CUL4A

Summary

CUL4A (cullin 4A, HGNC:2554) is a protein-coding gene on chromosome 13q34, encoding Cullin-4A (Q13619). Core component of multiple cullin-RING-based E3 ubiquitin-protein ligase complexes which mediate the ubiquitination of target proteins.

CUL4A is the ubiquitin ligase component of a multimeric complex involved in the degradation of DNA damage-response proteins (Liu et al., 2009 [PubMed 19481525]).

Source: NCBI Gene 8451 — RefSeq curated summary.

At a glance

• GWAS associations: 15
• Clinical variants (ClinVar): 105 total — 1 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_001008895

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2554
Approved symbol	CUL4A
Name	cullin 4A
Location	13q34
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000139842
Ensembl biotype	protein_coding
OMIM	603137
Entrez	8451

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 7 protein_coding, 6 protein_coding_CDS_not_defined

ENST00000326335, ENST00000375440, ENST00000375441, ENST00000451881, ENST00000463426, ENST00000470067, ENST00000472083, ENST00000474116, ENST00000488558, ENST00000494985, ENST00000498562, ENST00000617546, ENST00000909782

RefSeq mRNA: 11 — MANE Select: NM_001008895 NM_001008895, NM_001278513, NM_001278514, NM_001354938, NM_001354939, NM_001354940, NM_001354941, NM_001354942, NM_001354943, NM_001354944, NM_003589

CCDS: CCDS41908, CCDS73604, CCDS86363, CCDS9533

Canonical transcript exons

ENST00000375440 — 20 exons

Exon	Start	End
ENSE00000940408	113242968	113243160
ENSE00001133490	113244410	113244514
ENSE00001133496	113239433	113239551
ENSE00001592368	113260607	113260759
ENSE00001630009	113236823	113236890
ENSE00001953061	113209613	113209775
ENSE00003473731	113254953	113255125
ENSE00003481819	113227976	113228045
ENSE00003514540	113254693	113254798
ENSE00003520003	113233897	113233986
ENSE00003537456	113244949	113245059
ENSE00003571959	113233177	113233339
ENSE00003586159	113245152	113245237
ENSE00003622684	113253082	113253195
ENSE00003623478	113218945	113219048
ENSE00003625845	113209973	113210088
ENSE00003631909	113229446	113229519
ENSE00003659194	113235063	113235145
ENSE00003691787	113245956	113246063
ENSE00003898378	113263487	113267108

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 97.58.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.1248 / max 597.0157, expressed in 1807 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
136206	20.5783	1804
136205	1.1306	721
207117	0.7450	212
136207	0.5928	344
136208	0.0782	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gastrocnemius	UBERON:0001388	97.58	gold quality
muscle of leg	UBERON:0001383	97.40	gold quality
gluteal muscle	UBERON:0002000	97.30	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.18	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.96	gold quality
calcaneal tendon	UBERON:0003701	96.69	gold quality
triceps brachii	UBERON:0001509	96.01	gold quality
muscle organ	UBERON:0001630	95.99	gold quality
biceps brachii	UBERON:0001507	95.71	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	95.53	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	95.51	gold quality
mucosa of stomach	UBERON:0001199	95.31	gold quality
choroid plexus epithelium	UBERON:0003911	94.98	gold quality
skin of leg	UBERON:0001511	94.89	gold quality
right atrium auricular region	UBERON:0006631	94.86	gold quality
heart left ventricle	UBERON:0002084	94.71	gold quality
skeletal muscle tissue	UBERON:0001134	94.68	gold quality
parietal pleura	UBERON:0002400	94.68	gold quality
tendon	UBERON:0000043	94.64	gold quality
cardiac ventricle	UBERON:0002082	94.61	gold quality
blood vessel layer	UBERON:0004797	94.54	gold quality
skin of abdomen	UBERON:0001416	94.53	gold quality
right testis	UBERON:0004534	94.26	gold quality
left testis	UBERON:0004533	94.23	gold quality
stromal cell of endometrium	CL:0002255	94.09	gold quality
zone of skin	UBERON:0000014	94.00	gold quality
heart	UBERON:0000948	93.98	gold quality
diaphragm	UBERON:0001103	93.94	gold quality
germinal epithelium of ovary	UBERON:0001304	93.90	gold quality
testis	UBERON:0000473	93.87	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.73

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): DNMT3B

miRNA regulators (miRDB)

103 targeting CUL4A, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502

Literature-anchored findings (GeneRIF, showing 40)

