DTX3L

Summary

DTX3L (deltex E3 ubiquitin ligase 3L, HGNC:30323) is a protein-coding gene on chromosome 3q21.1, encoding E3 ubiquitin-protein ligase DTX3L (Q8TDB6). E3 ubiquitin-protein ligase which, in association with ADP-ribosyltransferase PARP9, plays a role in DNA damage repair and in interferon-mediated antiviral responses.

Enables several functions, including STAT family protein binding activity; histone H4K91 ubiquitin ligase activity; and protein ADP-ribosyltransferase-substrate adaptor activity. Involved in several processes, including positive regulation of protein localization; protein ubiquitination; and regulation of macromolecule metabolic process. Located in several cellular components, including early endosome; lysosome; and nucleoplasm. Part of protein-containing complex.

Source: NCBI Gene 151636 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 120 total
• Druggable target: yes
• MANE Select transcript: NM_138287

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30323
Approved symbol	DTX3L
Name	deltex E3 ubiquitin ligase 3L
Location	3q21.1
Locus type	gene with protein product
Status	Approved
Aliases	BBAP, RNF143
Ensembl gene	ENSG00000163840
Ensembl biotype	protein_coding
OMIM	613143
Entrez	151636

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000296161, ENST00000383661

RefSeq mRNA: 1 — MANE Select: NM_138287 NM_138287

CCDS: CCDS3015

Canonical transcript exons

ENST00000296161 — 5 exons

Exon	Start	End
ENSE00001078778	122568489	122570024
ENSE00001150175	122570455	122570672
ENSE00001150182	122565859	122566070
ENSE00001154789	122564338	122564613
ENSE00001212773	122571678	122575203

Expression profiles

Bgee: expression breadth ubiquitous, 250 present calls, max score 98.02.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 32.9047 / max 672.0646, expressed in 1752 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
38238	30.5395	1739
38239	2.0825	715
38240	0.2827	113

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	98.02	gold quality
pancreatic ductal cell	CL:0002079	97.79	gold quality
epithelial cell of pancreas	CL:0000083	96.77	silver quality
lower lobe of lung	UBERON:0008949	96.45	gold quality
decidua	UBERON:0002450	95.30	gold quality
epithelium of nasopharynx	UBERON:0001951	94.91	gold quality
nasopharynx	UBERON:0001728	94.89	gold quality
pericardium	UBERON:0002407	94.77	gold quality
mucosa of paranasal sinus	UBERON:0005030	94.21	gold quality
germinal epithelium of ovary	UBERON:0001304	93.99	gold quality
pylorus	UBERON:0001166	93.81	gold quality
penis	UBERON:0000989	93.59	gold quality
palpebral conjunctiva	UBERON:0001812	93.47	gold quality
jejunal mucosa	UBERON:0000399	93.46	gold quality
layer of synovial tissue	UBERON:0007616	93.20	gold quality
nasal cavity epithelium	UBERON:0005384	93.07	gold quality
superficial temporal artery	UBERON:0001614	92.88	gold quality
mammary duct	UBERON:0001765	92.79	gold quality
epithelium of mammary gland	UBERON:0003244	92.79	gold quality
gingival epithelium	UBERON:0001949	92.63	gold quality
trabecular bone tissue	UBERON:0002483	92.40	gold quality
cardia of stomach	UBERON:0001162	92.12	gold quality
gingiva	UBERON:0001828	91.64	gold quality
left ventricle myocardium	UBERON:0006566	91.58	silver quality
colonic mucosa	UBERON:0000317	91.50	gold quality
trigeminal ganglion	UBERON:0001675	91.34	gold quality
urethra	UBERON:0000057	91.31	gold quality
mucosa of sigmoid colon	UBERON:0004993	90.92	gold quality
visceral pleura	UBERON:0002401	90.91	gold quality
trachea	UBERON:0003126	90.80	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	12.01
E-CURD-10	no	488.18

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

133 targeting DTX3L, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-548P	99.98	72.25	3784

Literature-anchored findings (GeneRIF, showing 16)

