DTL

Summary

DTL (denticleless E3 ubiquitin protein ligase adapter, HGNC:30288) is a protein-coding gene on chromosome 1q32.3, encoding Denticleless protein homolog (Q9NZJ0). Substrate-specific adapter of a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex required for cell cycle control, DNA damage response and translesion DNA synthesis. It is a common-essential gene (DepMap: required in 100.0% of cancer cell lines).

Contributes to ubiquitin-protein transferase activity. Involved in several processes, including protein ubiquitination; regulation of G2/M transition of mitotic cell cycle; and translesion synthesis. Located in centrosome; cytosol; and nuclear lumen. Part of Cul4A-RING E3 ubiquitin ligase complex and Cul4B-RING E3 ubiquitin ligase complex.

Source: NCBI Gene 51514 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 83 total
• Cancer dependency (DepMap): dependent in 100.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_016448

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30288
Approved symbol	DTL
Name	denticleless E3 ubiquitin protein ligase adapter
Location	1q32.3
Locus type	gene with protein product
Status	Approved
Aliases	RAMP, L2DTL, DCAF2, CDT2
Ensembl gene	ENSG00000143476
Ensembl biotype	protein_coding
OMIM	610617
Entrez	51514

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 10 protein_coding, 4 protein_coding_CDS_not_defined

ENST00000366991, ENST00000463791, ENST00000475419, ENST00000489149, ENST00000496442, ENST00000542077, ENST00000935624, ENST00000935625, ENST00000935626, ENST00000935627, ENST00000935628, ENST00000935629, ENST00000935630, ENST00000935631

RefSeq mRNA: 3 — MANE Select: NM_016448 NM_001286229, NM_001286230, NM_016448

CCDS: CCDS1502, CCDS65778

Canonical transcript exons

ENST00000366991 — 15 exons

Exon	Start	End
ENSE00001068413	212042993	212043118
ENSE00001239264	212068224	212068327
ENSE00001355894	212035748	212035942
ENSE00003482774	212064917	212065029
ENSE00003501435	212072101	212072213
ENSE00003513254	212078173	212078262
ENSE00003517955	212047297	212047417
ENSE00003518890	212100252	212101084
ENSE00003520787	212062884	212062949
ENSE00003575910	212066812	212066885
ENSE00003596926	212044660	212044758
ENSE00003599515	212068599	212068703
ENSE00003664731	212047151	212047212
ENSE00003689757	212080615	212080750
ENSE00003846432	212102842	212105013

Expression profiles

Bgee: expression breadth ubiquitous, 196 present calls, max score 98.55.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.0181 / max 387.1359, expressed in 1377 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
8436	18.8122	1375
8437	0.1831	81
8440	0.0229	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	98.55	gold quality
oocyte	CL:0000023	97.59	gold quality
trabecular bone tissue	UBERON:0002483	92.98	gold quality
embryo	UBERON:0000922	91.62	gold quality
ventricular zone	UBERON:0003053	91.22	gold quality
bone marrow	UBERON:0002371	89.46	gold quality
ganglionic eminence	UBERON:0004023	89.40	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.35	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.83	gold quality
bone marrow cell	CL:0002092	86.04	gold quality
sperm	CL:0000019	85.35	gold quality
testis	UBERON:0000473	83.44	gold quality
male germ cell	CL:0000015	83.33	gold quality
left testis	UBERON:0004533	82.95	gold quality
right testis	UBERON:0004534	82.32	gold quality
hair follicle	UBERON:0002073	81.20	silver quality
thymus	UBERON:0002370	79.62	silver quality
mucosa of sigmoid colon	UBERON:0004993	78.18	gold quality
colonic mucosa	UBERON:0000317	77.57	gold quality
stromal cell of endometrium	CL:0002255	77.53	gold quality
oral cavity	UBERON:0000167	77.07	gold quality
placenta	UBERON:0001987	76.79	gold quality
rectum	UBERON:0001052	76.13	gold quality
vermiform appendix	UBERON:0001154	75.71	gold quality
tongue squamous epithelium	UBERON:0006919	74.81	silver quality
cartilage tissue	UBERON:0002418	74.51	gold quality
jejunal mucosa	UBERON:0000399	74.50	gold quality
esophagus squamous epithelium	UBERON:0006920	74.31	gold quality
caecum	UBERON:0001153	73.61	gold quality
visceral pleura	UBERON:0002401	73.03	gold quality