• TFDP1, CUL4A, and CDC16 are probable targets of an amplification mechanism and therefore may be involved, together or separately, in development and/or progression of some hepatocellular carcinomas (PMID:12029633)
• DET1 promotes ubiquitination and degradation of c-Jun by assembling a multisubunit ubiquitin ligase containing DNA Damage Binding Protein-1 (DDB1), cullin 4A (CUL4A), Regulator of Cullins-1 (ROC1), and constitutively photomorphogenic-1 (PMID:14739464)
• role of Cul4A in the MDM2-mediated proteolysis of p53 (PMID:15548678)
• PCNA is involved in mediating Cdt1 degradation by the Cul4-Ddb1 ligase in response to DNA damage. (PMID:16407242)
• Cul4A, PCNA, and DDB1 are involved in the degradation of Cdt1 after ultraviolet radiation (PMID:16407252)
• Monoubiquitinated histone H2A in native chromatin coimmunoprecipitates with the endogenous DDB1-CUL4A(DDB2) complex in response to UV irradiation. (PMID:16473935)
• CUL-4A mediates the proteolytic degradation of DDB2 and this degradation event, initiated at the lesion sites, regulates damage recognition by XPC. (PMID:16527807)
• The F-box protein Skp2, in addition to utilizing Cul1-Skp1, utilizes Cul4A-DDB1 to induce proteolysis of p27Kip1. (PMID:16537899)
• This study uncovers CUL4-DDB-ROC1 as a histone ubiquitin ligase and demonstrate that histone H3 and H4 ubiquitylation participates in the cellular response to DNA damage. (PMID:16678110)
• PCNA, L2DTL and the DDB1-CUL4A complex play critical and differential roles in regulating the protein stability of p53 and MDM2/HDM2 in unstressed and stressed cells. (PMID:16861890)
• L2DTL and PCNA interact with CUL4/DDB1 complexes and are involved in CDT1 degradation after DNA damage. (PMID:16861906)
• These studies uncover diverse substrate receptors for Cul4 and identify Cdt2 as a conserved component of the Cul4-Ddb1 E3 that is essential to destroy Cdt1 and ensure proper cell cycle regulation of DNA replication. (PMID:16949367)
• DDB2 can bind to damaged DNA in vivo as a monomer, whereas Cul4A recruitment to damage sites depends on the fully assembled complex. (PMID:16951172)
• crystallographic analyses of the virally hijacked form of the human DDB1-CUL4A-ROC1 machinery (PMID:16964240)
• These findings demonstrate that the conserved DET1 complex modulates Cul4A functions by a novel mechanism. (PMID:17452440)
• The HIV1 protein Vpr acts to promote G2 cell cycle arrest by engaging a DDB1 and Cullin4A-containing ubiquitin ligase complex using VprBP/DCAF1 as an adaptor. (PMID:17620334)
• VprBP depletion abolished the in vivo interaction of Merlin and Roc1-Cullin4A-DDB1, which resulted in Merlin stabilization and inhibited ERK and Rac activation (PMID:18332868)
• Results indicate that FBW5-DDB1-CUL4-ROC1 is an E3 ubiquitin ligase regulating TSC2 protein stability and TSC complex turnover. (PMID:18381890)
• Cul4A-DDB1DCAF1 ubiquitin ligase assembly protects HIV-1 Vpr from proteasomal degradation (PMID:18524771)
• Data show that human immunodeficiency virus type 1 Vpr-binding protein VprBP binds stoichiometrically with DDB1 through its WD40 domain and through DDB1 to CUL4A, subunits of the COP9/signalsome. (PMID:18606781)
• CDK inhibitor p21 is degraded by a proliferating cell nuclear antigen-coupled Cul4-DDB1Cdt2 pathway during S phase and after UV irradiation (PMID:18703516)
• CUL4A and CUL4B are therefore components of a conserved Wnt-induced proteasome targeting (WIPT) complex that regulates p27(KIP1) levels and cell cycle progression in mammalian cells. (PMID:19056892)
• DDB1-CUL4 and MLL1 complexes constitute a novel pathway that mediates p16 activation during oncogenic checkpoint response. (PMID:19208841)
• Cells depleted of Dda1 spontaneously accumulated double-stranded DNA breaks in a similar way to Cul4A-, Cul4B- or Wdr23-depleted cells, indicating that Dda1 interacts physically and functionally with cullin-RING E3 ligases complexes. (PMID:19295130)
• Data show that REDD1 is subject to ubiquitin-mediated degradation mediated by the CUL4A-DDB1-ROC1-beta-TRCP E3 ligase complex and through the activity of glycogen synthase kinase 3beta. (PMID:19557001)
• Studies indicate that CUL4 uses a large beta-propeller protein, DDB1, as a linker to interact with a subset of WD40 proteins. (PMID:19818632)
• study indicates that Cul4A amplification and overexpression play an oncogenic role in the pathogenesis of mesothelioma (PMID:19929949)
• 13q34 amplification may be of relevance in tumor progression of breast cancers by inducing overexpression of CUL4A and TFDP1, important in cell cycle regulation. These genes were also overexpressed in non-basal-like tumor samples. (PMID:19995430)
• the interplay between CUL4A and CUL4B in pathogenesis of CUL4B-deficiency in humans (PMID:20064923)
• DDB1 modulates the function of APC/C(Cdh1) in a manner independent of the Cul4-DDB1 complex (PMID:20395298)
• This study identifies CRL4-Cdt2 ubiquitin ligase to promote the ubiquitin-dependent proteolysis of the histone H4 methyltransferase Set8 during S-phase of the cell cycle and after UV-irradiation in a reaction that is dependent on PCNA. (PMID:20932471)
• Increased PRMT5 activity mediates key events associated with cyclin D1-dependent neoplastic growth, including CUL4 repression, CDT1 overexpression, and DNA rereplication. (PMID:20951943)
• the CUL4A.DDB1 E3 complex is important for regulation of RASSF1A during mitosis, and it may contribute to inactivation of RASSF1A and promoting cell cycle progression (PMID:21205828)
• Studies indicate the modular architecture of DDB1-CUL4 in complex with DDB2, CSA and CDT2 in DNA repair of UV-induced DNA lesions. (PMID:21550341)
• hCUL4A suppresses apoptosis and DNA damage by regulating apoptosis-related proteins and cell cycle regulators (Bcl-2, caspase-3, p53 and p27); consequently, hCUL4A promotes cell survival. (PMID:22120631)
• Artemis and DDB2 regulate p27 via the Cul4A-based E3 ligase complex. (PMID:22134138)
• subjects with tumors that highly expressed CUL4A had poor overall survival and CUL4A downregulation inhibited cell proliferation and induced apoptosis in vitro and in vivo. (PMID:22422151)
• Activation of EGFR inhibits the interaction of PCNA with CUL4A, whereas inhibition of EGFR leads to increased CUL4A-PCNA interaction and CUL4A-dependent ubiquitin-mediated degradation of PCNA (PMID:22692198)
• Findings indicate structural and conformational insights of the DDB1-CUL4A(DDB2) E3 ligase, with significant implications for the regulation and overall organization of the proteins responsible for initiation of nucleotide-excision repair (NER) pathway. (PMID:22822215)
• potential GRK5 interacting proteins and the association of GRK5 with DDB1 in cell and the regulation of GRK5 level by DDB1-CUL4 ubiquitin ligase complex-dependent proteolysis pathway (PMID:22952844)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	cul4a	ENSDARG00000096578
mus_musculus	Cul4a	ENSMUSG00000031446
rattus_norvegicus	Cul4a	ENSRNOG00000019649
drosophila_melanogaster	Cul4	FBGN0033260