• It is reported that BBAP and the human family of DTX proteins (DTX1, DTX2, and DTX3) function as E3 ligases based on their capacity for self-ubiquitination. (PMID:12670957)
• BAL1 and BBAP are located on chromosome 3q21 in a head-to-head orientation and are regulated by a IFN-gamma-responsive bidirectional promoter. (PMID:16809771)
• Overexpression of DTX3L, PIK3R4, ATP2C1, and SLC25A36, all located at 3q21.1-23 are associated with cervical cancer. (PMID:18618715)
• Data directly implicate BBAP in the monoubiquitylation and additional posttranslational modification of histone H4 and an associated DNA damage response. (PMID:19818714)
• we report the high-resolution crystal structure of this previously uncharacterized C-terminal domain of human DTX3L, which we term the Deltex C-terminal domain. (PMID:22411408)
• Data establish that BAL1 and BBAP are bona fide members of a DNA damage response pathway and are directly associated with PARP1 activation, BRCA1 recruitment, and double-strand break repair. (PMID:23230272)
• A novel role for the really interesting new gene-domain E3 ubiquitin ligase deltex-3-like (DTX3L) in regulating CXCR4 sorting from endosomes to lysosomes. (PMID:24790097)
• The present study further suggests that the combined targeted inhibition of STAT1, ARTD8, ARTD9 and/or DTX3L could increase the efficacy of chemotherapy or radiation treatment in prostate and other high-risk tumor types with an increased STAT1 signaling. (PMID:24886089)
• Dtx3L heterodimerization with Parp9 enables NAD(+) and poly(ADP-ribose) regulation of E3 activity. (PMID:28525742)
• Immunohistochemical analysis demonstrated that DTX3L was highly expressed in the glioma tissues and its level was correlated with the grade of malignancy. Multivariate analysis revealed the association between high expression of DTX3L and the poor prognosis of glioma patients. In addition, knockdown of DTX3L by siRNA transfection increased glioma cell apoptosis. (PMID:28627634)
• we also found that DTX3L expression was regulated by focal adhesion kinase. Taken together, the results of this study show that DTX3L plays an important role in the proliferation and cell adhesion-mediated drug resistance of multiple myeloma cells and as such may play a key role in the development of multiple myeloma. (PMID:28653881)
• The SARS-CoV-2 Nsp3 macrodomain reverses PARP9/DTX3L-dependent ADP-ribosylation induced by interferon signaling. (PMID:34358560)
• DTX3L Accelerates Pancreatic cancer Progression via FAK/PI3K/AKT Axis. (PMID:37460862)
• DTX3L mediated ubiquitination of cGAS suppresses antitumor immunity in pancreatic cancer. (PMID:37774567)
• DELTEX E3 ligases ubiquitylate ADP-ribosyl modification on nucleic acids. (PMID:38000390)
• Ubiquitylation of nucleic acids by DELTEX ubiquitin E3 ligase DTX3L. (PMID:39242775)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	dtx3lb.2	ENSDARG00000075504
danio_rerio	dtex3lb.1	ENSDARG00000097592
danio_rerio	dtx3lb.3	ENSDARG00000104649
mus_musculus	Dtx3l	ENSMUSG00000049502
rattus_norvegicus	Dtx3l	ENSRNOG00000023400

Paralogs (4): DTX2 (ENSG00000091073), DTX4 (ENSG00000110042), DTX1 (ENSG00000135144), DTX3 (ENSG00000178498)

Protein

Protein identifiers

E3 ubiquitin-protein ligase DTX3L — Q8TDB6 (reviewed: Q8TDB6)

Alternative names: B-lymphoma- and BAL-associated protein, Protein deltex-3-like, RING-type E3 ubiquitin transferase DTX3L, Rhysin-2