Single-cell (SCXA)

Detected in 11 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-ENAD-20	yes	469.18
E-GEOD-93593	yes	373.97
E-MTAB-11268	yes	204.62
E-GEOD-99795	yes	151.40
E-MTAB-7052	yes	129.82
E-ENAD-27	yes	86.90
E-ANND-3	yes	6.84
E-GEOD-110499	no	542.96
E-MTAB-6911	no	459.13
E-MTAB-7008	no	217.64
E-GEOD-76312	no	156.60

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, E2F4, E2F5, E2F6

miRNA regulators (miRDB)

91 targeting DTL, 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-4795-3P	100.00	74.62	4024
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-548A-3P	99.76	70.58	3524

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• 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)
• DTL promotes genomic stability through two distinct mechanisms. First, it is an essential component of the CUL4-DDB1 complex that controls CDT1 levels, thereby preventing rereplication. Second, it is required for the early G2/M checkpoint. (PMID:17085480)
• L2DTL encodes a nuclear protein with centrosome targeting in mitosis, and plays important roles in DNA synthesis, cell cycle progression, cytokinesis, proliferation, and differentiation. (PMID:17106265)
• roles of DTL/RAMP in growth of breast cancer cells and suggest that DTL/RAMP might be a promising molecular target for treatment of breast cancer. (PMID:18542055)
• CDK inhibitor p21 is degraded by a proliferating cell nuclear antigen-coupled Cul4-DDB1Cdt2 pathway during S phase and after UV irradiation (PMID:18703516)
• CDT2/DTL functions as a substrate recognition factor for the Cul4-DDB1-Roc1 E3 ubiquitin ligase to promote PCNA-dependent ubiquitylation and degradation of the CDK inhibitor CDKN1A, both in S-phase of the cell cycle and after UV irradiation. (PMID:18794347)
• RAMP plays an oncogenic role in gastric carcinogenesis (PMID:19672268)
• miR-215, through the suppression of DTL expression, induces a decreased cell proliferation leading to an increase in chemoresistance (PMID:20433742)
• Cdt1 degradation following UV irradiation occurs rapidly at damaged sites due to PCNA chromatin loading and the recruitment of Cdt1 and CRL4(Cdt2), before DNA damage repair is completed (PMID:20929861)
• Results demonstrate a central role of CRL4(Cdt2)-dependent cell-cycle regulation of Set8 for the maintenance of a stable epigenetic state essential for cell viability. (PMID:20932471)
• 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)
• CRL4(Cdt2)-dependent destruction of Set8 in S phase preserves genome stability by preventing aberrant chromatin compaction during DNA synthesis. (PMID:20932472)
• The turnover of SET8 is accelerated after ultraviolet irradiation dependent on the CRL4(CDT2) ubiquitin ligase and PCNA. (PMID:21220508)
• 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)
• N-methyl-N’-nitro-N-nitrosoguanidine (MNNG) triggers MSH2 and Cdt2 protein-dependent degradation of the cell cycle and mismatch repair (MMR) inhibitor protein p21Waf1/Cip1. (PMID:21725088)
• CDT2, a 1q-located candidate gene encoding a protein involved in ubiquitin ligase activity and significantly overexpressed in 1qG Ewing sarcoma, was validated in vitro and in vivo proving its major contribution to this molecular and clinical phenotype (PMID:21822310)
• Studies suggest that DNA damage-induced ubiquitination or sumoylation of PCNA prevents CRL4Cdt2-dependent degradation by inhibiting binding of Cdt1 to PCNA. (PMID:21846465)
• data identified miR-30a-5p as a tumor-suppressing miRNA in colon cancer cells exerting its function via modulation of DTL expression, which is frequently overexpressed in colorectal cancer (PMID:22287560)
