DUS4L

Summary

DUS4L (dihydrouridine synthase 4 like, HGNC:21517) is a protein-coding gene on chromosome 7q22.3, encoding tRNA-dihydrouridine(20a/20b) synthase [NAD(P)+]-like (O95620). Catalyzes the synthesis of dihydrouridine, a modified base found in the D-loop of most tRNAs.

Predicted to enable tRNA dihydrouridine synthase activity. Involved in tRNA dihydrouridine synthesis.

Source: NCBI Gene 11062 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 44 total — 3 pathogenic
• MANE Select transcript: NM_181581

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21517
Approved symbol	DUS4L
Name	dihydrouridine synthase 4 like
Location	7q22.3
Locus type	gene with protein product
Status	Approved
Aliases	PP35, DUS4
Ensembl gene	ENSG00000105865
Ensembl biotype	protein_coding
Entrez	11062

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 20 protein_coding, 5 nonsense_mediated_decay, 4 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000265720, ENST00000422290, ENST00000431839, ENST00000436411, ENST00000443233, ENST00000458611, ENST00000467916, ENST00000471763, ENST00000485825, ENST00000497798, ENST00000498786, ENST00000855200, ENST00000855201, ENST00000855202, ENST00000855203, ENST00000855204, ENST00000855205, ENST00000855206, ENST00000855207, ENST00000855208, ENST00000855209, ENST00000855210, ENST00000855211, ENST00000922285, ENST00000922286, ENST00000922287, ENST00000922288, ENST00000922289, ENST00000922290, ENST00000964367

RefSeq mRNA: 2 — MANE Select: NM_181581 NM_001270419, NM_181581

CCDS: CCDS5745

Canonical transcript exons

ENST00000265720 — 8 exons

Exon	Start	End
ENSE00000881763	107577313	107578523
ENSE00001025853	107564588	107564676
ENSE00003504179	107573704	107573821
ENSE00003520906	107576366	107576592
ENSE00003640712	107567050	107567186
ENSE00003668997	107571145	107571266
ENSE00003686032	107575188	107575310
ENSE00003846178	107563971	107564209

Expression profiles

Bgee: expression breadth ubiquitous, 140 present calls, max score 81.90.

FANTOM5 (CAGE): breadth broad, TPM avg 1.3772 / max 22.1598, expressed in 898 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
80446	7.4032	1729
80447	1.2718	824
80448	0.1054	34

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endometrium	UBERON:0001295	81.90	gold quality
cortical plate	UBERON:0005343	81.04	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.75	gold quality
ventricular zone	UBERON:0003053	80.69	gold quality
ganglionic eminence	UBERON:0004023	78.51	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.49	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	78.45	gold quality
islet of Langerhans	UBERON:0000006	78.16	gold quality
cortex of kidney	UBERON:0001225	77.33	gold quality
right adrenal gland cortex	UBERON:0035827	77.30	gold quality
uterus	UBERON:0000995	77.07	gold quality
bone marrow cell	CL:0002092	77.06	gold quality
adrenal tissue	UBERON:0018303	76.78	gold quality
rectum	UBERON:0001052	76.75	gold quality
right adrenal gland	UBERON:0001233	76.68	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	76.30	gold quality
kidney	UBERON:0002113	76.12	gold quality
calcaneal tendon	UBERON:0003701	76.12	gold quality
thyroid gland	UBERON:0002046	76.00	gold quality
substantia nigra	UBERON:0002038	75.98	gold quality
heart left ventricle	UBERON:0002084	75.92	gold quality
corpus callosum	UBERON:0002336	75.91	gold quality
adrenal gland	UBERON:0002369	75.91	gold quality
left adrenal gland	UBERON:0001234	75.87	gold quality
right lobe of thyroid gland	UBERON:0001119	75.83	gold quality
metanephros cortex	UBERON:0010533	75.82	gold quality
pancreas	UBERON:0001264	75.73	gold quality
left ovary	UBERON:0002119	75.66	gold quality
nucleus accumbens	UBERON:0001882	75.65	gold quality
monocyte	CL:0000576	75.61	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.25

