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IC
  original_reference_id: PMID:39920308
  qualifier: is_active_in
  review:
    summary: Curator-inferred (IC) "is_active_in cytoplasm", from the KIF12/ACC1 study where
      COP1 ubiquitinates the cytoplasmic enzyme acetyl-CoA carboxylase 1. The is_active_in
      qualifier appropriately marks the cytoplasm as a site of COP1 catalytic activity.
    action: ACCEPT
    reason: COP1 acts in the cytoplasm to ubiquitinate cytoplasmic substrates such as ACC1;
      the is_active_in qualifier captures functional cytoplasmic activity, which is more
      meaningful than the bare located_in cytoplasm annotation.
    supported_by:
    - reference_id: PMID:39920308
      supporting_text: lipogenic enzyme turnover
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: IMP
  original_reference_id: PMID:39920308
  qualifier: involved_in
  review:
    summary: IMP evidence that COP1 drives ubiquitin-dependent turnover of the lipogenic
      enzyme ACC1/ACACA. Supports COP1's core role in ubiquitin-dependent protein catabolism.
    action: ACCEPT
    reason: COP1 mediates ubiquitin-dependent degradation of ACC1 (and many other substrates);
      this is a core biological process. The more specific proteasome-mediated term is also
      annotated and preferred for the core synthesis, but this parent term is correct.
    supported_by:
    - reference_id: PMID:39920308
      supporting_text: lipogenic enzyme turnover
- term:
    id: GO:0045717
    label: negative regulation of fatty acid biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:39920308
  qualifier: involved_in
  review:
    summary: IMP evidence that COP1-mediated degradation of acetyl-CoA carboxylase 1 (ACC1),
      enhanced by KIF12, suppresses lipogenesis; loss promotes MASH/steatohepatitis. This
      is a downstream physiological consequence of COP1's catalytic activity.
    action: KEEP_AS_NON_CORE
    reason: The link between COP1 and fatty acid biosynthesis is genuine but is a tissue-/
      substrate-specific physiological outcome (ACC1 turnover in liver) rather than the core
      molecular/biological role of COP1, which is general substrate ubiquitination and
      degradation. Retained as a non-core process annotation.
    supported_by:
    - reference_id: PMID:39920308
      supporting_text: lipogenic enzyme turnover
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-264444
  qualifier: enables
  review:
    summary: TAS (Reactome) assignment of ubiquitin-protein transferase activity, capturing
      COP1 autoubiquitination. This is a correct molecular-function term for COP1's E3 ligase
      activity (a parent/sibling of GO:0061630).
    action: ACCEPT
    reason: COP1's catalytic activity (EC 2.3.2.27) is ubiquitin-protein transferase activity;
      the term is accurate and supported by Reactome's modeling of COP1 autoubiquitination
      and by experimental data.
    supported_by:
    - reference_id: file:human/COP1/COP1-uniprot.txt
      supporting_text: 'EC=2.3.2.27'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14739464
  qualifier: enables
  review:
    summary: Generic "protein binding" from the DET1/CUL4A study (interactor DET1, UniProtKB
      Q7L5Y6). COP1 is a component of the DCX(DET1-COP1) complex; the DET1 interaction is
      real but the bare term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 conveys no specific function. The COP1-DET1 interaction is captured by
      the Cul4A-RING E3 ligase complex membership annotation, which is far more informative.
- term:
    id: GO:0031464
    label: Cul4A-RING E3 ubiquitin ligase complex
  evidence_type: IDA
  original_reference_id: PMID:14739464
  qualifier: part_of
  review:
    summary: IDA evidence that COP1 is a component of the DCX(DET1-COP1) CUL4A-based E3
      ligase complex (with DET1, DDB1, CUL4A, RBX1) that ubiquitinates c-Jun. Well-supported
      complex membership and a core cellular component for COP1's adaptor function.
    action: ACCEPT
    reason: COP1 is directly demonstrated to assemble into a CUL4A-RING ligase complex, where
      it serves as the substrate-recognition subunit. This is an accurate and informative CC
      annotation central to COP1 biology.
    supported_by:
    - reference_id: PMID:14739464
      supporting_text: Human De-etiolated-1 regulates c-Jun by assembling a CUL4A ubiquitin
        ligase.