• ATR, activated after DNA damage, phosphorylates Cdt2 and promotes the rapid degradation of Cdt1 after UV irradiation in the G1 phase of the cell cycle. (PMID:23029527)
• CRL4 is a major regulator of CHK1 stability. CRL4CDT2 targets CHK1 for ubiquitination in the nucleoplasm, and for PCNA-independent degradation. CHK1 is required for G2 arrest in CDT2-depleted cells. (PMID:23109433)
• The functional interaction between FBXO11 and CDT2 is evolutionary conserved from worms to humans and plays an important role in regulating the timing of cell-cycle exit. (PMID:23478441)
• Migration of epithelial cells is stimulated by CRL1(FBXO11)-mediated downregulation of Cdt2 and the consequent stabilization of Set8. (PMID:23478445)
• Non-canonical CRL4A/4B(CDT2) interacts with RAD18 to modulate post replication repair and cell survival. (PMID:23555860)
• TGF-beta signaling promotes exit from the cell cycle and cellular migration through cullin cross-regulation: SCF-FBXO11 turns off CRL4-Cdt2. (PMID:23892434)
• Data indicate that CRL4(Cdt2) regulates the degradation of the p12 subunit of Pol delta4. (PMID:23913683)
• Data indicate that depleting ubiquitin E3 ligase CRL4(CDT2/DCAF2) mimicked the pharmacological effects of MLN4924. (PMID:23995842)
• ubiquitination of p12 through CRL4(Cdt2) and subsequent degradation form one mechanism by which a cell responds to DNA damage to inhibit fork progression. (PMID:24022480)
• while interaction with PCNA was important for targeting p21 to the CRL4Cdt2 ligase re-localized to MVM replication centers (PMID:24699724)
• CRL4(Cdt2)-dependent degradation of TDG occurs in S phase because of the requirement for TDG to interact with chromatin-loaded PCNA, and this degradation is important for preventing toxicity from excess TDG. (PMID:24962565)
• CDT2 likely is a non-oncogene to which transformed cells become addicted because of their enhanced cellular stress, such as replicative stress and DNA damage. (PMID:25115388)
• Data shows that phosphorylation of Cdt2 at T464 is important fot its interaction with Cdt2. (PMID:25154416)
• CDK1 activity blocks CRL4CDT2 by preventing chromatin recruitment of the substrate receptor, CDT2. (PMID:25411249)
• CDT2 mediated XPG elimination from DNA damage sites clears the chromatin space needed for repair. (PMID:25483071)
• These findings reveal C/EBPalpha regulates G1/S cell cycle arrest in response to DNA damage via the control of CRL4(Cdt2) mediated degradation of p21. (PMID:25483090)
• Findings suggest that DTL overexpression plays a crucial role in tumor cell proliferation in gastric carcinoma. (PMID:26472028)
• Results suggest that CDK-mediated phosphorylation of Cdt2 inactivates its ubiquitin ligase activity by reducing its affinity to PCNA, an important strategy for regulating the levels of key proteins in the cell cycle. (PMID:29424068)
• CDT2 has a PIP box-like motif at its C terminus. This motif directly interacts with PCNA to help promote degradation of CDT1 during replication or in response to DNA damage. (PMID:30301766)
• As the ligase activity of CRL4Cdt2 depends on proliferating cell nuclear antigen (PCNA) loading onto DNA, the present results suggest that the DNA-binding domain facilitates the CRL4Cdt2-mediated recognition and ubiquitination of substrates bound to PCNA on chromatin. (PMID:30649446)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	dtl	ENSDARG00000023002
mus_musculus	Dtl	ENSMUSG00000037474
rattus_norvegicus	Dtl	ENSRNOG00000004195
drosophila_melanogaster	l(2)dtl	FBGN0013548
caenorhabditis_elegans		WBGENE00011318