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

79 targeting DUS4L, 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-432-3P	100.00	67.86	705
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548O-5P	99.94	71.24	3488
HSA-MIR-548W	99.94	71.24	3488
HSA-MIR-548Y	99.94	71.28	3514
HSA-MIR-548A-5P	99.94	71.27	3482

Literature-anchored findings (GeneRIF, showing 2)

• we believe that in contrast to traditional gene fusions, DUS4L-BCAP29 cannot be used as a cancer biomarker. Instead, it is a fusion transcript that exists in normal physiology and that its pro-growth effect is not unique to cancer cells. (PMID:28415823)
• DUS4L suppresses invasion and metastasis in LUAD via modulation of PI3K/AKT and ERK/MAPK signaling through GRB2. (PMID:39216120)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	dus4l	ENSDARG00000006567
mus_musculus	Dus4l	ENSMUSG00000020648
rattus_norvegicus	Dus4l	ENSRNOG00000008155
drosophila_melanogaster	Dus4	FBGN0032750
caenorhabditis_elegans		WBGENE00016674

Paralogs (3): DUS3L (ENSG00000141994), DUS2 (ENSG00000167264), DUS1L (ENSG00000169718)

Protein

Protein identifiers

tRNA-dihydrouridine(20a/20b) synthase [NAD(P)+]-like — O95620 (reviewed: O95620)

Alternative names: pp35, tRNA-dihydrouridine synthase 4-like

All UniProt accessions (5): O95620, A4D0R5, F2Z2E4, F8WEL2, F8WFE3

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the synthesis of dihydrouridine, a modified base found in the D-loop of most tRNAs.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the Dus family. Dus4 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
O95620-1	1	yes
O95620-2	2

RefSeq proteins (2): NP_001257348, NP_853559* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001269	DUS_fam	Family
IPR013785	Aldolase_TIM	Homologous_superfamily
IPR018517	tRNA_hU_synthase_CS	Conserved_site
IPR035587	DUS-like_FMN-bd	Domain

Pfam: PF01207

Catalyzed reactions (Rhea), 4 shown:

• 5,6-dihydrouridine(20a) in tRNA + NADP(+) = uridine(20a) in tRNA + NADPH + H(+) (RHEA:53344)
• 5,6-dihydrouridine(20a) in tRNA + NAD(+) = uridine(20a) in tRNA + NADH + H(+) (RHEA:53348)
• 5,6-dihydrouridine(20b) in tRNA + NAD(+) = uridine(20b) in tRNA + NADH + H(+) (RHEA:53352)
• 5,6-dihydrouridine(20b) in tRNA + NADP(+) = uridine(20b) in tRNA + NADPH + H(+) (RHEA:53356)

UniProt features (13 total): binding site 6, sequence variant 2, sequence conflict 2, chain 1, active site 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95620-F1	94.36	0.92

Functional residue map

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

Catalytic / active sites (1): 116 (proton donor)

Ligand- & substrate-binding residues (6): 33–35; 87; 158; 186; 216–218; 240–241

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 119 (showing top): YAGI_AML_WITH_INV_16_TRANSLOCATION, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_THE_CH_CH_GROUP_OF_DONORS, GOBP_TRNA_METABOLIC_PROCESS, GAUSSMANN_MLL_AF4_FUSION_TARGETS_G_DN, RIZKI_TUMOR_INVASIVENESS_3D_DN, PATIL_LIVER_CANCER, GOBP_RNA_MODIFICATION, AACTTT_UNKNOWN, MARTORIATI_MDM4_TARGETS_FETAL_LIVER_UP, MODULE_207, GOBP_TRNA_PROCESSING, GOBP_TRNA_MODIFICATION, CASORELLI_ACUTE_PROMYELOCYTIC_LEUKEMIA_DN, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_THE_CH_CH_GROUP_OF_DONORS_NAD_OR_NADP_AS_ACCEPTOR, MODULE_7