Paralogs (7): CUL3 (ENSG00000036257), CUL1 (ENSG00000055130), CUL2 (ENSG00000108094), CACUL1 (ENSG00000151893), CUL4B (ENSG00000158290), CUL5 (ENSG00000166266), ANAPC2 (ENSG00000176248)

Protein

Protein identifiers

Cullin-4A — Q13619 (reviewed: Q13619)

All UniProt accessions (3): Q13619, A0A087WWN2, A0A0A0MR50

UniProt curated annotations — full annotation on UniProt →

Function. Core component of multiple cullin-RING-based E3 ubiquitin-protein ligase complexes which mediate the ubiquitination of target proteins. As a scaffold protein may contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme. The E3 ubiquitin-protein ligase activity of the complex is dependent on the neddylation of the cullin subunit and is inhibited by the association of the deneddylated cullin subunit with TIP120A/CAND1. The functional specificity of the E3 ubiquitin-protein ligase complex depends on the variable substrate recognition component. DCX(DET1-COP1) directs ubiquitination of JUN. DCX(DDB2) directs ubiquitination of XPC. DCX(DDB2) ubiquitinates histones H3-H4 and is required for efficient histone deposition during replication-coupled (H3.1) and replication-independent (H3.3) nucleosome assembly, probably by facilitating the transfer of H3 from ASF1A/ASF1B to other chaperones involved in histone deposition. DCX(DTL) plays a role in PCNA-dependent polyubiquitination of CDT1 and MDM2-dependent ubiquitination of p53/TP53 in response to radiation-induced DNA damage and during DNA replication. DCX(DTL) directs autoubiquitination of DTL. In association with DDB1 and SKP2 probably is involved in ubiquitination of CDKN1B/p27kip. Is involved in ubiquitination of HOXA9. The DDB1-CUL4A-DTL E3 ligase complex regulates the circadian clock function by mediating the ubiquitination and degradation of CRY1. The DCX(ERCC8) complex (also named CSA complex) plays a role in transcription-coupled repair (TCR). A number of DCX complexes (containing either TRPC4AP or DCAF12 as substrate-recognition component) are part of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation. The DCX(AMBRA1) complex is a master regulator of the transition from G1 to S cell phase by mediating ubiquitination of phosphorylated cyclin-D (CCND1, CCND2 and CCND3). The DCX(AMBRA1) complex also acts as a regulator of Cul5-RING (CRL5) E3 ubiquitin-protein ligase complexes by mediating ubiquitination and degradation of Elongin-C (ELOC) component of CRL5 complexes. With CUL4B, contributes to ribosome biogenesis.