Protein

Protein identifiers

Denticleless protein homolog — Q9NZJ0 (reviewed: Q9NZJ0)

Alternative names: DDB1- and CUL4-associated factor 2, Lethal(2) denticleless protein homolog, Retinoic acid-regulated nuclear matrix-associated protein

All UniProt accessions (2): Q9NZJ0, F5GZ90

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-specific adapter of a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex required for cell cycle control, DNA damage response and translesion DNA synthesis. The DCX(DTL) complex, also named CRL4(CDT2) complex, mediates the polyubiquitination and subsequent degradation of CDT1, CDKN1A/p21(CIP1), FBH1, KMT5A and SDE2. CDT1 degradation in response to DNA damage is necessary to ensure proper cell cycle regulation of DNA replication. CDKN1A/p21(CIP1) degradation during S phase or following UV irradiation is essential to control replication licensing. KMT5A degradation is also important for a proper regulation of mechanisms such as TGF-beta signaling, cell cycle progression, DNA repair and cell migration. Most substrates require their interaction with PCNA for their polyubiquitination: substrates interact with PCNA via their PIP-box, and those containing the ‘K+4’ motif in the PIP box, recruit the DCX(DTL) complex, leading to their degradation. In undamaged proliferating cells, the DCX(DTL) complex also promotes the ‘Lys-164’ monoubiquitination of PCNA, thereby being involved in PCNA-dependent translesion DNA synthesis. The DDB1-CUL4A-DTL E3 ligase complex regulates the circadian clock function by mediating the ubiquitination and degradation of CRY1.

Subunit / interactions. Component of the DCX(DTL) E3 ubiquitin ligase complex (also called CRL4(CDT2)), at least composed of CUL4 (CUL4A or CUL4B), DDB1, DTL/CDT2 and RBX1. Interacts with CDKN1A. Interacts with DDB1. Interacts with FBXO11; SCF(FBXWO11) controls DTL stability but DCX(DTL) does not control FBXO11 stability. Interacts with CRY1.

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

Tissue specificity. Expressed in placenta and testis, very low expression seen in skeletal muscle. Detected in all hematopoietic tissues examined, with highest expression in thymus and bone marrow. A low level detected in the spleen and lymph node, and barely detectable level in the peripheral leukocytes. RA treatment down-regulated the expression in NT2 cell.

Post-translational modifications. Ubiquitinated by the anaphase promoting complex/cyclosome (APC/C). Autoubiquitinated through ‘Lys-48’-polyubiquitin chains in a PCNA-independent reaction, allowing proteasomal turnover. Polyubiquitinated by SCF(FBXO11) when not phosphorylated, leading to its degradation. A tight regulation of the polyubiquitination by SCF(FBXO11) is involved in the control of different processes such as TGF-beta signaling, cell cycle progression and exit. Phosphorylated at Thr-464 by CDK1/Cyclin-B and CDK2/Cyclin-A but not by CDK2/Cyclin-E, MAPK1 or PLK1. Phosphorylation at Thr-464 inhibits the interaction with FBXO11 and decreases upon cell cycle exit induced by TGF-beta or serum starvation.