All UniProt accessions (1): Q8TDB6

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase which, in association with ADP-ribosyltransferase PARP9, plays a role in DNA damage repair and in interferon-mediated antiviral responses. Monoubiquitinates several histones, including histone H2A, H2B, H3 and H4. In response to DNA damage, mediates monoubiquitination of ‘Lys-91’ of histone H4 (H4K91ub1). The exact role of H4K91ub1 in DNA damage response is still unclear but it may function as a licensing signal for additional histone H4 post-translational modifications such as H4 ‘Lys-20’ methylation (H4K20me). PARP1-dependent PARP9-DTX3L-mediated ubiquitination promotes the rapid and specific recruitment of 53BP1/TP53BP1, UIMC1/RAP80, and BRCA1 to DNA damage sites. By monoubiquitinating histone H2B H2BC9/H2BJ and thereby promoting chromatin remodeling, positively regulates STAT1-dependent interferon-stimulated gene transcription and thus STAT1-mediated control of viral replication. Independently of its catalytic activity, promotes the sorting of chemokine receptor CXCR4 from early endosome to lysosome following CXCL12 stimulation by reducing E3 ligase ITCH activity and thus ITCH-mediated ubiquitination of endosomal sorting complex required for transport ESCRT-0 components HGS and STAM. In addition, required for the recruitment of HGS and STAM to early endosomes. In association with PARP9, plays a role in antiviral responses by mediating ‘Lys-48’-linked ubiquitination of encephalomyocarditis virus (EMCV) and human rhinovirus (HRV) C3 proteases and thus promoting their proteasomal-mediated degradation.

Subunit / interactions. Homodimer and heterodimer. Can heterodimerize with DTX1, enhancing its ubiquitin ligase activity in vitro. Interacts (via N-terminus) with ADP ribosyltransferase PARP9/BAL1 (via PARP catalytic domain) forming a stable complex; the interaction is required to activate PARP9 but is dispensable for DTX3L catalytic activity. Forms a complex with STAT1 and PARP9 independently of IFNB1 or IFNG-mediated STAT1 ‘Tyr-701’ phosphorylation. Found in a complex with PARP9, STAT1 and H2BC9. Found in a complex with E3 ligase ITCH and ESCRT-0 components HGS and STAM. Interacts (via C-terminus) with ITCH; the interaction is increased upon CXCL12 stimulation and inhibits ITCH catalytic activity; the interaction is direct. Interacts with HGS and STAM; the interaction brings together HGS and STAM and promotes their recruitment to early endosomes. (Microbial infection) Interacts with encephalomyocarditis virus (EMCV) C3 protease; the interaction results in C3 protease ‘Lys-48’-linked ubiquitination. (Microbial infection) Interacts with human rhinovirus (HRV) C3 protease; the interaction results in C3 protease ‘Lys-48’-linked ubiquitination.

Subcellular location. Cytoplasm. Nucleus. Early endosome membrane. Lysosome membrane.

Post-translational modifications. Autoubiquitinated.

Activity regulation. Binding to PARP9 enhances DTX3L catalytic activity.

Induction. Induced by IFNG. Induced by IFNB1.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the Deltex family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8TDB6-1	1	yes
Q8TDB6-2	2

RefSeq proteins (1): NP_612144* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR012677	Nucleotide-bd_a/b_plait_sf	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017907	Znf_RING_CS	Conserved_site
IPR039396	Deltex_C	Domain
IPR039398	Deltex_fam	Family
IPR039399	Deltex_C_sf	Homologous_superfamily
IPR042843	TX3L_RING-HC	Domain
IPR048409	DTX3L_KH-like	Domain
IPR048418	DTX3L_a/b_dom	Domain
IPR057051	PARP14_RPM_1	Domain

Pfam: PF13923, PF18102, PF21717, PF21718, PF23222

UniProt features (42 total): strand 10, modified residue 6, helix 6, mutagenesis site 4, sequence variant 3, region of interest 3, compositionally biased region 3, turn 2, initiator methionine 1, chain 1, splice variant 1, zinc finger region 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3PG6	X-RAY DIFFRACTION	1.7
8R79	X-RAY DIFFRACTION	2.18

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TDB6-F1	77.35	0.35

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 (6): 9, 202, 221, 532, 539, 2

Mutagenesis-validated functional residues (4):