- term:
    id: GO:0043161
    label: proteasome-mediated ubiquitin-dependent protein catabolic process
  evidence_type: IMP
  original_reference_id: PMID:14739464
  qualifier: involved_in
  review:
    summary: IMP evidence that the DET1-COP1 complex drives c-Jun ubiquitination and
      proteasomal degradation. Directly supports COP1's core role in proteasome-mediated
      protein catabolism.
    action: ACCEPT
    reason: Experimentally demonstrated that COP1 (within the CUL4A complex) targets c-Jun
      for proteasomal degradation; this is a core biological process for COP1.
    supported_by:
    - reference_id: PMID:14739464
      supporting_text: Human De-etiolated-1 regulates c-Jun by assembling a CUL4A ubiquitin
        ligase.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19805145
  qualifier: enables
  review:
    summary: Generic "protein binding" from the MTA1 study (interactor MTA1, UniProtKB
      Q13330), a COP1 substrate. The interaction is real but the bare term is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0005515 is uninformative. The COP1-MTA1 interaction (COP1 ubiquitinates MTA1;
      MTA1 reciprocally promotes COP1 autoubiquitination) is captured by the catalytic and
      regulatory annotations.
- term:
    id: GO:0010212
    label: response to ionizing radiation
  evidence_type: IDA
  original_reference_id: PMID:19805145
  qualifier: involved_in
  review:
    summary: IDA evidence that ionizing radiation modulates COP1-mediated MTA1 proteolysis
      (radiation stabilizes MTA1 by disrupting COP1 function). This is a contextual/stimulus
      response rather than a core function of COP1.
    action: KEEP_AS_NON_CORE
    reason: COP1's involvement in the ionizing-radiation/DNA-damage response (via MTA1 and p53
      regulation) is a real but context-specific physiological role, not the core ligase
      function. Retained as a non-core process annotation.
- term:
    id: GO:0032436
    label: positive regulation of proteasomal ubiquitin-dependent protein catabolic
      process
  evidence_type: IMP
  original_reference_id: PMID:19805145
  qualifier: involved_in
  review:
    summary: IMP evidence that COP1 promotes proteasomal degradation of MTA1 (and itself via
      autoubiquitination). Captures COP1's positive role in proteasomal protein catabolism.
    action: ACCEPT
    reason: As an E3 ligase, COP1 positively drives proteasomal degradation of its substrates;
      this is well supported and consistent with its core function.
    supported_by:
    - reference_id: PMID:19805145
      supporting_text: E3 ubiquitin ligase COP1 regulates the stability and functions of MTA1.
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IMP
  original_reference_id: PMID:19805145
  qualifier: enables
  review:
    summary: IMP evidence for COP1 ubiquitin protein ligase activity toward MTA1, with RING
      mutants (C156S/C159S, C136S/C139S) abolishing MTA1 ubiquitination. Reinforces the core
      catalytic MF.
    action: ACCEPT
    reason: Mutagenesis-supported demonstration of RING-dependent ubiquitin ligase activity
      toward a substrate firmly supports GO:0061630 as a core molecular function.
    supported_by:
    - reference_id: PMID:19805145
      supporting_text: E3 ubiquitin ligase COP1 regulates the stability and functions of MTA1.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-264418
  qualifier: located_in
  review:
    summary: Cytosol localization from Reactome (TAS), modeling COP1 nucleus-to-cytoplasm
      translocation. Consistent with the documented cytoplasmic pool of COP1.
    action: KEEP_AS_NON_CORE
    reason: Cytosolic localization is supported and COP1 acts in the cytoplasm on substrates
      like ACC1, but cytosol is a general location captured non-core; the nuclear speckle
      and CUL4A complex annotations are more functionally informative.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-264444
  qualifier: located_in
  review:
    summary: Cytosol localization from Reactome (TAS), modeling COP1 autoubiquitination of
      phospho-COP1(Ser387). Consistent with the cytoplasmic pool of COP1.