Induction. Induced by TGF-beta, the up-regulation is immediate and transient.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the WD repeat cdt2 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NZJ0-1	1	yes
Q9NZJ0-2	2

RefSeq proteins (3): NP_001273158, NP_001273159, NP_057532* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001680	WD40_rpt	Repeat
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR019775	WD40_repeat_CS	Conserved_site
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR051865	WD-repeat_CDT2_adapter	Family

Pfam: PF00400

UniProt features (60 total): modified residue 16, mutagenesis site 16, repeat 7, region of interest 5, short sequence motif 3, splice variant 3, sequence variant 3, sequence conflict 3, compositionally biased region 2, chain 1, turn 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
9C5U	ELECTRON MICROSCOPY	3.05
9UWG	ELECTRON MICROSCOPY	3.21
9C5T	ELECTRON MICROSCOPY	3.36
9C5V	ELECTRON MICROSCOPY	3.36
6QC0	X-RAY DIFFRACTION	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NZJ0-F1	63.29	0.40

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 (16): 1, 196, 410, 426, 464, 485, 490, 495, 512, 516, 557, 676, 679, 684, 702, 717

Mutagenesis-validated functional residues (16):

Position	Phenotype
246	blocks association with ddb1 and ubiquitination by dcx(dtl). no effect on ubiquitination by scf(fbxo11).
457	increases protein stability, but no effect on interaction with fbxo11 and polyubiquitination. delays cell migration.
462	blocks interaction with fbxo11 and ubiquitination, increasing protein stability. delays cell migration.
463	no effect on interaction with fbxo11. increases protein stability.
464	blocks interaction with fbxo11 and increases protein stability. not phosphorylated by cdk1 or cdk2.
464	blocks interaction with fbxo11.
465	inhibits phosphorylation on t-464. no effect on interaction with fbxo11.
466	no effect on interaction with fbxo11.
467	no effect on interaction with fbxo11.
468	no effect on interaction with fbxo11.
471	no effect on interaction with fbxo11.
472	no effect on interaction with fbxo11.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-110314	Recognition of DNA damage by PCNA-containing replication complex
R-HSA-8951664	Neddylation

MSigDB gene sets: 368 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_REGULATION_OF_DNA_TEMPLATED_DNA_REPLICATION, FISCHER_G1_S_CELL_CYCLE, GOBP_CELL_CYCLE_PHASE_TRANSITION, GEORGES_CELL_CYCLE_MIR192_TARGETS, GOBP_POSITIVE_REGULATION_OF_MITOTIC_CELL_CYCLE, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_DNA_DAMAGE_TOLERANCE, GNF2_MCM5, GOBP_MITOTIC_G2_M_TRANSITION_CHECKPOINT

GO Biological Process (16): protein polyubiquitination (GO:0000209), DNA replication (GO:0006260), ubiquitin-dependent protein catabolic process (GO:0006511), protein monoubiquitination (GO:0006513), DNA damage response (GO:0006974), mitotic G2 DNA damage checkpoint signaling (GO:0007095), response to UV (GO:0009411), positive regulation of G2/M transition of mitotic cell cycle (GO:0010971), translesion synthesis (GO:0019985), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), positive regulation of protein catabolic process (GO:0045732), rhythmic process (GO:0048511), regulation of cell cycle (GO:0051726), positive regulation of catabolic process (GO:0009896), protein ubiquitination (GO:0016567), positive regulation of protein metabolic process (GO:0051247)

GO Molecular Function (3): protein-macromolecule adaptor activity (GO:0030674), ubiquitin-protein transferase activity (GO:0004842), protein binding (GO:0005515)