Position	Phenotype
561–564	loss of catalytic activity. loss of histone h2b ubiquitination. no effect on stat1 phosphorylation and on the interactio
561	loss of catalytic activity but does not affect its capacity to inhibit itch catalytic activity; when associated with a-5
596	loss of catalytic activity but does not affect its capacity to inhibit itch catalytic activity; when associated with a-5
599	loss of catalytic activity but does not affect its capacity to inhibit itch catalytic activity; when associated with a-5

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

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

MSigDB gene sets: 284 (showing top): GOBP_POSITIVE_REGULATION_OF_PROTEIN_BINDING, GOBP_REGULATION_OF_PROTEIN_BINDING, GOBP_LYSOSOMAL_TRANSPORT, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_DEFENSE_RESPONSE_TO_VIRUS, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, GOCC_VACUOLAR_MEMBRANE, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_ENDOSOME_TO_LYSOSOME_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_VACUOLAR_TRANSPORT, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, GOBP_VESICLE_MEDIATED_TRANSPORT

GO Biological Process (24): DNA damage checkpoint signaling (GO:0000077), positive regulation of defense response to virus by host (GO:0002230), double-strand break repair (GO:0006302), ubiquitin-dependent protein catabolic process (GO:0006511), Notch signaling pathway (GO:0007219), endosome to lysosome transport (GO:0008333), protein transport (GO:0015031), protein ubiquitination (GO:0016567), positive regulation of protein binding (GO:0032092), positive regulation of chromatin binding (GO:0035563), innate immune response (GO:0045087), positive regulation of DNA-templated transcription (GO:0045893), negative regulation of ubiquitin-protein transferase activity (GO:0051444), defense response to virus (GO:0051607), protein autoubiquitination (GO:0051865), protein K48-linked ubiquitination (GO:0070936), DNA repair-dependent chromatin remodeling (GO:0140861), positive regulation of protein localization to nucleus (GO:1900182), positive regulation of protein localization to early endosome (GO:1902966), positive regulation of receptor catabolic process (GO:2000646), immune system process (GO:0002376), DNA repair (GO:0006281), chromatin organization (GO:0006325), DNA damage response (GO:0006974)

GO Molecular Function (14): ubiquitin-protein transferase activity (GO:0004842), enzyme inhibitor activity (GO:0004857), zinc ion binding (GO:0008270), enzyme binding (GO:0019899), histone binding (GO:0042393), ubiquitin-like protein ligase binding (GO:0044389), ubiquitin protein ligase activity (GO:0061630), STAT family protein binding (GO:0097677), protein ADP-ribosyltransferase-substrate adaptor activity (GO:0140768), histone ubiquitin ligase activity (GO:0140852), histone H4K91 ubiquitin ligase activity (GO:0141000), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (11): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), lysosome (GO:0005764), lysosomal membrane (GO:0005765), cytosol (GO:0005829), early endosome membrane (GO:0031901), protein-containing complex (GO:0032991), endosome (GO:0005768), early endosome (GO:0005769), membrane (GO:0016020)

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	4
protein binding	3
protein ubiquitination	2
positive regulation of binding	2
ubiquitin-protein transferase activity	2
catalytic activity	2
DNA integrity checkpoint signaling	1
signal transduction in response to DNA damage	1
regulation of defense response to virus by host	1
DNA repair	1
modification-dependent protein catabolic process	1
cell surface receptor signaling pathway	1
lysosomal transport	1
intercellular transport	1
vesicle-mediated transport	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
protein modification by small protein conjugation	1
regulation of protein binding	1
chromatin binding	1
immune response	1
defense response to symbiont	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
negative regulation of protein ubiquitination	1
negative regulation of catalytic activity	1
regulation of ubiquitin-protein transferase activity	1
defense response	1
response to virus	1
protein polyubiquitination	1
chromatin remodeling	1
DNA damage response	1
protein localization to nucleus	1
regulation of protein localization to nucleus	1
positive regulation of protein localization	1
protein localization to early endosome	1
regulation of protein localization to early endosome	1
positive regulation of protein localization to endosome	1