    action: KEEP_AS_NON_CORE
    reason: Supported general cytosolic localization; retained as non-core in favor of the more
      informative nuclear speckle and complex-membership annotations.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-264458
  qualifier: located_in
  review:
    summary: Cytosol localization from Reactome (TAS), modeling proteasome-mediated degradation
      of COP1. Consistent with the cytoplasmic pool of COP1.
    action: KEEP_AS_NON_CORE
    reason: Supported general cytosolic localization; retained as non-core in favor of more
      functionally informative location annotations.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-264418
  qualifier: located_in
  review:
    summary: Nucleoplasm localization from Reactome (TAS), modeling COP1 nuclear-to-cytoplasmic
      translocation. Consistent with COP1's documented nuclear pool and nuclear-speckle
      localization.
    action: KEEP_AS_NON_CORE
    reason: COP1 is present in the nucleus; nucleoplasm is supported but is a general location.
      The nuclear speck annotation is the more specific and informative CC term for COP1.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-264435
  qualifier: located_in
  review:
    summary: Nucleoplasm localization from Reactome (TAS), modeling dissociation of the
      COP1-p53 complex. Consistent with COP1's nuclear pool where it regulates p53.
    action: KEEP_AS_NON_CORE
    reason: Supported nuclear localization; nucleoplasm is a general location retained as
      non-core, with nuclear speck preferred as the specific informative term.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-349444
  qualifier: located_in
  review:
    summary: Nucleoplasm localization from Reactome (TAS), modeling ATM phosphorylation of
      COP1 at Ser387 in the nucleus following DNA damage. Consistent with COP1's nuclear pool.
    action: KEEP_AS_NON_CORE
    reason: Supported nuclear localization; nucleoplasm is general and retained as non-core,
      with nuclear speck preferred as the specific informative term.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952638
  qualifier: located_in
  review:
    summary: Nucleoplasm localization from Reactome (TAS) within the CRL4 neddylation cycle
      (NEDD8 transfer to the CRL4 complex). Consistent with COP1's nuclear CRL4-associated pool.
    action: KEEP_AS_NON_CORE
    reason: Supported nuclear localization as part of the CRL4 complex; nucleoplasm is a general
      CC term retained as non-core, with nuclear speck preferred.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952639
  qualifier: located_in
  review:
    summary: Nucleoplasm localization from Reactome (TAS) within the CRL4 neddylation cycle
      (NEDD8:UBE2M binding the CRL4 complex). Consistent with COP1's nuclear CRL4 pool.
    action: KEEP_AS_NON_CORE
    reason: Supported nuclear localization as part of the CRL4 complex; nucleoplasm is general
      and retained as non-core, with nuclear speck preferred.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955245
  qualifier: located_in
  review:
    summary: Nucleoplasm localization from Reactome (TAS) within the CRL4 regulatory cycle
      (CAND1 binding the nuclear CRL4 complex). Consistent with COP1's nuclear CRL4 pool.
    action: KEEP_AS_NON_CORE
    reason: Supported nuclear localization as part of the CRL4 complex; nucleoplasm is general
      and retained as non-core, with nuclear speck preferred.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8955285
  qualifier: located_in
  review:
    summary: Nucleoplasm localization from Reactome (TAS) within the CRL4 regulatory cycle
      (COMMDs displacing CAND1 from the CRL4 complex). Consistent with COP1's nuclear CRL4 pool.
    action: KEEP_AS_NON_CORE
    reason: Supported nuclear localization as part of the CRL4 complex; nucleoplasm is general
      and retained as non-core, with nuclear speck preferred.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8956045
  qualifier: located_in
  review:
    summary: Nucleoplasm localization from Reactome (TAS) within the CRL4 regulatory cycle
      (COP9 signalosome deneddylation of the nuclear CRL4 complex). Consistent with COP1's
      nuclear CRL4 pool.
