DCAF1

Summary

DCAF1 (DDB1 and CUL4 associated factor 1, HGNC:30911) is a protein-coding gene on chromosome 3p21.2, encoding DDB1- and CUL4-associated factor 1 (Q9Y4B6). Acts both as a substrate recognition component of E3 ubiquitin-protein ligase complexes and as an atypical serine/threonine-protein kinase, playing key roles in various processes such as cell cycle, telomerase regulation and histone modification. It is a common-essential gene (DepMap: required in 100.0% of cancer cell lines).

Enables histone H2AT120 kinase activity; nuclear estrogen receptor binding activity; and ubiquitin-like ligase-substrate adaptor activity. Involved in several processes, including cell competition in a multicellular organism; proteasome-mediated ubiquitin-dependent protein catabolic process; and regulation of primary metabolic process. Located in COP9 signalosome; fibrillar center; and nucleoplasm. Part of Cul4-RING E3 ubiquitin ligase complex. Is active in centrosome.

Source: NCBI Gene 9730 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 27 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 100.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_001387579

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30911
Approved symbol	DCAF1
Name	DDB1 and CUL4 associated factor 1
Location	3p21.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0800, MGC102804
Ensembl gene	ENSG00000145041
Ensembl biotype	protein_coding
OMIM	617259
Entrez	9730

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 13 protein_coding

ENST00000423656, ENST00000504652, ENST00000684031, ENST00000855691, ENST00000855692, ENST00000855693, ENST00000855694, ENST00000855695, ENST00000926456, ENST00000926457, ENST00000926458, ENST00000926459, ENST00000940896

RefSeq mRNA: 12 — MANE Select: NM_001387579 NM_001171904, NM_001349168, NM_001349169, NM_001349170, NM_001349171, NM_001387578, NM_001387579, NM_001387580, NM_001387581, NM_001387582, NM_001387583, NM_014703

CCDS: CCDS74943, CCDS74944

Canonical transcript exons

ENST00000684031 — 25 exons

Exon	Start	End
ENSE00000968469	51422307	51422431
ENSE00000968470	51419734	51420997
ENSE00000968471	51418678	51418876
ENSE00000968472	51443766	51443903
ENSE00000968473	51441385	51441897
ENSE00000968474	51414624	51414857
ENSE00000968475	51470929	51471005
ENSE00000968477	51418116	51418198
ENSE00000968478	51416787	51416871
ENSE00000968488	51413950	51414043
ENSE00000968489	51413282	51413386
ENSE00000968490	51412993	51413066
ENSE00000968491	51412379	51412480
ENSE00000968492	51403143	51403395
ENSE00001063662	51463114	51463227
ENSE00001063663	51427372	51427541
ENSE00001063667	51466803	51466876
ENSE00001063668	51430033	51430212
ENSE00001063670	51429261	51429470
ENSE00001639388	51483719	51483836
ENSE00002209628	51397842	51398827
ENSE00002259695	51440970	51441071
ENSE00003721829	51433106	51433264
ENSE00003916265	51496734	51496780
ENSE00003917625	51499873	51500015

Expression profiles

Bgee: expression breadth ubiquitous, 265 present calls, max score 98.79.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.9972 / max 176.1941, expressed in 1788 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
42362	12.9972	1788

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	98.79	gold quality
male germ cell	CL:0000015	98.00	gold quality
right testis	UBERON:0004534	94.39	gold quality
left testis	UBERON:0004533	94.30	gold quality
testis	UBERON:0000473	92.51	gold quality
pericardium	UBERON:0002407	90.99	gold quality
tendon of biceps brachii	UBERON:0008188	90.89	gold quality
vena cava	UBERON:0004087	90.07	silver quality
ventricular zone	UBERON:0003053	89.81	gold quality
gastrocnemius	UBERON:0001388	89.31	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	88.93	gold quality
ganglionic eminence	UBERON:0004023	88.51	gold quality
muscle of leg	UBERON:0001383	88.41	gold quality
cortical plate	UBERON:0005343	87.61	gold quality
body of tongue	UBERON:0011876	87.21	gold quality
biceps brachii	UBERON:0001507	87.15	gold quality
renal medulla	UBERON:0000362	87.14	gold quality
middle temporal gyrus	UBERON:0002771	87.13	gold quality
cardia of stomach	UBERON:0001162	87.11	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	87.11	gold quality
heart right ventricle	UBERON:0002080	86.78	gold quality
muscle organ	UBERON:0001630	86.53	gold quality
Brodmann (1909) area 23	UBERON:0013554	86.40	gold quality
gingival epithelium	UBERON:0001949	86.28	gold quality
hindlimb stylopod muscle	UBERON:0004252	86.27	gold quality
buccal mucosa cell	CL:0002336	86.12	gold quality
islet of Langerhans	UBERON:0000006	86.10	gold quality
pylorus	UBERON:0001166	86.08	gold quality
tongue	UBERON:0001723	85.77	gold quality
superior surface of tongue	UBERON:0007371	85.76	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-7316	yes	28.19
E-ANND-3	yes	5.02