Protein interactions and networks

STRING

842 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DTX3L	PARP9	Q8IXQ6	999
DTX3L	PARP14	Q460N5	898
DTX3L	PARP15	Q460N3	862
DTX3L	STAT1	P42224	786
DTX3L	DTX1	Q86Y01	738
DTX3L	MX1	P20591	636
DTX3L	IFI44L	Q53G44	635
DTX3L	TP53BP1	Q12888	582
DTX3L	MACROH2A1	O75367	549
DTX3L	UBE2D1	P51668	520
DTX3L	H4C7	Q99525	516
DTX3L	H4C16	P02304	495
DTX3L	IRF7	Q92985	493
DTX3L	SQSTM1	Q13501	481
DTX3L	PARP10	Q53GL7	481

IntAct

49 interactions, top by confidence:

A	B	Type	Score
SPG21	DTX3L	psi-mi:“MI:0915”(physical association)	0.720
DTX3L	SPG21	psi-mi:“MI:0915”(physical association)	0.720
ERP29	GLB1L	psi-mi:“MI:0914”(association)	0.640
DTX3L	UBE2K	psi-mi:“MI:0915”(physical association)	0.560
DTX3L	PARP9	psi-mi:“MI:0915”(physical association)	0.560
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
DTX3L	UQCRFS1P1	psi-mi:“MI:0915”(physical association)	0.400
DTX3L	PPIB	psi-mi:“MI:0915”(physical association)	0.400
DTX3L	PARP9	psi-mi:“MI:0915”(physical association)	0.400
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
UBE2D1	DTX3L	psi-mi:“MI:0915”(physical association)	0.370
UBE2D2	DTX3L	psi-mi:“MI:0915”(physical association)	0.370
DTX3L	UBE2D3	psi-mi:“MI:0915”(physical association)	0.370
DTX3L	UBE2E1	psi-mi:“MI:0915”(physical association)	0.370
UBE2E2	DTX3L	psi-mi:“MI:0915”(physical association)	0.370
DTX3L	UBE2E3	psi-mi:“MI:0915”(physical association)	0.370
UBE2D4	DTX3L	psi-mi:“MI:0915”(physical association)	0.370
DTX3L	UBE2W	psi-mi:“MI:0915”(physical association)	0.370
HIP2	DTX3L	psi-mi:“MI:0915”(physical association)	0.370
DTX3L	UBE2H	psi-mi:“MI:0915”(physical association)	0.370
UBE2I	DTX3L	psi-mi:“MI:0915”(physical association)	0.370
UBE2R2	DTX3L	psi-mi:“MI:0915”(physical association)	0.370
RNF111	DTX3L	psi-mi:“MI:0915”(physical association)	0.370
PHF7	DTX3L	psi-mi:“MI:0915”(physical association)	0.370
DTX3L	TRIM9	psi-mi:“MI:0915”(physical association)	0.370
NUDCD1	APOBEC3B	psi-mi:“MI:0914”(association)	0.350

BioGRID (121): HIST1H4A (Affinity Capture-Western), DTX3L (Two-hybrid), DTX3L (Affinity Capture-MS), DTX3L (Affinity Capture-Western), HIST1H2BJ (Biochemical Activity), H2AFV (Biochemical Activity), STAT1 (Affinity Capture-Western), DTX3L (Affinity Capture-Western), PARP9 (Affinity Capture-Western), DTX3L (Affinity Capture-Western), HIST1H2BJ (Affinity Capture-Western), DTX3L (Co-localization), PARP9 (Affinity Capture-MS), DTX3L (Affinity Capture-MS), DTX3L (Affinity Capture-Western)