    action: KEEP_AS_NON_CORE
    reason: Supported nuclear localization as part of the CRL4 complex; nucleoplasm is general
      and retained as non-core, with nuclear speck preferred.
core_functions:
- description: RING-type E3 ubiquitin-protein ligase activity. COP1 transfers ubiquitin
    from an E2 conjugating enzyme to substrate lysines (EC 2.3.2.27), either as a stand-alone
    RING ligase or as part of a CUL4A-based cullin-RING ligase, driving substrate ubiquitination.
  molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  directly_involved_in:
  - id: GO:0016567
    label: protein ubiquitination
  locations:
  - id: GO:0016607
    label: nuclear speck
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:12615916
    supporting_text: The RING domain of huCOP1 displays ubiquitin ligase activity in an
      autoubiquitination assay in vitro
- description: Substrate-recognition adaptor of a CUL4A-RING ubiquitin ligase. Via its
    C-terminal WD40 beta-propeller, COP1 binds degron motifs in substrate transcription
    factors and signaling proteins and recruits them to the DCX(DET1-COP1) CUL4A ligase
    for ubiquitination and proteasomal degradation; substrate selection is regulated by
    the pseudokinase adaptors TRIB1/TRIB2.
  molecular_function:
    id: GO:1990756
    label: ubiquitin-like ligase-substrate adaptor activity
  directly_involved_in:
  - id: GO:0043161
    label: proteasome-mediated ubiquitin-dependent protein catabolic process
  - id: GO:0032436
    label: positive regulation of proteasomal ubiquitin-dependent protein catabolic process
  locations:
  - id: GO:0016607
    label: nuclear speck
  substrates:
  - id: UniProtKB:P05412
    label: JUN
  - id: UniProtKB:P04637
    label: TP53
  - id: UniProtKB:P50549
    label: ETV1
  - id: UniProtKB:P31947
    label: SFN
  in_complex:
    id: GO:0031464
    label: Cul4A-RING E3 ubiquitin ligase complex
  supported_by:
  - reference_id: PMID:14739464
    supporting_text: Human De-etiolated-1 regulates c-Jun by assembling a CUL4A ubiquitin
      ligase.
  - reference_id: PMID:21572435
    supporting_text: COP1 is a tumour suppressor that causes degradation of ETS transcription
      factors.
  - reference_id: file:human/COP1/COP1-deep-research-falcon.md
    supporting_text: Substrate selection is mediated by the WD40 domain, which recognizes
      a consensus VP (Val-Pro) degron motif present in many COP1 targets.
proposed_new_terms: []
suggested_questions:
- question: Does COP1 possess intrinsic, stand-alone E3 ligase activity toward all of its reported substrates, or is its physiological activity primarily channeled through the CUL4A-RING (DCX DET1-COP1) module in which RBX1 is the catalytic RING?
- question: How is COP1 substrate choice partitioned in vivo between its canonical WD40 degron binding and the TRIB1/TRIB2-mediated recruitment of non-canonical substrates such as C/EBPalpha?
- question: Which COP1 substrates are physiologically dominant in specific tissues (e.g., ETS factors in prostate, ACC1 in liver, c-Jun/p53 broadly), and does this explain its context-dependent tumor-suppressor versus other roles?
suggested_experiments:
- description: Define the COP1 ubiquitinome in cells with degron-binding-deficient WD40 mutants versus RING-catalytic mutants (e.g., quantitative diGly/ubiquitin-remnant proteomics) to separate substrate-recognition from catalytic contributions.
- description: Reconstitute the DCX(DET1-COP1) CUL4A-RBX1 complex in vitro and compare ubiquitination kinetics of c-Jun, p53, ETV1, SFN and ACC1 with and without TRIB1/TRIB2 to map the rules of substrate selectivity and adaptor competition.
- description: Use structure-guided degron mutagenesis of individual substrates (and the COP1 WD40 pocket) combined with cellular stability assays to validate which proteins are direct COP1 substrates versus indirect.
