DCUN1D4

gene
On this page

Also known as KIAA0276

Summary

DCUN1D4 (defective in cullin neddylation 1 domain containing 4, HGNC:28998) is a protein-coding gene on chromosome 4q12, encoding DCN1-like protein 4 (Q92564). Contributes to the neddylation of all cullins by transferring NEDD8 from N-terminally acetylated NEDD8-conjugating E2s enzyme to different cullin C-terminal domain-RBX complexes which are necessary for the activation of cullin-RING E3 ubiquitin ligases (CRLs).

Enables cullin family protein binding activity. Involved in positive regulation of protein neddylation. Located in nucleus.

Source: NCBI Gene 23142 — RefSeq curated summary.

At a glance

  • GWAS associations: 4
  • Clinical variants (ClinVar): 38 total
  • Druggable target: yes
  • MANE Select transcript: NM_001040402

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:28998
Approved symbolDCUN1D4
Namedefective in cullin neddylation 1 domain containing 4
Location4q12
Locus typegene with protein product
StatusApproved
AliasesKIAA0276
Ensembl geneENSG00000109184
Ensembl biotypeprotein_coding
OMIM612977
Entrez23142

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 11 protein_coding, 7 nonsense_mediated_decay, 7 protein_coding_CDS_not_defined, 3 retained_intron

ENST00000334635, ENST00000381441, ENST00000451288, ENST00000477560, ENST00000502930, ENST00000504113, ENST00000504661, ENST00000504923, ENST00000505403, ENST00000505634, ENST00000506673, ENST00000507659, ENST00000507741, ENST00000508257, ENST00000509068, ENST00000509376, ENST00000510518, ENST00000510587, ENST00000510808, ENST00000511675, ENST00000512199, ENST00000513800, ENST00000893398, ENST00000893399, ENST00000927742, ENST00000927743, ENST00000960096, ENST00000960097

RefSeq mRNA: 4 — MANE Select: NM_001040402 NM_001040402, NM_001287755, NM_001287757, NM_015115

CCDS: CCDS33982, CCDS3487, CCDS75123

Canonical transcript exons

ENST00000334635 — 11 exons

ExonStartEnd
ENSE000035031485186367051863709
ENSE000035081645187427151874385
ENSE000035227125191352951916837
ENSE000035232835188656851886638
ENSE000035778845191329051913392
ENSE000035871755184315351843267
ENSE000036111165189927051899378
ENSE000036481005187776351877854
ENSE000036515545186343751863507
ENSE000036816375191107051911174
ENSE000037896455189176051891851

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 98.11.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.7649 / max 169.1686, expressed in 1807 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter IDTPM avgSamples expressed
4760425.76491807

Top tissues by expression

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

TissueAnatomy IDExpression scoreQuality
calcaneal tendonUBERON:000370198.11gold quality
colonic epitheliumUBERON:000039795.44gold quality
germinal epithelium of ovaryUBERON:000130494.62gold quality
male germ line stem cell (sensu Vertebrata) in testisCL:0000089 ∩ UBERON:000047393.64gold quality
left ovaryUBERON:000211993.35gold quality
right ovaryUBERON:000211893.12gold quality
cauda epididymisUBERON:000436093.05gold quality
mucosa of stomachUBERON:000119992.88gold quality
popliteal arteryUBERON:000225092.88gold quality
tibial arteryUBERON:000761092.87gold quality
stromal cell of endometriumCL:000225592.68gold quality
blood vessel layerUBERON:000479792.55gold quality
lower esophagus muscularis layerUBERON:003583392.55gold quality
descending thoracic aortaUBERON:000234592.53gold quality
lower esophagusUBERON:001347392.53gold quality
right adrenal gland cortexUBERON:003582792.43gold quality
esophagogastric junction muscularis propriaUBERON:003584192.41gold quality
tendonUBERON:000004392.40gold quality
ovaryUBERON:000099292.40gold quality
aortaUBERON:000094792.39gold quality
left testisUBERON:000453392.29gold quality
right adrenal glandUBERON:000123392.05gold quality
right testisUBERON:000453492.05gold quality
urinary bladderUBERON:000125592.01gold quality
testisUBERON:000047391.95gold quality
right coronary arteryUBERON:000162591.95gold quality
adenohypophysisUBERON:000219691.94gold quality
tibial nerveUBERON:000132391.91gold quality
left adrenal gland cortexUBERON:003582591.89gold quality
spermCL:000001991.88gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