GO Cellular Component (13): nucleus (GO:0005634), nucleoplasm (GO:0005654), chromosome (GO:0005694), nucleolus (GO:0005730), centrosome (GO:0005813), cytosol (GO:0005829), Cul4A-RING E3 ubiquitin ligase complex (GO:0031464), Cul4B-RING E3 ubiquitin ligase complex (GO:0031465), nuclear membrane (GO:0031965), Cul4-RING E3 ubiquitin ligase complex (GO:0080008), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
DNA Damage Bypass	1
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
protein ubiquitination	3
intracellular membraneless organelle	3
nuclear lumen	2
Cul4-RING E3 ubiquitin ligase complex	2
DNA metabolic process	1
DNA biosynthetic process	1
modification-dependent protein catabolic process	1
cellular response to stress	1
mitotic G2 phase	1
mitotic DNA damage checkpoint signaling	1
mitotic G2/M transition checkpoint	1
response to light stimulus	1
G2/M transition of mitotic cell cycle	1
regulation of G2/M transition of mitotic cell cycle	1
positive regulation of mitotic cell cycle phase transition	1
positive regulation of cell cycle G2/M phase transition	1
DNA damage tolerance	1
DNA synthesis involved in DNA replication	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
cell cycle	1
regulation of cellular process	1
catabolic process	1
positive regulation of metabolic process	1
regulation of catabolic process	1
protein modification by small protein conjugation	1
positive regulation of macromolecule metabolic process	1
protein metabolic process	1
regulation of protein metabolic process	1
protein binding	1
molecular adaptor activity	1
ubiquitin-like protein transferase activity	1
binding	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1706 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DTL	DDB1	Q16531	998
DTL	CUL4A	Q13619	990
DTL	CUL4B	Q13620	982
DTL	CDT1	Q9H211	980
DTL	DCAF1	Q9Y4B6	962
DTL	RBX1	P62877	908
DTL	TRAM2	Q15035	826
DTL	DDB2	Q92466	745
DTL	FBXO11	Q86XK2	726
DTL	KMT5A	Q9NQR1	717
DTL	CDC6	Q99741	641
DTL	AUNIP	Q9H7T9	623
DTL	CUL1	Q13616	609
DTL	CHEK1	O14757	585
DTL	MDM2	Q00987	562

IntAct

77 interactions, top by confidence:

A	B	Type	Score
CUL4B	DDB1	psi-mi:“MI:0914”(association)	0.940
CUL4B	COPS2	psi-mi:“MI:0914”(association)	0.790
NHERF2	PODXL	psi-mi:“MI:0914”(association)	0.770
DTL	DDB1	psi-mi:“MI:0914”(association)	0.740
DTL	DDB1	psi-mi:“MI:0915”(physical association)	0.740
CUL4B	CUL4A	psi-mi:“MI:0914”(association)	0.730
DTL	CUL4B	psi-mi:“MI:0914”(association)	0.730
COPS6	RHOBTB1	psi-mi:“MI:0914”(association)	0.730
CCT2	TXNDC9	psi-mi:“MI:0914”(association)	0.730
CUL4A	COPS2	psi-mi:“MI:0914”(association)	0.640
CARNMT1	NUP42	psi-mi:“MI:0914”(association)	0.640
PFDN1	PFDN6	psi-mi:“MI:0914”(association)	0.640
GLMN	FKBP5	psi-mi:“MI:0914”(association)	0.640
CCT3	TXNDC9	psi-mi:“MI:0914”(association)	0.640
CCT5	TXNDC9	psi-mi:“MI:0914”(association)	0.640
Dtl	COPS2	psi-mi:“MI:0915”(physical association)	0.560
VHL	DTL	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (349): YWHAE (Two-hybrid), YWHAE (Affinity Capture-Western), YWHAQ (Affinity Capture-Western), YWHAZ (Affinity Capture-Western), YWHAB (Affinity Capture-Western), YWHAG (Affinity Capture-Western), YWHAH (Affinity Capture-Western), SFN (Affinity Capture-Western), DTL (Affinity Capture-Western), DTL (Affinity Capture-Western), DTL (Affinity Capture-Western), DTL (Affinity Capture-Western), DTL (Affinity Capture-Western), DTL (Affinity Capture-Western), DTL (Affinity Capture-Western)

ESM2 similar proteins: A0A1L8GLK3, A0A974CYQ5, A2AHJ4, A5WW08, D2HNY3, D2HWM5, E7F6T8, F1ND48, O15040, O70260, O95071, P59328, Q3TLR7, Q4V837, Q58DC2, Q58WW2, Q5E9J6, Q5F479, Q5FWP4, Q5NVC7, Q5R9B8, Q5RF77, Q5RGA4, Q5RHI5, Q5ZLG9, Q62671, Q66JG1, Q6DDH2, Q6P1W0, Q6P256, Q6PCD5, Q6PJI9, Q6RI45, Q80TP3, Q80U93, Q810L3, Q8C0M0, Q8CBW4, Q8CIK8, Q8CIN9