Subunit / interactions. Can self-associate. Component of multiple DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes that seem to consist of DDB1, CUL4A or CUL4B, RBX1 and a variable substrate recognition component which seems to belong to a protein family described as DCAF (Ddb1- and Cul4-associated factor) or CDW (CUL4-DDB1-associated WD40-repeat) proteins. Component of the CSA complex (DCX(ERCC8) complex) containing ERCC8, RBX1, DDB1 and CUL4A; the CSA complex interacts with RNA polymerase II; upon UV irradiation it interacts with the COP9 signalosome and preferentially with the hyperphosphorylated form of RNA polymerase II. Component of the DCX(DET1-COP1) complex with the substrate recognition component DET1 and COP1. Component of the DCX(DDB2) complex with the substrate recognition component DDB2. Component of the DCX(DTL) complex with the putative substrate recognition component DTL. Component of DCX complexes part of the DesCEND (destruction via C-end degrons) pathway, which contain either TRPC4AP or DCAF12 as substrate-recognition component. Component of the DCX(AMBRA1) complex with the substrate recognition component AMBRA1. Interacts with DDB1, RBX1, RNF7, CDT1, TIP120A/CAND1, SKP2, CDKN1B, MDM2, TP53 and HOXA9. Interacts with DDB2; the interactions with DDB2 and CAND1 are mutually exclusive. Interacts with DCAF1, DTL, DDA1, DCAF6, DCAF4, DCAF16, DCAF17, DET1, WDTC1, DCAF5, DCAF11, WDR24A, COP1, PAFAH1B1, ERCC8, GRWD1, FBXW5, RBBP7, GNB2, WSB1, WSB2, NUP43, PWP1, FBXW8, ATG16L1, KATNB1, RBBP4, RBBP5, LRWD1 and DCAF8. May interact with WDR26, WDR51B, SNRNP40, WDR61, WDR76, WDR5. Interacts (when neddylated) with ARIH1; leading to activate the E3 ligase activity of ARIH1. The DDB1-CUL4A complex interacts with CRY1. Interacts (unneddylated form) with DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4 and DCUN1D5; these interactions promote the cullin neddylation. (Microbial infection) Interacts with Epstein-Barr virus BPLF1.

Post-translational modifications. Neddylated; required for activity of cullin-RING-based E3 ubiquitin-protein ligase complexes. Deneddylated via its interaction with the COP9 signalosome (CSN) complex. (Microbial infection) Deneddylated by Epstein-Barr virus BPLF1 leading to a S-phase-like environment that is required for efficient replication of the viral genome.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the cullin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q13619-1	1	yes
Q13619-2	2

RefSeq proteins (11): NP_001008895, NP_001265442, NP_001265443, NP_001341867, NP_001341868, NP_001341869, NP_001341870, NP_001341871, NP_001341872, NP_001341873, NP_003580 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001373	Cullin_N	Domain
IPR016157	Cullin_CS	Conserved_site
IPR016158	Cullin_homology	Domain
IPR016159	Cullin_repeat-like_dom_sf	Homologous_superfamily
IPR019559	Cullin_neddylation_domain	Domain
IPR036317	Cullin_homology_sf	Homologous_superfamily
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR045093	Cullin	Family
IPR059120	Cullin-like_AB	Domain

Pfam: PF00888, PF10557, PF26557

UniProt features (80 total): helix 35, strand 22, turn 11, cross-link 3, sequence conflict 2, mutagenesis site 2, chain 1, domain 1, modified residue 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
7OPC	ELECTRON MICROSCOPY	3
7OPD	ELECTRON MICROSCOPY	3
2HYE	X-RAY DIFFRACTION	3.1
9LWI	ELECTRON MICROSCOPY	3.12
9EG8	ELECTRON MICROSCOPY	3.39
8B3I	ELECTRON MICROSCOPY	3.5
8B3G	ELECTRON MICROSCOPY	4.4
4A0K	X-RAY DIFFRACTION	5.93
9LWJ	ELECTRON MICROSCOPY	7.19
9LWL	ELECTRON MICROSCOPY	7.25
7OKQ	ELECTRON MICROSCOPY	8.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13619-F1	89.26	0.74

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 (4): 10, 8, 33, 705

Mutagenesis-validated functional residues (2):

Position	Phenotype
86–90	largely reduces interaction with ddb1; abolishes interaction with ddb2.
139–142	largely reduces interaction with ddb1; abolishes interaction with ddb2.