ExperimentMarker?Max mean expression
E-MTAB-6379no1316.61
E-ANND-3no0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

289 targeting DCUN1D4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNAMax scoreAvg scoremiRNA target_count
HSA-LET-7A-3P100.0074.033932
HSA-LET-7B-3P100.0074.083913
HSA-LET-7F-1-3P100.0074.023928
HSA-MIR-98-3P100.0074.083907
HSA-MIR-513A-5P100.0069.772465
HSA-MIR-3064-3P100.0070.091254
HSA-MIR-3613-3P100.0076.367965
HSA-MIR-5692A100.0074.406850
HSA-MIR-29A-3P100.0073.111835
HSA-MIR-29B-3P100.0073.181833
HSA-MIR-29C-3P100.0073.151833
HSA-MIR-9-5P100.0072.282361
HSA-MIR-3163100.0077.238605
HSA-MIR-3689D100.0066.141181
HSA-MIR-6851-5P100.0065.631294
HSA-MIR-3162-3P100.0065.37363
HSA-MIR-4789-3P99.9970.752484
HSA-MIR-186-5P99.9970.833707
HSA-MIR-428299.9975.366408
HSA-MIR-548AW99.9972.573559
HSA-MIR-4789-5P99.9870.762721
HSA-MIR-27A-3P99.9872.132955
HSA-MIR-27B-3P99.9872.132955
HSA-MIR-998599.9872.112939
HSA-LET-7F-2-3P99.9870.982588
HSA-MIR-1185-1-3P99.9871.042593
HSA-MIR-1185-2-3P99.9871.042593
HSA-MIR-477599.9875.006394
HSA-MIR-1213699.9872.815713
HSA-MIR-548P99.9872.253784

Cross-species orthologs

6 orthologs

OrganismSymbolGene ID
danio_reriodcun1d4ENSDARG00000092394
mus_musculusDcun1d4ENSMUSG00000051674
rattus_norvegicusDcun1d4ENSRNOG00000002152
drosophila_melanogasterSCCROFBGN0036510
drosophila_melanogasterSCCRO4FBGN0036967
caenorhabditis_elegansWBGENE00010428

Paralogs (4): DCUN1D1 (ENSG00000043093), DCUN1D5 (ENSG00000137692), DCUN1D2 (ENSG00000150401), DCUN1D3 (ENSG00000188215)

Protein

Protein identifiers

DCN1-like protein 4Q92564 (reviewed: Q92564)

Alternative names: DCUN1 domain-containing protein 4, Defective in cullin neddylation protein 1-like protein 4

All UniProt accessions (9): Q92564, D6RB33, D6RCB7, D6RDV8, D6RGX7, D6RIY3, H0Y907, H0Y9C5, H0YA35

UniProt curated annotations — full annotation on UniProt →

Function. Contributes to the neddylation of all cullins by transferring NEDD8 from N-terminally acetylated NEDD8-conjugating E2s enzyme to different cullin C-terminal domain-RBX complexes which are necessary for the activation of cullin-RING E3 ubiquitin ligases (CRLs).

Subunit / interactions. Interacts (via the DCUN1 domain) with the unneddylated cullins: interacts with CUL1, CUL2, CUL3, CUL4A, CUL4B and CUL5; these interactions promote the cullin neddylation and the identity of the cullin dictates the affinity of the interaction. Interacts with RBX1 and RNF7. Interacts with CAND1; this interaction is bridged by cullins such as CUL3 and strongly inhibits the neddylation of CUL3. These CAND-cullin-DCNL complexes can only be neddylated in the presence of a substrate adapter. Interacts (via DCUN1 domain) with UBE2M (N-terminally acetylated form) and probably with UBE2F (N-terminally acetylated form).

Subcellular location. Nucleus.

Domain organisation. The DCUN1 domain, also known as PONY domain, mediates the interaction with different cullins. The DCUN1 domain mediates the interaction with the N-terminally acetylated NEDD8-conjugating E2s enzyme leading to the NEDD8 transfer from N-terminally acetylated NEDD8-conjugating E2s enzyme to different cullin C-terminal domain-RBX complexes; the neddylation efficiency correlates with the DCUN1D5-cullin and DCUN1D5-E2 interaction affinities.