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TP53

miRNA regulators (miRDB)

41 targeting DCAF1, 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-6778-3P	99.96	67.29	2693
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-520F-3P	99.82	71.32	1216
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-3120-3P	99.54	70.28	2669
HSA-MIR-578	99.46	68.36	1787
HSA-MIR-4480	99.42	66.02	735
HSA-MIR-942-5P	99.41	68.40	1977
HSA-MIR-4758-3P	99.12	63.96	869
HSA-MIR-877-3P	99.09	68.10	1637
HSA-MIR-4650-3P	99.01	68.39	1062
HSA-MIR-4751	98.80	64.95	525
HSA-MIR-6512-5P	98.76	69.29	1195
HSA-MIR-6868-3P	98.63	69.64	2259
HSA-MIR-6731-3P	98.61	67.86	749
HSA-MIR-4710	98.61	65.96	1048
HSA-MIR-323A-5P	98.59	65.13	651
HSA-MIR-210-5P	98.57	64.37	832
HSA-MIR-7114-3P	98.42	66.53	569
HSA-MIR-581	98.39	67.42	835
HSA-MIR-6509-3P	98.32	67.33	1343
HSA-MIR-6882-3P	98.23	67.01	1119
HSA-MIR-1180-5P	98.16	65.32	460

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 100.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• demonstration that a novel human gene, KIAA0800, is preferentially expressed in the testis and is transactivated by Sox9 (PMID:12111997)
• Hence, this chimeric peptide (TEAM-VP) constitutes the first example of a virus-derived mitochondriotoxic compound as a candidate to kill selectively tumor neo-endothelia. (PMID:16888644)
• Recruitment of cytoplasmic protein Vpr binding protein (VprBP) by HIV-1 regulatory protein Vpr is essential for its cytostatic activity. (PMID:17314515)
• The Cul4-DDB1[VprBP] E3 ubiquitin ligase complex is identified as the downstream effector of lentiviral Vpr for the induction of cell cycle arrest in G2 phase. (PMID:17609381)
• 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)
• 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)
• Anti-tumor activity mediated by protein and peptide transduction of HIV viral protein R is reported. (PMID:19029839)
• Study concludes that Merlin suppresses tumorigenesis by translocating to the nucleus to inhibit CRL4(DCAF1). (PMID:20178741)
• This review focuses on Vpr and its HIV2/SIV counterparts, Vpx and Vpr, which all engage the DDB1.Cullin4 ubiquitin ligase complex through the DCAF1 adaptor protein. (PMID:20347598)
• UNG specifically interacts with Vpr forming a heterotrimeric complex with DCAF1. (PMID:20870715)
• Promoter-localized deacetylation of H3 tails is a prerequisite for VprBP to tether and act as a bona fide inhibitor at p53 target genes. (PMID:22184063)
• Vpr acts to enhance constitutive DCAF1-dependent UNG2 turnover. (PMID:22292079)
• Data show that VPRBP (viral protein R-binding protein)-LC3B (light-chain 3B)/p62(SQSTM1) were in the same protein complex. (PMID:22963397)
• The EZH2-DCAF1/DDB1/CUL4 represents a previously unrecognized methylation-dependent ubiquitination machinery specifically recognizing “methyl degron”; nonhistone protein stability can be dynamically regulated in a methylation-dependent manner. (PMID:23063525)
• Data indicate that Dyrk2 phosphorylates TERT protein, which is then associated with the EDD-DDB1-VprBP E3 ligase complex for subsequent ubiquitin-mediated TERT protein degradation. (PMID:23362280)
• As a molecular adaptor, Vpr enhanced the interaction between TERT and the VPRBP substrate receptor of the DYRK2-associated EDD-DDB1-VPRBP E3 ligase complex, resulting in increased ubiquitination of TERT. (PMID:23612978)
• Our findings establish VprBP as a major kinase responsible for H2AT120p in cancer cells and suggest that VprBP inhibition could be a new strategy for the development of anticancer therapeutics. (PMID:24140421)
• the crystal structure of a ternary complex of Vpx with the human E3 ligase substrate adaptor DCAF1 and the carboxy-terminal region of human SAMHD1 (PMID:24336198)
• The predicted beta-propeller conformation of DCAF1 is likely to be critical for Vpr association. (PMID:24558487)
• Data indicate that DCAF1 protein folds into a beta-hairpin structure and binds to the F3 lobe of neurofibromin 2 (Merlin) FERM domain. (PMID:24706749)