Diamond homologs: A2QHM1, A2QPW4, A3LNW3, A3LVM1, A5E2R6, A7EZJ5, A7RWD2, A7TLU2, A7YY75, A8IZG4, A8PWQ8, A9VDW7, B0XAF3, B3MC74, B3NQR5, B3RNR8, B4GDM7, B4GMG4, B4HRQ6, B4JW81, B4KTK4, B4LJT7, B4MY77, B4P7Q3, B4QFZ8, B5X212, B5X9P2, B7QKS1, B9WHJ2, G0SA60, O13923, O14186, O22607, O60907, O76071, O80990, O94319, P0CS50, P0CS51, P53011

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
FBXO11	down-regulates	DTL	binding
DTL	“down-regulates quantity by destabilization”	SDE2	binding
DTL	up-regulates	Cullin4-RBX1-DDB1	binding
DTL	“down-regulates quantity by destabilization”	TDG	binding
DTL	“up-regulates activity”	Cullin4-RBX1-DDB1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 67 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
Prefoldin mediated transfer of substrate to CCT/TriC	7	61.3×	2e-09
RHOBTB1 GTPase cycle	5	52.9×	2e-06
DNA Damage Recognition in GG-NER	8	50.8×	7e-10
Formation of TC-NER Pre-Incision Complex	8	37.6×	3e-09
Cargo recognition for clathrin-mediated endocytosis	5	11.6×	2e-03
Neddylation	11	11.6×	1e-07

GO biological processes:

GO term	Partners	Fold	FDR
regulation of protein neddylation	5	78.0×	9e-07
protein neddylation	5	58.5×	2e-06
protein folding	8	13.8×	8e-06
protein stabilization	7	7.8×	1e-03
protein ubiquitination	8	5.5×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	63
Likely benign	5
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1820 predictions. Top by Δscore:

Variant	Effect	Δscore
1:212044647:A:AG	acceptor_gain	1.0000
1:212044648:T:G	acceptor_gain	1.0000
1:212044652:T:A	acceptor_gain	1.0000
1:212044656:TTAG:T	acceptor_loss	1.0000
1:212044657:TAGC:T	acceptor_loss	1.0000
1:212044658:A:AC	acceptor_loss	1.0000
1:212044658:A:AG	acceptor_gain	1.0000
1:212044659:G:GT	acceptor_gain	1.0000
1:212044659:GC:G	acceptor_gain	1.0000
1:212044659:GCT:G	acceptor_gain	1.0000
1:212044659:GCTC:G	acceptor_gain	1.0000
1:212044659:GCTCC:G	acceptor_gain	1.0000
1:212044755:AAAG:A	donor_gain	1.0000
1:212044756:AAG:A	donor_gain	1.0000
1:212044757:AG:A	donor_gain	1.0000
1:212044758:GG:G	donor_gain	1.0000
1:212044759:G:GG	donor_gain	1.0000
1:212044759:GTAA:G	donor_loss	1.0000
1:212047149:A:AG	acceptor_gain	1.0000
1:212047150:G:GG	acceptor_gain	1.0000
1:212047210:CTT:C	donor_gain	1.0000
1:212047213:G:GG	donor_gain	1.0000
1:212047291:T:TA	acceptor_gain	1.0000
1:212047294:AAG:A	acceptor_gain	1.0000
1:212047295:A:AG	acceptor_gain	1.0000
1:212047296:G:GG	acceptor_gain	1.0000
1:212047413:GAAAG:G	donor_gain	1.0000
1:212047418:G:A	donor_loss	1.0000
1:212047419:T:G	donor_loss	1.0000
1:212063139:TTAC:T	donor_gain	1.0000