Isoforms (3)

UniProt IDNamesCanonical?
Q92564-11yes
Q92564-22
Q92564-33

RefSeq proteins (4): NP_001035492, NP_001274684, NP_001274686, NP_055930 (=MANE)

Domains & families (InterPro)

IDNameType
IPR005176PONY_domDomain
IPR014764DCN-protFamily
IPR042460DCN1-like_PONYHomologous_superfamily

Pfam: PF03556

UniProt features (27 total): helix 12, strand 3, mutagenesis site 3, turn 2, splice variant 2, chain 1, domain 1, region of interest 1, compositionally biased region 1, cross-link 1

Structure

Experimental structures (PDB)

1 structures.

PDBMethodResolution (Å)
5V89X-RAY DIFFRACTION1.55

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-Q92564-F181.390.65

Functional residue map

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

Post-translational modifications (1): 95

Mutagenesis-validated functional residues (3):

PositionPhenotype
250does not affect localization at nucleus; when associated with r-274 and a-280.
274does not affect localization at nucleus; when associated with a-250 and a-280.
280does not affect localization at nucleus; when associated with a-250 and r-274.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

IDPathway
R-HSA-8951664Neddylation

MSigDB gene sets: 275 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, GCM_MAP4K4, MULLIGHAN_NPM1_SIGNATURE_3_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, RORA1_01, AMIT_EGF_RESPONSE_60_HELA, ATACCTC_MIR202, GOBP_PROTEIN_NEDDYLATION, TGACCTY_ERR1_Q2, CACCAGC_MIR138, USF_C, SP1_Q2_01, SCHUHMACHER_MYC_TARGETS_UP, AAACCAC_MIR140

GO Biological Process (2): protein neddylation (GO:0045116), positive regulation of protein neddylation (GO:2000436)

GO Molecular Function (4): ubiquitin conjugating enzyme binding (GO:0031624), ubiquitin-like protein binding (GO:0032182), cullin family protein binding (GO:0097602), protein binding (GO:0005515)

GO Cellular Component (2): ubiquitin ligase complex (GO:0000151), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-1 pathways:

CategoryPathways
Post-translational protein modification1

GO top-level categories

Rollup of top GO terms by namespace:

CategoryTerms
protein binding2
protein modification by small protein conjugation1
protein neddylation1
positive regulation of protein modification by small protein conjugation or removal1
regulation of protein neddylation1
ubiquitin-like protein conjugating enzyme binding1
binding1
intracellular protein-containing complex1
transferase complex1
intracellular membrane-bounded organelle1

Protein interactions and networks

STRING

889 interactions, top by confidence (×1000):

Protein AProtein BPartner UniProtScore
DCUN1D4CWH43Q9H720581
DCUN1D4OCIAD1Q9NX40547
DCUN1D4OCIAD2Q56VL3507
DCUN1D4FBXL13Q8NEE6497
DCUN1D4CUL3Q13618477
DCUN1D4LRRC66Q68CR7475
DCUN1D4SDAD1Q9NVU7473
DCUN1D4COPS2P61201468
DCUN1D4SPATA18Q8TC71466
DCUN1D4DCUN1D1Q96GG9450
DCUN1D4FBXL3Q9UKT7442
DCUN1D4FRYLO94915434
DCUN1D4ARHGAP24Q8N264417
DCUN1D4A0A087WY85A0A087WY85412
DCUN1D4NFXL1Q6ZNB6407

IntAct

10 interactions, top by confidence:

ABTypeScore
DCUN1D4psi-mi:“MI:0915”(physical association)0.490
DDX21MED19psi-mi:“MI:2364”(proximity)0.480
ECE1DCUN1D4psi-mi:“MI:0915”(physical association)0.370
DCUN1D4ARL4Cpsi-mi:“MI:0914”(association)0.350
DCUN1D4AFPpsi-mi:“MI:0914”(association)0.350
NPM1SBNO1psi-mi:“MI:2364”(proximity)0.270
VAV2DCUN1D4psi-mi:“MI:0915”(physical association)0.000

BioGRID (54): CUL1 (Biochemical Activity), CUL2 (Biochemical Activity), CUL3 (Biochemical Activity), CUL4A (Biochemical Activity), CUL4B (Biochemical Activity), CUL5 (Biochemical Activity), DCUN1D4 (Co-fractionation), TOP3A (Co-fractionation), DCUN1D4 (Affinity Capture-MS), CUL1 (Affinity Capture-MS), CUL2 (Affinity Capture-MS), CUL3 (Affinity Capture-MS), CUL5 (Affinity Capture-MS), CAND1 (Affinity Capture-MS), RBX1 (Affinity Capture-MS)