• CD44 cytoplasmic tail cleaved by RIP could release DCAF1 from merlin by competing for binding to the merlin FERM domain, which results in the inhibition of merlin-mediated suppression of tumorigenesis. (PMID:24912773)
• The identification of Vpr mutants which associate with DCAF1 but only poorly with DDB1 suggests that DCAF1 is necessary but is not sufficient for the Vpr association with DDB1-containing E3 ligase complex. (PMID:24912982)
• VprBP transcription was repressed by cellular miRNA-1236, which contributes to HIV-1 restriction in monocytes. miR-1236 inhibitors enhanced translation of VprBP and promoted infection. miR-1236 mimetics suppressed translation of VprBP. (PMID:24932481)
• NF2 loss-driven derepressed CRL4(DCAF1) promotes activation of YAP by inhibiting hippo pathwat kinases Lats1 and 2 in the nucleus. (PMID:25026211)
• Vpr downregulated APOBEC3G through Vpr-binding protein (VprBP)-mediated proteasomal degradation, and further confirmed that the reduction of APOBEC3G encapsidation associated with Vpr was due to Vpr’s degradation-inducing activity. (PMID:25200749)
• Vpr and Vpx share a highly similar DCAF1-binding motif, they interact with a different set of residues in DCAF1. (PMID:25499532)
• VprBP, but not DDB1, directly binds to TET2-catalytic domain. (PMID:25557551)
• MCM10 is the natural substrate of the Cul4-DDB1[VprBP] E3 ubiquitin ligase whose degradation is regulated by VprBP, but Vpr enhances the proteasomal degradation of MCM10 by interacting with VprBP. (PMID:26032416)
• Data show that neurofibromin 2 (Merlin) suppresses proliferation and adhesion, at least partly, through inhibiting kinase suppressor of Ras 1 (KSR1) and DCAF1 protein. (PMID:26549023)
• This study presents the crystal structure of the DDB1-DCAF1-HIV-1-Vpr-uracil-DNA glycosylase (cyclin U) complex. (PMID:27571178)
• RNA interference-mediated knockdown of differentially regulated host factors identified Vpr binding protein (VprBP) as proviral host factor because its downregulation inhibited efficient propagation of seasonal influenza A virus. (PMID:28289176)
• High VPRBP expression is associated with high-grade serous ovarian cancer. (PMID:28416635)
• Together, these results characterize a novel postintegration restriction of HIV-1 replication in monocyte-derived dendritic cells and show that the interaction of Vpr with the DCAF1/DDB1 E3 ubiquitin ligase complex and the yet-to-be-identified host factor might alleviate this restriction by inducing transcription from the viral long terminal repeat. (PMID:28424288)
• Data suggest that HIV-1 vpr mediates polyubiquitination of HLTF by directly loading it onto C-terminal WD40 domain of DCAF1 in complex the CRL4, an E3 ubiquitin ligase. (vpr = vpr gene product of Human immunodeficiency virus 1; HLTF = human helicase like transcription factor; DCAF1 = human Vpr (HIV-1) binding protein; CRL4 = human E3 ubiquitin ligase CRL4) (PMID:29079575)
• The study suggests that DCAF1 is involved in hepatitis C virus (HCV) replication through regulation of miR-122, and thus provides new insights into the interaction between HCV and the host cell. (PMID:29327233)
• HIV-1 Vpr degrades TET2 by CRL4 E3 ligase to sustain IL-6 expression to enhance viral replication and disease progression. (PMID:29883611)
• lentiviral accessory protein Vpx exploits DCAF1 to counteract Vpx-mediated SAMHD1 degradation (PMID:31003777)
• VprBP mitigates TGF-beta and Activin signaling by promoting Smurf1-mediated type I receptor degradation. (PMID:31291647)
• Human Immunodeficiency Virus Type 1 Vpr Mediates Degradation of APC1, a Scaffolding Component of the Anaphase-Promoting Complex/Cyclosome. (PMID:34011540)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
		ENSDARG00000108136
mus_musculus	Dcaf1	ENSMUSG00000040325
rattus_norvegicus	Dcaf1	ENSRNOG00000013841
drosophila_melanogaster	mahj	FBGN0034641
caenorhabditis_elegans		WBGENE00014243

Protein

Protein identifiers

DDB1- and CUL4-associated factor 1 — Q9Y4B6 (reviewed: Q9Y4B6)

Alternative names: HIV-1 Vpr-binding protein, Serine/threonine-protein kinase VPRBP, Vpr-interacting protein