GO Biological Process (2): tRNA dihydrouridine synthesis (GO:0002943), tRNA processing (GO:0008033)

GO Molecular Function (6): tRNA dihydrouridine synthase activity (GO:0017150), flavin adenine dinucleotide binding (GO:0050660), tRNA-dihydrouridine20a synthase activity (GO:0102266), tRNA-dihydrouridine20b synthase activity (GO:0102267), nucleotide binding (GO:0000166), oxidoreductase activity (GO:0016491)

GO Cellular Component (0):

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
tRNA dihydrouridine synthase activity	2
tRNA modification	1
RNA processing	1
tRNA metabolic process	1
tRNA dihydrouridine synthesis	1
RNA dihydrouridine synthase activity	1
catalytic activity, acting on a tRNA	1
nucleotide binding	1
anion binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
catalytic activity	1

Protein interactions and networks

STRING

1350 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DUS4L	GPR22	Q99680	733
DUS4L	BCAP29	Q9UHQ4	721
DUS4L	COG5	Q9UP83	714
DUS4L	TRMT10A	Q8TBZ6	565
DUS4L	MCF2L	O15068	553
DUS4L	TRMT61A	Q96FX7	532
DUS4L	DTWD1	Q8N5C7	523
DUS4L	PLCG1	P19174	520
DUS4L	PRKAR2B	P31323	517
DUS4L	HEBP2	Q9Y5Z4	506
DUS4L	TRMT5	Q32P41	496
DUS4L	DTWD2	Q8NBA8	494
DUS4L	TSR3	Q9UJK0	473
DUS4L	PPP6C	O00743	442
DUS4L	TRMT1	Q9NXH9	437

IntAct

3 interactions, top by confidence:

A	B	Type	Score
DUS4L	CAMK2B	psi-mi:“MI:0915”(physical association)	0.400
DUS4L	CDH1	psi-mi:“MI:0914”(association)	0.350

BioGRID (15): PTPRG (Affinity Capture-MS), ULBP2 (Affinity Capture-MS), HRAS (Affinity Capture-MS), TOP1 (Affinity Capture-MS), GCA (Affinity Capture-MS), DUS4L (Two-hybrid), DUS4L (Affinity Capture-RNA), DUS4L (Affinity Capture-RNA), CDH1 (Affinity Capture-MS), PTPRG (Affinity Capture-MS), GCA (Affinity Capture-MS), CAMK2B (Affinity Capture-MS), DUS4L (Reconstituted Complex), ZMYM4 (Cross-Linking-MS (XL-MS)), DUS4L (Co-fractionation)

ESM2 similar proteins: A1A4M4, A4JPX7, A6TAC4, A7ZI99, A7ZWZ9, B1J0S7, B1LIN7, B2JQW0, B5XQJ4, B5Z2Q7, B6HZX8, B7L508, B7M300, B7MPB9, B7N8Q9, B7NK03, C1DF10, C1DRJ0, O95620, P00813, P03958, P51020, P56658, Q05AV0, Q0VC13, Q13QH6, Q13VU3, Q17R31, Q32M08, Q3U1C6, Q3Z554, Q46NW8, Q47B13, Q4V831, Q4V9P6, Q503T5, Q56Y42, Q5ZKP6, Q63ZU0, Q640V9

Diamond homologs: A3LUK5, A5DBS1, O25427, O27281, O52532, O52533, O52536, O52539, O67533, O68273, O83945, O95620, P0A2R6, P0A2R7, P0ABT5, P0ABT6, P0ABT7, P0CN28, P0CN29, P33371, P37567, P41504, P44606, P44965, P45672, P9WNS6, P9WNS7, Q06063, Q08111, Q09504, Q1RH84, Q28BT8, Q3KRC5, Q3SWF0, Q4UNJ4, Q50049, Q54CU9, Q55724, Q68XZ3, Q6CWM0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	29
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1457841	NC_000007.13:g.(?107204228)(107204434_?)del	Pathogenic
60284	GRCh38/hg38 7q22.3-31.1(chr7:106261939-111228036)x1	Pathogenic
805920	GRCh37/hg19 7q22.3-31.1(chr7:104506008-107408857)	Pathogenic