ESM2 similar proteins: A4D161, B1AR13, D3ZV31, E1BBQ2, E1BGQ2, F1N2W9, O42148, O42224, O70524, O95453, P0C7P0, P56726, P97698, Q2T9V7, Q3UGM2, Q497H0, Q56K12, Q5RC51, Q5T6S3, Q5U2M7, Q5XII8, Q5ZIA0, Q60769, Q66J85, Q6DDJ3, Q6DJB3, Q6ZN54, Q7T0P6, Q7Z2E3, Q8BKW4, Q8BYN3, Q8CCA0, Q8IWR0, Q8K214, Q8K2I9, Q8NE86, Q8NFZ0, Q8TDW4, Q92564, Q96GD3

Diamond homologs: A4IHK8, Q1RMX9, Q4V8B2, Q54GP1, Q5ADL9, Q5E9V1, Q5PPL2, Q5R9G1, Q5RDF9, Q5RHX6, Q5ZKU1, Q60YT5, Q6C0B6, Q6DFA1, Q6PH85, Q86JM4, Q8BZJ7, Q8CCA0, Q8IWE4, Q8K0V2, Q8T8S1, Q92564, Q96GG9, Q9BTE7, Q9CXV9, Q9QZ73, Q9U3C8, Q9VUQ8, Q9VWB1, Q5AWS1, Q8WZK4, Q9MBG8, Q4PF67, Q12395, Q750Y3, P0CN06, P0CN07, Q6FJR2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

ClassificationCount (floor)
Pathogenic0
Likely pathogenic0
Uncertain significance23
Likely benign1
Benign0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2547 predictions. Top by Δscore:

VariantEffectΔscore
4:51843264:GTCA:Gdonor_gain1.0000
4:51843268:G:GGdonor_gain1.0000
4:51863434:A:AGacceptor_gain1.0000
4:51863435:A:Gacceptor_gain1.0000
4:51863436:G:GAacceptor_gain1.0000
4:51863436:GA:Gacceptor_gain1.0000
4:51863436:GAT:Gacceptor_gain1.0000
4:51863436:GATT:Gacceptor_gain1.0000
4:51863436:GATTT:Gacceptor_gain1.0000
4:51863503:AGCTG:Adonor_gain1.0000
4:51863504:GCTG:Gdonor_gain1.0000
4:51863504:GCTGG:Gdonor_gain1.0000
4:51863505:CTG:Cdonor_gain1.0000
4:51863505:CTGG:Cdonor_loss1.0000
4:51863507:GGT:Gdonor_loss1.0000
4:51863508:G:GGdonor_gain1.0000
4:51863508:G:Tdonor_loss1.0000
4:51863509:T:Gdonor_loss1.0000
4:51874270:GGAA:Gacceptor_gain1.0000
4:51874382:A:Gdonor_gain1.0000
4:51877754:A:AGacceptor_gain1.0000
4:51877755:A:Gacceptor_gain1.0000
4:51877761:A:AGacceptor_gain1.0000
4:51877761:AGCAT:Aacceptor_gain1.0000
4:51877762:G:GAacceptor_gain1.0000
4:51877762:GC:Gacceptor_gain1.0000
4:51877762:GCA:Gacceptor_gain1.0000
4:51877762:GCAT:Gacceptor_gain1.0000
4:51877762:GCATG:Gacceptor_gain1.0000
4:51877851:GCAG:Gdonor_gain1.0000

AlphaMissense

1953 scored. Top likely-pathogenic:

VariantProtein changeam_pathogenicity
4:51877829:C:GC106W1.000
4:51877836:T:AW109R1.000
4:51877836:T:CW109R1.000
4:51886607:T:CF128S1.000
4:51886609:T:CC129R1.000
4:51886610:G:AC129Y1.000
4:51886611:T:GC129W1.000
4:51886631:C:AP136Q1.000
4:51891770:T:AL142H1.000
4:51891770:T:CL142P1.000
4:51891779:C:AA145D1.000
4:51891794:C:AA150E1.000
4:51891805:G:CG154R1.000
4:51891806:G:AG154D1.000
4:51891812:T:CF156S1.000
4:51891826:T:AW161R1.000
4:51891826:T:CW161R1.000
4:51891827:G:CW161S1.000
4:51891828:G:CW161C1.000
4:51891828:G:TW161C1.000
4:51891835:G:AG164R1.000
4:51891835:G:CG164R1.000
4:51891836:G:AG164E1.000
4:51899290:T:CL176P1.000
4:51899352:T:GY197D1.000
4:51899361:G:CA200P1.000
4:51899362:C:AA200E1.000
4:51899364:T:CF201L1.000
4:51899366:T:AF201L1.000
4:51899366:T:GF201L1.000