All UniProt accessions (1): Q9Y4B6

UniProt curated annotations — full annotation on UniProt →

Function. Acts both as a substrate recognition component of E3 ubiquitin-protein ligase complexes and as an atypical serine/threonine-protein kinase, playing key roles in various processes such as cell cycle, telomerase regulation and histone modification. Probable substrate-specific adapter of a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex, named CUL4A-RBX1-DDB1-DCAF1/VPRBP complex, which mediates ubiquitination and proteasome-dependent degradation of proteins such as NF2. Involved in the turnover of methylated proteins: recognizes and binds methylated proteins via its chromo domain, leading to ubiquitination of target proteins by the RBX1-DDB1-DCAF1/VPRBP complex. The CUL4A-RBX1-DDB1-DCAF1/VPRBP complex is also involved in B-cell development: DCAF1 is recruited by RAG1 to ubiquitinate proteins, leading to limit error-prone repair during V(D)J recombination. Also part of the EDVP complex, an E3 ligase complex that mediates ubiquitination of proteins such as TERT, leading to TERT degradation and telomerase inhibition. The EDVP complex also mediates ubiquitination and degradation of CCP110. Also acts as an atypical serine/threonine-protein kinase that specifically mediates phosphorylation of ‘Thr-120’ of histone H2A (H2AT120ph) in a nucleosomal context, thereby repressing transcription. H2AT120ph is present in the regulatory region of many tumor suppresor genes, down-regulates their transcription and is present at high level in a number of tumors. Involved in JNK-mediated apoptosis during cell competition process via its interaction with LLGL1 and LLGL2. By acting on TET dioxygenses, essential for oocyte maintenance at the primordial follicle stage, hence essential for female fertility. (Microbial infection) In case of infection by HIV-1 virus, it is recruited by HIV-1 Vpr in order to hijack the CUL4A-RBX1-DDB1-DCAF1/VPRBP function leading to arrest the cell cycle in G2 phase, and also to protect the viral protein from proteasomal degradation by another E3 ubiquitin ligase. The HIV-1 Vpr protein hijacks the CUL4A-RBX1-DDB1-DCAF1/VPRBP complex to promote ubiquitination and degradation of proteins such as TERT and ZIP/ZGPAT. (Microbial infection) In case of infection by HIV-2 virus, it is recruited by HIV-2 Vpx in order to hijack the CUL4A-RBX1-DDB1-DCAF1/VPRBP function leading to enhanced efficiency of macrophage infection and promotion of the replication of cognate primate lentiviruses in cells of monocyte/macrophage lineage.

Subunit / interactions. Component of the DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex, named CUL4A-RBX1-DDB1-DCAF1/VPRBP complex. Interacts with DDB1; the interaction is direct. Also forms a ternary complex with DDA1 and DDB1. Interacts with NF2 (via FERM domain). Component of the EDVP complex, a E3 ligase complex containing DYRK2, EDD/UBR5, DDB1 and DCAF1. Interacts with DYRK2; the interaction is direct. Interacts with RAG1; the interaction is direct. Interacts with LLGL1 and LLGL2. Interacts with histone H3. Interacts with ESR1 and LATS1; probably recruited by LATS1 to promote ESR1 ubiquitination and ubiquitin-mediated proteasomal degradation. Directly interacts with TET1, TET2 and TET3 (via C-terminus). Interacts with CEP78; promoting DCAF1 localization to centrosomes. (Microbial infection) Interacts with HIV-1 virus Vpr protein; the interaction is direct. (Microbial infection) Interacts with HIV-2 virus Vpx protein; the interaction is direct and the complex recruits SAMHD1 or TASOR to promote their ubiquitin-dependent proteasomal degradation. (Microbial infection) Interacts (via C-terminus) with human cytomegalovirus protein UL35; this interaction induces the accumulation of cells in the G2 phase of the cell cycle.

Subcellular location. Cytoplasm. Nucleus. Cytoskeleton. Microtubule organizing center. Centrosome.

Tissue specificity. Ubiquitously expressed.

Domain organisation. The protein kinase-like region mediates the threonine-protein kinase activity. The DWD boxes are required for interaction with DDB1. The chromo domain with a restricted pocket directly recognizes monomethylated substrates.

Induction. Up-regulated in a number of cancer cell lines (at protein level).

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the VPRBP/DCAF1 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9Y4B6-1	1	yes
Q9Y4B6-2	2
Q9Y4B6-3	3

RefSeq proteins (12): NP_001165375, NP_001336097, NP_001336098, NP_001336099, NP_001336100, NP_001374507, NP_001374508, NP_001374509, NP_001374510, NP_001374511, NP_001374512, NP_055518 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006594	LisH	Conserved_site
IPR011989	ARM-like	Homologous_superfamily
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR033270	VPRBP/DCAF1	Family
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (82 total): strand 34, modified residue 10, region of interest 6, turn 6, repeat 5, mutagenesis site 5, helix 4, sequence variant 3, domain 2, short sequence motif 2, compositionally biased region 2, splice variant 2, chain 1

Structure

Experimental structures (PDB)

46 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
9PLY	X-RAY DIFFRACTION	1.4
9BHS	X-RAY DIFFRACTION	1.43
9Y4Q	X-RAY DIFFRACTION	1.48
8OOD	X-RAY DIFFRACTION	1.5
9YDG	X-RAY DIFFRACTION	1.54
8F8E	X-RAY DIFFRACTION	1.55
9Y76	X-RAY DIFFRACTION	1.56
9YV4	X-RAY DIFFRACTION	1.6
7SSE	X-RAY DIFFRACTION	1.62
9BHR	X-RAY DIFFRACTION	1.62
9D4E	X-RAY DIFFRACTION	1.7
4PXW	X-RAY DIFFRACTION	1.72
9YE4	X-RAY DIFFRACTION	1.74
9C1Q	X-RAY DIFFRACTION	1.8
9NSN	X-RAY DIFFRACTION	1.85
9NSO	X-RAY DIFFRACTION	1.85
7UFV	X-RAY DIFFRACTION	1.9
9B9W	X-RAY DIFFRACTION	1.92
9B9T	X-RAY DIFFRACTION	2.05
9B9H	X-RAY DIFFRACTION	2.06
9DLW	X-RAY DIFFRACTION	2.07
8OGC	X-RAY DIFFRACTION	2.09
8OG8	X-RAY DIFFRACTION	2.11
8OG5	X-RAY DIFFRACTION	2.2
8OGA	X-RAY DIFFRACTION	2.2
8OG6	X-RAY DIFFRACTION	2.25
8OO5	X-RAY DIFFRACTION	2.25
8OGB	X-RAY DIFFRACTION	2.27
9ZLG	X-RAY DIFFRACTION	2.3
3WA0	X-RAY DIFFRACTION	2.31