ESM2 similar proteins: A0A386CAB9, A0A7H0DNF0, A2CI98, A6QR20, C6FG12, F1M649, F1MHT9, F6R2G2, O15050, O70167, O70173, P59045, Q13075, Q20CR4, Q2LKV2, Q3UIR3, Q3UP24, Q4TVR5, Q4VSN3, Q4VSN4, Q4VSN5, Q5EB20, Q5H9U9, Q5RBY8, Q5U228, Q66X01, Q66X03, Q66X05, Q66X22, Q6NU22, Q6NU51, Q6XUX0, Q6XUX1, Q6XUX2, Q6XUX3, Q6ZN28, Q7Z2W4, Q80VH0, Q8CCN1, Q8QMP8

Diamond homologs: Q23985, Q3UIR3, Q5REG4, Q61010, Q80V91, Q86UW9, Q86Y01, Q8N9I9, Q8R3P2, Q8TDB6, Q6PDK8, Q8AW93, Q9Y2E6, Q07G17, Q2KJ29, Q3KNV8, Q80Z37, Q8BTQ0, Q9NS56, B4F6W9, F1LP64, G5E870, Q13670, F4KGU4, Q2EMV9, Q9NS91, Q9QXK2, P23798, P35227, Q28H21, Q2YDF9, Q4QR06, Q6DLV9, Q7T3E6, Q7ZYZ7, Q8JIR0, Q8R023, Q9BSM1, P25916, P35226

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	DTX3L	ubiquitination
DTX3L	“down-regulates activity”	H4C1	monoubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 47 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
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	8	86.7×	5e-12
Antigen processing: Ubiquitination & Proteasome degradation	13	14.2×	2e-10

GO biological processes:

GO term	Partners	Fold	FDR
protein K11-linked ubiquitination	6	57.4×	6e-08
protein monoubiquitination	6	50.3×	1e-07
protein K48-linked ubiquitination	10	41.1×	9e-12
protein polyubiquitination	9	25.3×	8e-09
ubiquitin-dependent protein catabolic process	10	18.1×	1e-08

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	89
Likely benign	15
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

797 predictions. Top by Δscore:

Variant	Effect	Δscore
3:122564515:T:TA	donor_gain	1.0000
3:122565843:A:AG	acceptor_gain	1.0000
3:122565845:T:G	acceptor_gain	1.0000
3:122565854:T:A	acceptor_gain	1.0000
3:122565928:T:TA	acceptor_gain	1.0000
3:122570524:G:GT	donor_gain	1.0000
3:122570532:G:GT	donor_gain	1.0000
3:122570533:A:T	donor_gain	1.0000
3:122564516:C:A	donor_gain	0.9900
3:122564565:G:GT	donor_gain	0.9900
3:122564593:TG:T	donor_gain	0.9900
3:122564594:GG:G	donor_gain	0.9900
3:122564609:GGCAG:G	donor_gain	0.9900
3:122564610:GCAG:G	donor_gain	0.9900
3:122564610:GCAGG:G	donor_gain	0.9900
3:122564611:C:T	donor_gain	0.9900
3:122564611:CAGGT:C	donor_loss	0.9900
3:122564612:AG:A	donor_loss	0.9900
3:122564613:GG:G	donor_loss	0.9900
3:122564614:GTGAG:G	donor_loss	0.9900
3:122564615:T:G	donor_loss	0.9900
3:122565832:T:G	acceptor_gain	0.9900
3:122565843:AAT:A	acceptor_gain	0.9900
3:122565844:A:G	acceptor_gain	0.9900
3:122565845:T:A	acceptor_gain	0.9900
3:122565852:A:AG	acceptor_gain	0.9900
3:122565852:ACT:A	acceptor_gain	0.9900
3:122565853:C:G	acceptor_gain	0.9900
3:122565929:G:A	acceptor_gain	0.9900
3:122565938:T:A	acceptor_gain	0.9900