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-110314	Recognition of DNA damage by PCNA-containing replication complex
R-HSA-5696394	DNA Damage Recognition in GG-NER
R-HSA-5696395	Formation of Incision Complex in GG-NER
R-HSA-5696400	Dual Incision in GG-NER
R-HSA-6781823	Formation of TC-NER Pre-Incision Complex
R-HSA-6781827	Transcription-Coupled Nucleotide Excision Repair (TC-NER)
R-HSA-6782135	Dual incision in TC-NER
R-HSA-6782210	Gap-filling DNA repair synthesis and ligation in TC-NER
R-HSA-8951664	Neddylation

MSigDB gene sets: 358 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_DNA_TEMPLATED_DNA_REPLICATION_MAINTENANCE_OF_FIDELITY, REACTOME_FORMATION_OF_INCISION_COMPLEX_IN_GG_NER, GOBP_MITOTIC_CYTOKINESIS, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_RIBOSOME_BIOGENESIS, GOBP_REGULATION_OF_CELL_CYCLE_CHECKPOINT, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, AAGCAAT_MIR137, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_SOMATIC_STEM_CELL_POPULATION_MAINTENANCE, GOBP_REGULATION_OF_DNA_TEMPLATED_DNA_REPLICATION, GOBP_CELLULAR_RESPONSE_TO_UV, GOBP_CELLULAR_RESPONSE_TO_LIGHT_STIMULUS

GO Biological Process (29): G1/S transition of mitotic cell cycle (GO:0000082), in utero embryonic development (GO:0001701), DNA repair (GO:0006281), DNA damage response (GO:0006974), spermatogenesis (GO:0007283), cell population proliferation (GO:0008283), positive regulation of cell population proliferation (GO:0008284), protein ubiquitination (GO:0016567), hemopoiesis (GO:0030097), negative regulation of granulocyte differentiation (GO:0030853), cellular response to UV (GO:0034644), somatic stem cell population maintenance (GO:0035019), T cell activation (GO:0042110), ribosome biogenesis (GO:0042254), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), positive regulation of protein catabolic process (GO:0045732), rhythmic process (GO:0048511), intrinsic apoptotic signaling pathway (GO:0097193), ubiquitin-dependent protein catabolic process via the C-end degron rule pathway (GO:0140627), positive regulation of G1/S transition of mitotic cell cycle (GO:1900087), regulation of DNA damage checkpoint (GO:2000001), regulation of nucleotide-excision repair (GO:2000819), ubiquitin-dependent protein catabolic process (GO:0006511), proteasomal protein catabolic process (GO:0010498), developmental process (GO:0032502), miRNA-mediated gene silencing by mRNA destabilization (GO:0035279), regulation of protein metabolic process (GO:0051246), type I interferon-mediated signaling pathway (GO:0060337), base-excision repair, AP site formation via deaminated base removal (GO:0097510)

GO Molecular Function (4): ubiquitin protein ligase binding (GO:0031625), ubiquitin protein ligase activity (GO:0061630), ubiquitin ligase complex scaffold activity (GO:0160072), protein binding (GO:0005515)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), Cul4A-RING E3 ubiquitin ligase complex (GO:0031464), Cul4-RING E3 ubiquitin ligase complex (GO:0080008), cullin-RING ubiquitin ligase complex (GO:0031461), Cul4B-RING E3 ubiquitin ligase complex (GO:0031465)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Global Genome Nucleotide Excision Repair (GG-NER)	3
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	3
DNA Damage Bypass	1
Nucleotide Excision Repair	1
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
Cul4-RING E3 ubiquitin ligase complex	2
mitotic cell cycle	1
mitotic cell cycle phase transition	1
cell cycle G1/S phase transition	1
chordate embryonic development	1
DNA metabolic process	1
DNA damage response	1
cellular response to stress	1
developmental process involved in reproduction	1
male gamete generation	1
cellular process	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
protein modification by small protein conjugation	1
cell development	1
negative regulation of myeloid leukocyte differentiation	1
granulocyte differentiation	1
regulation of granulocyte differentiation	1
response to UV	1
cellular response to light stimulus	1
stem cell population maintenance	1
lymphocyte activation	1
ribonucleoprotein complex biogenesis	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
positive regulation of catabolic process	1
protein catabolic process	1
regulation of protein catabolic process	1
positive regulation of protein metabolic process	1
biological_process	1
intracellular signal transduction	1
apoptotic signaling pathway	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
G1/S transition of mitotic cell cycle	1
positive regulation of mitotic cell cycle phase transition	1
positive regulation of cell cycle G1/S phase transition	1
regulation of G1/S transition of mitotic cell cycle	1
ubiquitin-like protein ligase binding	1

Protein interactions and networks

STRING

2692 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CUL4A	RBX1	P62877	999
CUL4A	CRBN	Q96SW2	999
CUL4A	DDB1	Q16531	999
CUL4A	DCAF1	Q9Y4B6	999
CUL4A	DDB2	Q92466	998
CUL4A	DET1	Q7L5Y6	996
CUL4A	RNF7	Q9UBF6	995
CUL4A	DTL	Q9NZJ0	990
CUL4A	CUL1	Q13616	987
CUL4A	CUL2	Q13617	972
CUL4A	DDA1	Q9BW61	970
CUL4A	CUL4B	Q13620	967
CUL4A	CUL3	Q13618	966
CUL4A	NEDD8	Q15843	956
CUL4A	CUL7	Q14999	954