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y4B6-F1	75.45	0.45

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 (10): 202, 255, 701, 828, 888, 895, 898, 979, 1000, 1328

Mutagenesis-validated functional residues (5):

Position	Phenotype
194	abolishes serine/threonine-protein kinase kinase activity.
361	abolishes serine/threonine-protein kinase kinase activity.
363	abolishes serine/threonine-protein kinase kinase activity.
1247	loss of interaction with ddb1, no effect on interaction with tet3; when associated with a-1283.
1283	loss of interaction with ddb1, no effect on interaction with tet3; when associated with a-1247.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 210 (showing top): RNGTGGGC_UNKNOWN, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_B_CELL_ACTIVATION, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GCANCTGNY_MYOD_Q6, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_GROWTH, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, AACYNNNNTTCCS_UNKNOWN

GO Biological Process (11): negative regulation of transcription by RNA polymerase II (GO:0000122), protein ubiquitination (GO:0016567), B cell differentiation (GO:0030183), V(D)J recombination (GO:0033151), cell competition in a multicellular organism (GO:0035212), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), post-translational protein modification (GO:0043687), positive regulation of protein catabolic process (GO:0045732), chromatin organization (GO:0006325), chromatin remodeling (GO:0006338), base-excision repair, AP site formation via deaminated base removal (GO:0097510)

GO Molecular Function (10): ATP binding (GO:0005524), nuclear estrogen receptor binding (GO:0030331), protein serine kinase activity (GO:0106310), histone H2AT120 kinase activity (GO:1990244), ubiquitin-like ligase-substrate adaptor activity (GO:1990756), nucleotide binding (GO:0000166), protein serine/threonine kinase activity (GO:0004674), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (8): fibrillar center (GO:0001650), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), centrosome (GO:0005813), Cul4-RING E3 ubiquitin ligase complex (GO:0080008), cytoskeleton (GO:0005856), COP9 signalosome (GO:0008180)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein kinase activity	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
protein modification by small protein conjugation	1
lymphocyte differentiation	1
B cell activation	1
somatic diversification of immune receptors via germline recombination within a single locus	1
multicellular organism development	1
cellular process	1
regulation of growth	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
protein modification 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
cellular component organization	1
chromatin organization	1
base-excision repair, AP site formation	1
deaminated base DNA N-glycosylase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nuclear receptor binding	1
protein serine/threonine kinase activity	1
histone H2A kinase activity	1
enzyme-substrate adaptor activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
nucleolus	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
centriole	1
microtubule organizing center	1

Protein interactions and networks

STRING

1662 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DCAF1	DDB1	Q16531	999
DCAF1	CUL4A	Q13619	999
DCAF1	CUL4B	Q13620	985
DCAF1	DTL	Q9NZJ0	962
DCAF1	RBX1	P62877	961
DCAF1	SAMHD1	Q9Y3Z3	850
DCAF1	CDT1	Q9H211	841
DCAF1	SLX4	Q8IY92	803
DCAF1	TET2	Q6N021	775
DCAF1	NF2	P35240	756
DCAF1	DDA1	Q9BW61	745
DCAF1	MCM10	Q7L590	738
DCAF1	DYRK2	Q92630	737
DCAF1	UBR5	O95071	718
DCAF1	CCNL2	Q96S94	714

IntAct

194 interactions, top by confidence:

A	B	Type	Score
NEDD8	UBE2M	psi-mi:“MI:0914”(association)	0.940
LLGL2	PRKCI	psi-mi:“MI:0914”(association)	0.890
COPS8	COPS2	psi-mi:“MI:0914”(association)	0.850
COPS5	CUL4A	psi-mi:“MI:0914”(association)	0.840
CUL4B	COPS2	psi-mi:“MI:0914”(association)	0.790
COPS6	RHOBTB1	psi-mi:“MI:0914”(association)	0.730
DDB1	DCAF1	psi-mi:“MI:0915”(physical association)	0.690
DCAF1	DDB1	psi-mi:“MI:0915”(physical association)	0.690
DCAF1	vpx	psi-mi:“MI:0407”(direct interaction)	0.670
DCAF1	vpx	psi-mi:“MI:0915”(physical association)	0.670
vpx	DCAF1	psi-mi:“MI:0915”(physical association)	0.670
CUL4A	COPS2	psi-mi:“MI:0914”(association)	0.640
RPL14	RRP8	psi-mi:“MI:0914”(association)	0.640
DCAF1	LATS1	psi-mi:“MI:0915”(physical association)	0.600
LATS1	DCAF1	psi-mi:“MI:0915”(physical association)	0.600
DCAF1	LATS1	psi-mi:“MI:0220”(ubiquitination reaction)	0.600
Cep78	UBR5	psi-mi:“MI:0915”(physical association)	0.560
PLK1	C1orf226	psi-mi:“MI:0914”(association)	0.560
DCAF1	vpr	psi-mi:“MI:0915”(physical association)	0.560
DCAF1	LATS2	psi-mi:“MI:0915”(physical association)	0.540
Nf2	LATS1	psi-mi:“MI:0914”(association)	0.540
COPS5	KLHL18	psi-mi:“MI:0914”(association)	0.530

BioGRID (641): CUL4A (Affinity Capture-Western), CUL4B (Affinity Capture-Western), VPRBP (Affinity Capture-RNA), VPRBP (Affinity Capture-MS), VPRBP (Affinity Capture-MS), VPRBP (Affinity Capture-Western), VPRBP (Affinity Capture-Western), HIST3H3 (Biochemical Activity), SAMHD1 (Biochemical Activity), VPRBP (Affinity Capture-MS), VPRBP (Affinity Capture-MS), VPRBP (Affinity Capture-MS), VPRBP (Affinity Capture-MS), VPRBP (Affinity Capture-MS), VPRBP (Affinity Capture-MS)

ESM2 similar proteins: A0JNG7, A0JPF5, A0JPG1, A2VE70, B0V207, B1AY13, B4F766, F1QFR9, F1R2X6, O17482, O43156, P49021, P50851, Q05DH4, Q0P4Q0, Q15021, Q4S6U8, Q505K2, Q5PNP1, Q5RAW5, Q5SP90, Q5SSW2, Q5W0V3, Q5ZLW3, Q6DCP6, Q6IN85, Q6INN7, Q6NRP2, Q6P2K6, Q7RTS9, Q80TR8, Q80YR2, Q86V87, Q8CDM8, Q8CHY3, Q8IV36, Q8IY22, Q8K2Z4, Q8NFP9, Q8R1F6

Diamond homologs: Q21106, Q80TR8, Q9W2F2, Q9Y4B6

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
DCAF1	“down-regulates quantity by destabilization”	NF2	binding
DCAF1	“up-regulates activity”	Cullin4-RBX1-DDB1	binding
DCAF1	“form complex”	EDVP	binding
DCAF1	“down-regulates quantity by destabilization”	MCM10	binding
DCAF1	“down-regulates quantity by destabilization”	LATS1	binding
DCAF1	“down-regulates quantity by destabilization”	LATS2	binding
DCAF1	“up-regulates activity”	H2AC14	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 199 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	10	21.0×	1e-09
Peptide chain elongation	16	14.9×	1e-12
Viral mRNA Translation	16	14.9×	1e-12
PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA	16	14.8×	1e-12
ZNF598 and the Ribosome-associated Quality Trigger (RQT) complex dissociate a ribosome stalled on a no-go mRNA	17	14.7×	8e-13
Selenocysteine synthesis	16	14.1×	1e-12
Eukaryotic Translation Termination	16	14.1×	1e-12
Formation of a pool of free 40S subunits	17	14.0×	8e-13

GO biological processes:

GO term	Partners	Fold	FDR
protein neddylation	8	32.7×	2e-08
regulation of protein neddylation	6	32.7×	4e-06
cytoplasmic translation	16	17.2×	9e-13
positive regulation of G1/S transition of mitotic cell cycle	5	11.7×	9e-03
translation	18	10.8×	4e-11
G1/S transition of mitotic cell cycle	7	8.2×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	0
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3810 predictions. Top by Δscore:

Variant	Effect	Δscore
3:51398825:CAG:C	acceptor_gain	1.0000
3:51398826:AGCT:A	acceptor_loss	1.0000
3:51398828:C:CA	acceptor_loss	1.0000
3:51398828:C:CC	acceptor_gain	1.0000
3:51403141:A:AC	donor_gain	1.0000
3:51403141:ACTGT:A	donor_gain	1.0000
3:51403142:C:CC	donor_gain	1.0000
3:51403142:CTGT:C	donor_gain	1.0000
3:51403142:CTGTC:C	donor_gain	1.0000
3:51403166:T:TA	donor_gain	1.0000
3:51403265:T:TA	donor_gain	1.0000
3:51403392:CTTC:C	acceptor_gain	1.0000
3:51412374:CTGA:C	donor_loss	1.0000
3:51412378:CCTGG:C	donor_loss	1.0000
3:51412476:TGATT:T	acceptor_gain	1.0000
3:51412479:TT:T	acceptor_gain	1.0000
3:51412480:TCTG:T	acceptor_loss	1.0000
3:51412481:C:A	acceptor_loss	1.0000
3:51412481:C:CC	acceptor_gain	1.0000
3:51412486:A:AC	acceptor_gain	1.0000
3:51413276:GCTTA:G	donor_loss	1.0000
3:51413277:CTTAC:C	donor_loss	1.0000
3:51413278:TTAC:T	donor_loss	1.0000
3:51413279:TA:T	donor_loss	1.0000
3:51413280:A:AC	donor_gain	1.0000
3:51413280:A:C	donor_loss	1.0000
3:51413281:C:CC	donor_gain	1.0000
3:51413382:CATAG:C	acceptor_gain	1.0000
3:51413383:ATAG:A	acceptor_gain	1.0000
3:51413384:TAG:T	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000072244 (3:51431536 A>C), RS1000164994 (3:51413506 T>C), RS1000204905 (3:51424363 A>G), RS1000228223 (3:51470197 A>T), RS1000274512 (3:51482300 T>A), RS1000366943 (3:51408988 G>A), RS1000426522 (3:51431992 G>A,T), RS1000427739 (3:51464333 A>G), RS1000490363 (3:51448403 T>C), RS1000529810 (3:51431251 C>G), RS1000537441 (3:51498745 T>C), RS1000551549 (3:51402221 T>C), RS1000609512 (3:51498496 G>A,C), RS1000624451 (3:51396109 A>C), RS1000649914 (3:51409180 G>C)

Disease associations

OMIM: gene MIM:617259 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST006409_7	Allergic rhinitis	2.000000e-13
GCST007732_15	Allergic disease (asthma, hay fever or eczema)	1.000000e-07
GCST008595_32	Cognitive ability, years of educational attainment or schizophrenia (pleiotropy)	3.000000e-08
GCST009720_95	Asthma	2.000000e-09
GCST010042_121	Asthma	5.000000e-08
GCST012232_7	Lipoprotein (a) levels	3.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment
EFO:0006925	lipoprotein A measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL5465396 (PROTEIN-PROTEIN INTERACTION), CHEMBL5465521 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — E3 ubiquitin ligase components

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
compound 13 [PMID: 37465299]	Binding	7.51	pKd
OICR-8268	Binding	7.42	pKd

ChEMBL bioactivities

20 potent at pChembl≥5 of 43 total, top 19 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.42	Kd	38	nM	CHEMBL5407645
7.07	Kd	85	nM	CHEMBL5413067
6.77	Kd	170	nM	CHEMBL5394730
6.70	Kd	200	nM	CHEMBL5415393
6.67	Kd	216	nM	CHEMBL5407645
6.58	Kd	265	nM	CHEMBL5404025
6.31	Kd	490	nM	CHEMBL5412474
6.03	Kd	932	nM	CHEMBL5412474
5.54	Kd	2890	nM	CHEMBL5406860
5.54	Kd	2890	nM	CHEMBL5395769
5.47	Kd	3400	nM	CHEMBL5396812
5.40	Kd	4000	nM	CHEMBL5398414
5.40	Kd	4000	nM	CHEMBL5413113
5.22	Kd	6000	nM	CHEMBL5395769
5.22	Kd	6000	nM	CHEMBL6134254
5.17	Kd	6800	nM	CHEMBL5399714
5.10	Kd	8000	nM	CHEMBL6132819
5.05	Kd	9000	nM	CHEMBL5418547
5.00	Kd	9900	nM	CHEMBL5418143