AlphaMissense

4896 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:122570626:T:A	W703R	0.997
3:122570626:T:C	W703R	0.997
3:122570646:A:C	K709N	0.997
3:122570646:A:T	K709N	0.997
3:122570510:T:C	L664S	0.996
3:122564598:T:C	F58L	0.995
3:122564600:C:A	F58L	0.995
3:122564600:C:G	F58L	0.995
3:122570578:T:C	F687L	0.995
3:122570580:T:A	F687L	0.995
3:122570580:T:G	F687L	0.995
3:122570645:A:T	K709I	0.995
3:122570560:T:C	F681L	0.994
3:122570562:T:A	F681L	0.994
3:122570562:T:G	F681L	0.994
3:122564599:T:C	F58S	0.992
3:122570579:T:C	F687S	0.992
3:122570628:G:C	W703C	0.992
3:122570628:G:T	W703C	0.992
3:122571725:T:C	L734P	0.992
3:122570644:A:G	K709E	0.991
3:122570510:T:G	L664W	0.989
3:122570513:C:A	P665H	0.989
3:122570498:G:C	R660P	0.988
3:122570645:A:C	K709T	0.988
3:122570527:G:A	G670R	0.987
3:122570527:G:C	G670R	0.987
3:122570021:A:C	Q644H	0.986
3:122570021:A:T	Q644H	0.986
3:122570504:C:A	A662E	0.986

dbSNP variants (sampled 300 via entrez): RS1000455364 (3:122571256 C>A,T), RS1000724738 (3:122572651 C>A,T), RS1000819033 (3:122566193 A>G), RS1001535967 (3:122563304 C>G), RS1001916801 (3:122571272 T>A,C), RS1002029057 (3:122563007 G>A), RS1002032854 (3:122571032 C>A,G,T), RS1002985041 (3:122569637 TG>T), RS1003014238 (3:122568883 T>C), RS1003182494 (3:122574740 G>A,C), RS1003429579 (3:122564069 C>T), RS1003555655 (3:122574215 T>C), RS1003879902 (3:122575387 T>C), RS1004162949 (3:122575196 G>A), RS1004278069 (3:122574767 G>A,T)

Disease associations

OMIM: gene MIM:613143 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001469_2	Major depressive disorder	6.000000e-06
GCST010204_85	Low density lipoprotein cholesterol levels	1.000000e-19

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004611	low density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4742303 (PROTEIN-PROTEIN INTERACTION)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Nickel	decreases expression, increases expression	3
Air Pollutants	decreases expression, increases abundance	2
Lipopolysaccharides	increases expression, affects response to substance	2
Smoke	increases abundance, decreases expression	2
Valproic Acid	decreases methylation, affects expression, decreases expression	2
FR900359	decreases phosphorylation	1
dicrotophos	increases expression	1
bisphenol A	increases expression	1
methylparaben	decreases expression	1
butyraldehyde	decreases expression	1
hydroquinone	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	increases expression, affects response to substance	1
2,2’,4,4’,5-brominated diphenyl ether	increases expression	1
belinostat	decreases expression	1
abrine	decreases expression	1
licochalcone B	decreases expression	1
(+)-JQ1 compound	decreases expression	1
nabiximols	decreases expression	1
Sunitinib	decreases expression	1
Vorinostat	decreases expression	1
Acetaminophen	decreases expression	1
Air Pollutants, Occupational	decreases expression	1
Caffeine	decreases phosphorylation	1
Diethylhexyl Phthalate	increases expression	1
Diethylstilbestrol	decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	increases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Naled	affects expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4713750	Binding	Protac activity at CRBN/DTX3L in human BxPC-3 cells assessed as DTX3L degradation incubated for 16 hrs by proteomic analysis	Discovery of a Napabucasin PROTAC as an Effective Degrader of the E3 Ligase ZFP91. — J Med Chem

Cellosaurus cell lines

6 cell lines: 5 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1F5	Abcam A-549 DTX3L KO 2	Cancer cell line	Male
CVCL_B2MN	Abcam A-549 DTX3L KO 1	Cancer cell line	Male
CVCL_D7NX	Ubigene A-549 DTX3L KO	Cancer cell line	Male
CVCL_D8KB	Ubigene HCT 116 DTX3L KO	Cancer cell line	Male
CVCL_D9DP	Ubigene HEK293 DTX3L KO	Transformed cell line	Female
CVCL_E0BX	Ubigene HeLa DTX3L KO	Cancer cell line	Female

Clinical trials (associated diseases)

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