dbSNP variants (sampled 300 via entrez): RS1000039344 (4:51839338 G>A,T), RS1000043555 (4:51879269 T>G), RS1000111279 (4:51914646 G>A,T), RS1000149939 (4:51884917 G>A,T), RS1000163884 (4:51915016 G>A), RS1000214392 (4:51833139 T>C), RS1000227149 (4:51898585 A>G), RS1000258977 (4:51902584 C>G,T), RS1000372477 (4:51874562 C>T), RS1000379244 (4:51851133 G>T), RS1000500826 (4:51897486 C>G,T), RS1000508924 (4:51884628 C>T), RS1000517338 (4:51901617 C>G,T), RS1000569997 (4:51901892 G>A,T), RS1000589095 (4:51857463 C>G,T)

Disease associations

OMIM: gene MIM:612977 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

StudyTraitp-value
GCST006088_36Familial squamous cell lung carcinoma4.000000e-07
GCST008058_1Estimated glomerular filtration rate4.000000e-10
GCST008059_248Estimated glomerular filtration rate2.000000e-10
GCST008163_485Height1.000000e-06

EFO canonical traits (1, from GWAS)

EFO IDTrait name
EFO:0006953family history of lung cancer

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295914 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 3 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChemblTypeValueUnitMolecule
6.09Ki807nMCHEMBL4592844
6.09Ki810nMCHEMBL4592844

PubChem BioAssay actives

2 with measured affinity, of 6 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

CompoundAssayTypeValueUnit
4-(4-methylphenyl)-2-prop-2-ynylsulfanyl-6-(1,3-thiazol-2-ylsulfanyl)pyrimidine-5-carbonitrile1599586: Binding affinity to N-terminal GST tagged recombinant DCN4 (unknown origin) (102 to 292 residues) expressed in Escherichia coli BL21(DE3) assessed as reduction in DCN1/FAM-labelled N-terminal acetylated UBE2M (1 to 21 residues) protein-protein interaction after 30 mins by HTRF assayki0.8070uM

CTD chemical–gene interactions

41 total (human), top 30 by PubMed support.

ChemicalActions (top 5)PubMed papers
Valproic Acidaffects cotreatment, decreases expression, affects expression, increases methylation7
trichostatin Aaffects cotreatment, decreases expression3
potassium chromate(VI)affects cotreatment, decreases expression2
Phenylmercuric Acetateaffects cotreatment, decreases expression2
aristolochic acid Idecreases expression1
FR900359decreases phosphorylation1
dicrotophosdecreases expression1
methylmercuric chloridedecreases expression1
triphenyl phosphateaffects expression1
salinomycindecreases expression1
beta-lapachonedecreases expression1
sodium arsenitedecreases expression1
epigallocatechin gallatedecreases expression, affects cotreatment1
chromium hexavalent iondecreases expression1
CGP 52608affects binding, increases reaction1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamideaffects cotreatment, decreases expression1
dorsomorphinaffects cotreatment, decreases expression1
bisphenol Saffects cotreatment, increases expression1
jinfukangdecreases expression1
picoxystrobinincreases expression1
PCI 5002affects cotreatment, increases expression1
Temozolomidedecreases expression1
Zoledronic Acidincreases expression1
Vorinostatincreases expression1
Panobinostataffects cotreatment, decreases expression1
Acetaminophendecreases expression1
Dexamethasoneincreases expression, affects cotreatment1
Indomethacinaffects cotreatment, increases expression1
Methyl Methanesulfonatedecreases expression1
Phthalic Acidsincreases methylation1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay IDTypeDescriptionSource paper
CHEMBL4222551BindingInhibition of human DCN4-mediated cullin neddylation assessed as reduction in transfer of fluorescein-5-maleimide-tagged NEDD8 from N-terminally acetylated human UBE2M to CUL2-CTD at 50 uM measured for 1 min by pulse-chase assayPiperidinyl Ureas Chemically Control Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation. — J Med Chem

Clinical trials (associated diseases)

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

No linked Atlas pages yet — the cross-entity mesh grows as the corpus expands.