IntAct

229 interactions, top by confidence:

A	B	Type	Score
NEDD8	UBE2M	psi-mi:“MI:0914”(association)	0.940
DDB1	CUL4A	psi-mi:“MI:0914”(association)	0.920
DDB1	CUL4A	psi-mi:“MI:0915”(physical association)	0.920
CUL4A	DDB1	psi-mi:“MI:0915”(physical association)	0.920
COPS5	COPS2	psi-mi:“MI:0914”(association)	0.910
CUL4A	DDB2	psi-mi:“MI:0915”(physical association)	0.900
DDB2	CUL4A	psi-mi:“MI:0914”(association)	0.900
GPS1	COPS2	psi-mi:“MI:0915”(physical association)	0.860
COPS2	GPS1	psi-mi:“MI:0914”(association)	0.860
COPS8	COPS2	psi-mi:“MI:0914”(association)	0.850
COPS5	CUL4A	psi-mi:“MI:0914”(association)	0.840
UBXN7	VCP	psi-mi:“MI:0914”(association)	0.820
CUL4B	RBX1	psi-mi:“MI:0914”(association)	0.820
CUL4B	COPS2	psi-mi:“MI:0914”(association)	0.790
CUL4B	CUL4A	psi-mi:“MI:0914”(association)	0.730
COPS6	RHOBTB1	psi-mi:“MI:0914”(association)	0.730
DDB2	CCT2	psi-mi:“MI:0914”(association)	0.730
DCAF4L1	CUL4A	psi-mi:“MI:0914”(association)	0.730

BioGRID (1660): CUL4A (Affinity Capture-Western), CUL4A (Affinity Capture-Western), CUL4A (Affinity Capture-Western), CUL4A (Affinity Capture-Western), CUL4A (Affinity Capture-Western), CUL4A (Affinity Capture-Western), CUL4A (Affinity Capture-Western), CUL4A (Affinity Capture-Western), CUL4A (Affinity Capture-Western), CUL4A (Affinity Capture-Western), CUL4A (Affinity Capture-Western), CUL4A (Affinity Capture-Western), CUL4A (Affinity Capture-Western), CUL4A (Affinity Capture-Western), CUL4A (Affinity Capture-Western)

ESM2 similar proteins: A2A432, A6H5Z3, A9X1D0, B0VX69, B1MTJ4, B2KI88, B5FW36, C1FXW2, E2R766, E2RBS6, F1LSG8, O43242, O54923, O55047, O70133, P60762, Q13098, Q13619, Q13620, Q29425, Q2KJ46, Q3TCH7, Q4V860, Q5NVP9, Q5R5J4, Q5RAN1, Q5RB36, Q5VIR6, Q5ZKV9, Q5ZLD7, Q5ZML9, Q6AYU1, Q6NRT5, Q6NZH6, Q86TU7, Q8CCB4, Q8CI71, Q8K4Q0, Q8N122, Q8R3S6

Diamond homologs: A2A432, A4IHP4, B5DF89, O13790, O14122, O60999, P0CH31, Q09760, Q13616, Q13618, Q13619, Q13620, Q17391, Q17392, Q24311, Q3TCH7, Q54CS2, Q54NZ5, Q54XF7, Q5R4G6, Q5ZC88, Q6DE95, Q6GPF3, Q8LGH4, Q94AH6, Q9C9L0, Q9JLV5, Q9SRZ0, Q9WTX6, Q9ZVH4, Q12018, Q13617, Q17389, Q17390, Q21346, Q5RCF3, Q9D4H8, Q9SZ75, Q9XZJ3, Q9XIE8

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
CUL4A	“form complex”	“DCX DET1-COP1”	binding
CUL4A	“form complex”	Cullin4-RBX1-DDB1	binding
NAE	“up-regulates activity”	CUL4A	neddylation
CUL4A	“up-regulates activity”	ARIH1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 150 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
DNA Damage Recognition in GG-NER	13	36.4×	3e-15
Formation of TC-NER Pre-Incision Complex	12	24.9×	7e-12
RHOBTB1 GTPase cycle	5	23.3×	2e-04
Recognition of DNA damage by PCNA-containing replication complex	5	18.7×	6e-04
Neddylation	36	16.7×	3e-32
Dual Incision in GG-NER	5	12.7×	3e-03
Formation of Incision Complex in GG-NER	5	12.4×	3e-03
GSK3B-mediated proteasomal degradation of PD-L1(CD274)	5	11.7×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
regulation of protein neddylation	10	75.5×	5e-15
protein neddylation	13	73.6×	2e-19
intrinsic apoptotic signaling pathway	5	14.5×	2e-03
cellular response to UV	5	11.9×	4e-03
protein ubiquitination	23	7.7×	4e-12
proteasome-mediated ubiquitin-dependent protein catabolic process	17	7.2×	3e-08
ubiquitin-dependent protein catabolic process	11	6.6×	1e-04
protein folding	7	5.8×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	70
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
57684	GRCh38/hg38 13q33.1-34(chr13:101537045-114327173)x1	Pathogenic