PubChem BioAssay actives

16 with measured affinity, of 55 total; 14 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-[(1S)-3-amino-1-(3-chloro-4-fluorophenyl)-3-oxopropyl]-5-(4-chloro-2-fluorophenyl)-1H-pyrazole-4-carboxamide	2029459: Binding affinity to biotinylated human DCAF1 (1038 to 1400 residues) expressed in baculovirus infected in Sf9 insect cells assessed as dissociation constant measured for 60 secs by SPR analysis	kd	0.0380	uM
N-[(1S)-3-amino-1-(3-chlorophenyl)-3-oxopropyl]-5-(4-chloro-2-fluorophenyl)-1H-pyrazole-4-carboxamide	2029459: Binding affinity to biotinylated human DCAF1 (1038 to 1400 residues) expressed in baculovirus infected in Sf9 insect cells assessed as dissociation constant measured for 60 secs by SPR analysis	kd	0.0850	uM
N-[(1S)-3-amino-1-(3-chloro-4-fluorophenyl)-3-oxopropyl]-5-(2-fluorophenyl)-1H-pyrazole-4-carboxamide	2029459: Binding affinity to biotinylated human DCAF1 (1038 to 1400 residues) expressed in baculovirus infected in Sf9 insect cells assessed as dissociation constant measured for 60 secs by SPR analysis	kd	0.1700	uM
N-[(1S)-3-amino-1-(3,4-dichlorophenyl)-3-oxopropyl]-5-(2-fluorophenyl)-1H-pyrazole-4-carboxamide	2029459: Binding affinity to biotinylated human DCAF1 (1038 to 1400 residues) expressed in baculovirus infected in Sf9 insect cells assessed as dissociation constant measured for 60 secs by SPR analysis	kd	0.2000	uM
N-[(1S)-3-amino-1-(3-chlorophenyl)-3-oxopropyl]-5-(2,4-difluorophenyl)-1H-pyrazole-4-carboxamide	2029459: Binding affinity to biotinylated human DCAF1 (1038 to 1400 residues) expressed in baculovirus infected in Sf9 insect cells assessed as dissociation constant measured for 60 secs by SPR analysis	kd	0.2650	uM
N-[(1S)-3-amino-1-(3-chlorophenyl)-3-oxopropyl]-5-(2-fluorophenyl)-1H-pyrazole-4-carboxamide	2029459: Binding affinity to biotinylated human DCAF1 (1038 to 1400 residues) expressed in baculovirus infected in Sf9 insect cells assessed as dissociation constant measured for 60 secs by SPR analysis	kd	0.4900	uM
N-[(1S)-3-amino-3-oxo-1-phenylpropyl]-5-(4-chlorophenyl)-1H-pyrazole-4-carboxamide	2029459: Binding affinity to biotinylated human DCAF1 (1038 to 1400 residues) expressed in baculovirus infected in Sf9 insect cells assessed as dissociation constant measured for 60 secs by SPR analysis	kd	2.8900	uM
N-[(1S)-1-(3-chlorophenyl)-2-cyanoethyl]-5-(2-fluorophenyl)-1H-pyrazole-4-carboxamide	2029459: Binding affinity to biotinylated human DCAF1 (1038 to 1400 residues) expressed in baculovirus infected in Sf9 insect cells assessed as dissociation constant measured for 60 secs by SPR analysis	kd	2.8900	uM
N-[(1S)-3-amino-3-oxo-1-phenylpropyl]-5-(2-fluorophenyl)-1H-pyrazole-4-carboxamide	2029459: Binding affinity to biotinylated human DCAF1 (1038 to 1400 residues) expressed in baculovirus infected in Sf9 insect cells assessed as dissociation constant measured for 60 secs by SPR analysis	kd	3.4000	uM
N-[(1S)-3-amino-3-oxo-1-phenylpropyl]-5-(2-chlorophenyl)-1H-pyrazole-4-carboxamide	2029459: Binding affinity to biotinylated human DCAF1 (1038 to 1400 residues) expressed in baculovirus infected in Sf9 insect cells assessed as dissociation constant measured for 60 secs by SPR analysis	kd	4.0000	uM
N-[(1S)-3-amino-1-(3-chlorophenyl)-3-oxopropyl]-5-phenyl-1H-pyrazole-4-carboxamide	2029459: Binding affinity to biotinylated human DCAF1 (1038 to 1400 residues) expressed in baculovirus infected in Sf9 insect cells assessed as dissociation constant measured for 60 secs by SPR analysis	kd	4.0000	uM
N-[(1S)-3-amino-1-(4-methylphenyl)-3-oxopropyl]-5-phenyl-1H-pyrazole-4-carboxamide	2029459: Binding affinity to biotinylated human DCAF1 (1038 to 1400 residues) expressed in baculovirus infected in Sf9 insect cells assessed as dissociation constant measured for 60 secs by SPR analysis	kd	6.8000	uM
N-[(1R)-3-amino-1-(3-chlorophenyl)-3-oxopropyl]-5-(2-fluorophenyl)-1H-pyrazole-4-carboxamide	2029460: Binding affinity to biotinylated human DCAF1 (1038 to 1400 residues) expressed in baculovirus infected in Sf9 insect cells assessed as dissociation constant by ITC analysis	kd	9.0000	uM
N-[(1S)-3-amino-1-(3-chlorophenyl)-3-oxopropyl]-1-methyl-3-phenylpyrazole-4-carboxamide	2029459: Binding affinity to biotinylated human DCAF1 (1038 to 1400 residues) expressed in baculovirus infected in Sf9 insect cells assessed as dissociation constant measured for 60 secs by SPR analysis	kd	9.9000	uM

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
titanium dioxide	decreases methylation	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
pentanal	decreases expression	1
2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
Benzo(a)pyrene	decreases expression	1
Caffeine	decreases phosphorylation	1
Ethyl Methanesulfonate	decreases expression	1
Ivermectin	decreases expression	1
Methotrexate	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Valproic Acid	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Cadmium Chloride	decreases expression	1

ChEMBL screening assays

18 unique, capped per target: 18 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5369323	Binding	PROTAC activity at DCAF1/BRD9 in HEK293T cells co expressing HiBit/FF/CAS9 assessed as reduction of protein degradation measured after 6 hrs by immunoblotting analysis	Unlocking DCAFs To Catalyze Degrader Development: An Arena for Innovative Approaches. — J Med Chem

Clinical trials (associated diseases)

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