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:12615916
  title: Characterization of human constitutive photomorphogenesis protein 1, a RING
    finger ubiquitin ligase that interacts with Jun transcription factors and modulates
    their transcriptional activity.
  findings: []
- id: PMID:14739464
  title: Human De-etiolated-1 regulates c-Jun by assembling a CUL4A ubiquitin ligase.
  findings: []
- id: PMID:19805145
  title: E3 ubiquitin ligase COP1 regulates the stability and functions of MTA1.
  findings: []
- id: PMID:20843328
  title: Nuclear export regulation of COP1 by 14-3-3ฯƒ in response to DNA damage.
  findings: []
- id: PMID:21572435
  title: COP1 is a tumour suppressor that causes degradation of ETS transcription
    factors.
  findings: []
- id: PMID:21625211
  title: COP9 signalosome subunit 6 stabilizes COP1, which functions as an E3 ubiquitin
    ligase for 14-3-3ฯƒ.
  findings: []
- id: PMID:25117710
  title: Phosphorylation of ETS1 by Src family kinases prevents its recognition by
    the COP1 tumor suppressor.
  findings: []
- id: PMID:26496610
  title: A human interactome in three quantitative dimensions organized by stoichiometries
    and abundances.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: PMID:35140242
  title: Human transcription factor protein interaction networks.
  findings: []
- id: PMID:39920308
  title: Mutations in the kinesin KIF12 promote MASH in humans and mice by disrupting
    lipogenic enzyme turnover.
  findings: []
- id: Reactome:R-HSA-264418
  title: Translocation of COP1 from the nucleus to the cytoplasm
  findings: []
- id: Reactome:R-HSA-264435
  title: Dissociation of the COP1-p53 complex
  findings: []
- id: Reactome:R-HSA-264444
  title: Autoubiquitination of phospho-COP1(Ser-387 )
  findings: []
- id: Reactome:R-HSA-264458
  title: Proteasome mediated degradation of COP1
  findings: []
- id: Reactome:R-HSA-349444
  title: Phosphorylation of COP1 at Ser-387  by ATM
  findings: []
- id: Reactome:R-HSA-8952638
  title: AcM-UBE2M transfers NEDD8 to CRL4 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-8952639
  title: NEDD8:AcM-UBE2M binds CRL4 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-8955245
  title: CAND1 binds CRL4 E3 ubiquitin ligase in the nucleus
  findings: []
- id: Reactome:R-HSA-8955285
  title: COMMDs displace CAND1 from CRL4 E3 ubiquitin ligase complex
  findings: []
- id: Reactome:R-HSA-8956045
  title: COP9 signalosome deneddylates nuclear CRL4 E3 ubiquitin ligase complex
  findings: []
- id: file:human/COP1/COP1-deep-research-falcon.md
  title: Falcon deep research report for COP1
  reference_review:
    relevance: HIGH
    correctness: UNVERIFIED
    review_notes: "LLM-synthesized deep-research report (Edison/Falcon). Correctly
      scopes to human COP1/RFWD2 (Q8NHY2) and does NOT conflate it with plant
      Arabidopsis COP1; the MANDATORY VERIFICATION preamble appears heeded.
      Usefully consolidates the WD40 VP (Val-Pro) degron mechanism, the CRL4(COP1/DET1)
      substrate-receptor architecture, and ERK1/2-regulated nucleus/nuclear-envelope
      redistribution (Ouyang 2020). Treat substrate table skeptically: it mixes
      well-established substrates (p53, c-Jun, ETS factors, C/EBPalpha) with newer
      single-study or review-sourced claims (ACSL4, LUZP1, UTX/KDM6A, P57Kip2/CDKN1C,
      CDH18) and a c/EBPbeta-in-microglia claim (Ndoja 2020) that are not in the
      current GOA; these are not used to add or remove annotations here without
      primary verification. Primary PMIDs for the cited works were not all resolvable
      from the cache, so correctness is left UNVERIFIED pending PubMed checks."