SpliceAI

3519 predictions. Top by Δscore:

Variant	Effect	Δscore
13:113209758:TCATC:T	donor_gain	1.0000
13:113209773:GAG:G	donor_gain	1.0000
13:113209774:AGG:A	donor_loss	1.0000
13:113209776:G:GG	donor_gain	1.0000
13:113209971:A:AG	acceptor_gain	1.0000
13:113209972:G:GG	acceptor_gain	1.0000
13:113209972:GAC:G	acceptor_gain	1.0000
13:113209972:GACA:G	acceptor_gain	1.0000
13:113219027:C:T	donor_gain	1.0000
13:113229439:T:A	acceptor_gain	1.0000
13:113242962:TTGTA:T	acceptor_gain	1.0000
13:113242963:T:TA	acceptor_gain	1.0000
13:113242963:TGTAG:T	acceptor_gain	1.0000
13:113242964:GTAGA:G	acceptor_gain	1.0000
13:113242965:TAGAC:T	acceptor_gain	1.0000
13:113242966:A:AG	acceptor_gain	1.0000
13:113242966:A:C	acceptor_gain	1.0000
13:113242967:G:GT	acceptor_gain	1.0000
13:113242967:G:T	acceptor_gain	1.0000
13:113242967:GA:G	acceptor_gain	1.0000
13:113242967:GAC:G	acceptor_gain	1.0000
13:113242967:GACT:G	acceptor_gain	1.0000
13:113242967:GACTT:G	acceptor_gain	1.0000
13:113243156:GATCG:G	donor_gain	1.0000
13:113243157:A:G	donor_gain	1.0000
13:113243157:ATCGG:A	donor_loss	1.0000
13:113243158:TCGG:T	donor_loss	1.0000
13:113243159:CGGTA:C	donor_loss	1.0000
13:113243160:GGT:G	donor_loss	1.0000
13:113243161:G:C	donor_loss	1.0000

AlphaMissense

5071 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:113236855:T:C	L294P	1.000
13:113242975:G:A	G348E	1.000
13:113243026:T:C	L365P	1.000
13:113243155:T:C	L408P	1.000
13:113244410:C:A	A410E	1.000
13:113244422:A:T	D414V	1.000
13:113244431:T:C	L417S	1.000
13:113244435:A:C	R418S	1.000
13:113244435:A:T	R418S	1.000
13:113244499:T:C	F440L	1.000
13:113244501:C:A	F440L	1.000
13:113244501:C:G	F440L	1.000
13:113244503:G:T	R441M	1.000
13:113244952:A:T	K446I	1.000
13:113244953:A:C	K446N	1.000
13:113244953:A:T	K446N	1.000
13:113244954:G:C	D447H	1.000
13:113244960:T:C	F449L	1.000
13:113244962:T:A	F449L	1.000
13:113244962:T:G	F449L	1.000
13:113244966:G:C	A451P	1.000
13:113244969:T:C	F452L	1.000
13:113244971:T:A	F452L	1.000
13:113244971:T:G	F452L	1.000
13:113244972:T:G	Y453D	1.000
13:113244985:T:C	L457S	1.000
13:113244988:C:A	A458E	1.000
13:113244993:A:G	R460G	1.000
13:113244994:G:C	R460T	1.000
13:113244994:G:T	R460I	1.000

dbSNP variants (sampled 300 via entrez): RS1000026576 (13:113248368 G>A), RS1000048623 (13:113224309 C>T), RS1000084944 (13:113265404 T>C), RS1000132352 (13:113249055 C>T), RS1000134625 (13:113219725 G>A), RS1000141513 (13:113207608 A>G), RS1000236744 (13:113242736 T>G), RS1000247618 (13:113212233 C>T), RS1000342276 (13:113237519 C>A), RS1000489504 (13:113207950 G>A,C,T), RS1000669809 (13:113222483 G>C), RS1000721667 (13:113222184 G>A), RS1000745540 (13:113257702 G>A), RS1000808921 (13:113258596 G>C), RS1000845171 (13:113206313 G>A)

Disease associations

OMIM: gene MIM:603137 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST004616_52	Platelet distribution width	4.000000e-10
GCST006414_18	Atrial fibrillation	1.000000e-08
GCST007354_14	Intracranial aneurysm	1.000000e-10
GCST008103_78	Bipolar disorder	1.000000e-06
GCST010241_361	Apolipoprotein A1 levels	6.000000e-11
GCST010242_306	HDL cholesterol levels	2.000000e-14
GCST012465_34	Bipolar disorder	4.000000e-09
GCST90002387_136	Immature fraction of reticulocytes	5.000000e-14
GCST90002390_198	Mean corpuscular hemoglobin	4.000000e-21
GCST90002392_418	Mean corpuscular volume	4.000000e-18
GCST90002395_162	Mean platelet volume	3.000000e-13
GCST90002396_556	Mean reticulocyte volume	6.000000e-18
GCST90002397_67	Mean spheric corpuscular volume	1.000000e-13
GCST90002401_65	Platelet distribution width	3.000000e-16
GCST90002404_383	Red cell distribution width	2.000000e-13