AlphaMissense

4755 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:212044696:A:T	E72V	1.000
1:212044701:G:C	G74R	1.000
1:212044702:G:A	G74D	1.000
1:212044702:G:T	G74V	1.000
1:212044708:T:A	V76D	1.000
1:212047170:T:A	N99K	1.000
1:212047170:T:G	N99K	1.000
1:212047172:C:A	A100D	1.000
1:212047177:T:C	F102L	1.000
1:212047178:T:C	F102S	1.000
1:212047179:T:A	F102L	1.000
1:212047179:T:G	F102L	1.000
1:212047298:T:A	V114D	1.000
1:212047309:G:C	G118R	1.000
1:212047309:G:T	G118C	1.000
1:212047310:G:A	G118D	1.000
1:212047310:G:T	G118V	1.000
1:212047322:C:A	A122D	1.000
1:212047372:C:G	H139D	1.000
1:212047381:A:C	S142R	1.000
1:212047383:C:A	S142R	1.000
1:212047383:C:G	S142R	1.000
1:212047387:A:G	K144E	1.000
1:212047389:G:C	K144N	1.000
1:212047389:G:T	K144N	1.000
1:212047394:T:A	V146D	1.000
1:212062899:G:A	G159D	1.000
1:212062905:G:C	R161T	1.000
1:212062905:G:T	R161I	1.000
1:212062906:A:C	R161S	1.000

dbSNP variants (sampled 300 via entrez): RS1000023006 (1:212041177 A>C,G), RS1000033015 (1:212062239 T>G), RS1000077903 (1:212059854 CA>C,CAA), RS1000084737 (1:212052736 A>G), RS1000100761 (1:212103427 C>G), RS1000151205 (1:212059576 A>G), RS1000155689 (1:212043044 G>C), RS1000175893 (1:212043228 T>C), RS1000205182 (1:212093617 G>A,C), RS1000252003 (1:212087257 C>G,T), RS1000330879 (1:212037312 T>C,G), RS1000409393 (1:212056300 G>A), RS1000519169 (1:212085023 G>T), RS1000535844 (1:212095153 G>C,T), RS1000564543 (1:212088885 G>A)

Disease associations

OMIM: gene MIM:610617 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST000817_132	Height	2.000000e-09
GCST002928_11	Nickel levels	9.000000e-06
GCST005146_50	Birth weight	5.000000e-08
GCST007991_6	Large artery stroke	7.000000e-06
GCST008362_95	Birth weight	1.000000e-09
GCST90000025_847	Appendicular lean mass	1.000000e-12
GCST90000026_9	Appendicular lean mass	1.000000e-09
GCST90002400_541	Plateletcrit	4.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004344	birth weight
EFO:0004980	appendicular lean mass
EFO:0007985	platelet crit

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	decreases expression, affects cotreatment, increases expression, affects expression	4
bisphenol A	affects expression, decreases expression, increases expression	3
sodium arsenite	decreases expression, increases expression	3
Benzo(a)pyrene	decreases expression, increases expression	3
Valproic Acid	decreases expression, decreases methylation	3
Cyclosporine	affects expression, decreases expression	3
Acetaminophen	decreases expression, increases expression	2
Doxorubicin	decreases expression	2
Estradiol	increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tunicamycin	decreases expression, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
Aflatoxin B1	affects expression, increases expression	2
GSK-J4	decreases expression	1
afuresertib	decreases expression	1
FR900359	affects phosphorylation	1
TAK-243	increases sumoylation	1
lasiocarpine	increases expression	1
triphenyl phosphate	affects expression	1
methylparaben	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
cupric chloride	increases expression	1
coumarin	affects phosphorylation	1
beta-methylcholine	affects expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
2-palmitoylglycerol	increases expression	1
bazedoxifene	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1

Clinical trials (associated diseases)

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