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007984	platelet component distribution width
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004527	mean corpuscular hemoglobin
EFO:0010701	mean reticulocyte volume
EFO:0009188	Red cell distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (9): CHEMBL3833061 (PROTEIN COMPLEX), CHEMBL4296133 (PROTEIN-PROTEIN INTERACTION), CHEMBL4296134 (PROTEIN-PROTEIN INTERACTION), CHEMBL4296135 (PROTEIN-PROTEIN INTERACTION), CHEMBL4523598 (SINGLE PROTEIN), CHEMBL4523713 (PROTEIN-PROTEIN INTERACTION), CHEMBL4523714 (PROTEIN-PROTEIN INTERACTION), CHEMBL4524003 (PROTEIN-PROTEIN INTERACTION), CHEMBL5169084 (PROTEIN-PROTEIN INTERACTION)

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

ChEMBL bioactivities

22 potent at pChembl≥5 of 27 total, top 22 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.94	IC50	114	nM	CHEMBL4539276
6.85	IC50	140	nM	CHEMBL4585473
6.72	IC50	191	nM	CHEMBL4462527
6.63	IC50	236	nM	CHEMBL4444266
6.33	IC50	464	nM	CHEMBL4475993
6.26	IC50	554	nM	CHEMBL1532407
6.13	IC50	738	nM	CHEMBL4592960
6.03	IC50	943	nM	CHEMBL4442009
6.00	IC50	997	nM	CHEMBL1540912
5.98	IC50	1050	nM	CHEMBL4558831
5.96	IC50	1090	nM	CHEMBL4464485
5.73	IC50	1856	nM	CHEMBL4461222
5.67	IC50	2150	nM	CHEMBL4514292
5.62	IC50	2400	nM	CHEMBL1516871
5.59	IC50	2541	nM	CHEMBL4447585
5.58	IC50	2599	nM	CHEMBL4530371
5.57	IC50	2680	nM	CHEMBL1387495
5.43	IC50	3680	nM	CHEMBL1329020
5.34	IC50	4610	nM	CHEMBL4569600
5.32	IC50	4830	nM	CHEMBL4469728
5.30	IC50	5040	nM	CHEMBL4450637
5.07	IC50	8492	nM	CHEMBL4450438

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, decreases expression, increases abundance	3
Valproic Acid	affects expression, decreases expression, decreases methylation	3
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	2
Acrolein	affects cotreatment, decreases expression, increases abundance	2
Ozone	affects cotreatment, decreases expression, increases abundance	2
Tretinoin	decreases expression	2
Cyclosporine	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
2,4,6-tribromophenol	increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	decreases expression, increases abundance, affects cotreatment	1
decabromobiphenyl ether	increases expression	1
tetrabromobisphenol A	increases expression	1
bleomycetin	increases expression	1
beta-methylcholine	affects expression	1
CPG-oligonucleotide	decreases expression	1
candoxin	decreases expression	1
hexabrominated diphenyl ether 153	increases expression	1
(+)-JQ1 compound	decreases expression	1
Irinotecan	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Zoledronic Acid	increases expression	1
Acetaminophen	decreases expression	1
Glyphosate	decreases expression	1
Air Pollutants	affects cotreatment, decreases expression, increases abundance	1
Arsenic	decreases expression, increases abundance	1
Vehicle Emissions	increases abundance, decreases expression	1

ChEMBL screening assays

107 unique, capped per target: 106 binding, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4219275	Binding	Induction of cereblon/cullin 4A-mediated BRD4 degradation in human RS4:11 cells at 1 nM after 3 hrs in presence of proteosome inhibitor MG-132 by Western blot method	Discovery of a Small-Molecule Degrader of Bromodomain and Extra-Terminal (BET) Proteins with Picomolar Cellular Potencies and Capable of Achieving Tumor Regression. — J Med Chem
CHEMBL4610576	ADMET	Protac activity at cereblon/cullin4A/BRD3 in human MV4-11 cells assessed as induction of BRD3 degradation at 50 nM measured after 18 hrs by Western blot analysis	Discovery of novel small molecule induced selective degradation of the bromodomain and extra-terminal (BET) bromodomain protein BRD4 and BRD2 with cellular potencies. — Bioorg Med Chem

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1W0	Abcam A-549 CUL4A KO	Cancer cell line	Male
CVCL_D2AF	Abcam HCT 116 CUL4A KO	Cancer cell line	Male
CVCL_D2NA	Abcam THP-1 CUL4A KO	Cancer cell line	Male
CVCL_D8JN	Ubigene HCT 116 CUL4A KO	Cancer cell line	Male

Clinical trials (associated diseases)

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