SpliceAI

1714 predictions. Top by Δscore:

Variant	Effect	Δscore
7:107567185:AA:A	donor_gain	1.0000
7:107567186:AG:A	donor_loss	1.0000
7:107567187:G:GG	donor_gain	1.0000
7:107567187:GTAAG:G	donor_loss	1.0000
7:107567188:T:TC	donor_loss	1.0000
7:107567189:AAGT:A	donor_loss	1.0000
7:107575184:AAAG:A	acceptor_gain	1.0000
7:107575185:A:G	acceptor_gain	1.0000
7:107576361:TGTA:T	acceptor_loss	1.0000
7:107576362:GTAG:G	acceptor_loss	1.0000
7:107576363:TAG:T	acceptor_loss	1.0000
7:107576364:A:AG	acceptor_gain	1.0000
7:107576364:A:AT	acceptor_loss	1.0000
7:107576364:AG:A	acceptor_gain	1.0000
7:107576365:G:GG	acceptor_gain	1.0000
7:107576365:GG:G	acceptor_gain	1.0000
7:107576589:GATG:G	donor_gain	1.0000
7:107576593:G:GG	donor_gain	1.0000
7:107576594:T:A	donor_loss	1.0000
7:107576600:A:AG	donor_gain	1.0000
7:107563797:CCTTA:C	donor_loss	0.9900
7:107563798:CTTA:C	donor_loss	0.9900
7:107563800:TA:T	donor_loss	0.9900
7:107563801:A:AC	donor_gain	0.9900
7:107563801:ACC:A	donor_loss	0.9900
7:107563801:ACCGT:A	donor_gain	0.9900
7:107563802:C:CA	donor_loss	0.9900
7:107563802:C:CC	donor_gain	0.9900
7:107563802:CCGT:C	donor_gain	0.9900
7:107563802:CCGTC:C	donor_gain	0.9900

AlphaMissense

2106 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:107571156:G:T	R43M	1.000
7:107571156:G:C	R43T	0.999
7:107571157:G:C	R43S	0.999
7:107571157:G:T	R43S	0.999
7:107576440:T:A	V185D	0.999
7:107573804:C:A	N113K	0.998
7:107573804:C:G	N113K	0.998
7:107573811:T:C	C116R	0.998
7:107575304:A:T	K158I	0.998
7:107576449:G:C	R188T	0.998
7:107576450:A:C	R188S	0.998
7:107576450:A:T	R188S	0.998
7:107571152:T:C	F42L	0.997
7:107571154:T:A	F42L	0.997
7:107571154:T:G	F42L	0.997
7:107571155:A:G	R43G	0.997
7:107573728:T:C	F88S	0.997
7:107573805:T:C	C114R	0.997
7:107575189:T:A	W120R	0.997
7:107575189:T:C	W120R	0.997
7:107575211:G:A	G127E	0.997
7:107575303:A:G	K158E	0.997
7:107575310:G:C	R160T	0.997
7:107575310:G:T	R160M	0.997
7:107576442:C:G	H186D	0.997
7:107576449:G:T	R188I	0.997
7:107576536:G:A	G217E	0.997
7:107577396:T:A	W264R	0.997
7:107577396:T:C	W264R	0.997
7:107567165:C:A	A32D	0.996

dbSNP variants (sampled 300 via entrez): RS1000036361 (7:107577546 C>A,T), RS1000102261 (7:107574408 G>A), RS1000163276 (7:107562659 C>T), RS1000210184 (7:107571535 A>G), RS1000469546 (7:107574701 A>C), RS1000747556 (7:107562710 T>C), RS1001041205 (7:107575945 A>G), RS1001152269 (7:107566219 A>G), RS1001709800 (7:107578870 G>A), RS1001714559 (7:107566574 C>A), RS1001927057 (7:107562476 T>C), RS1001936582 (7:107572667 T>G), RS1002135852 (7:107566001 T>G), RS1002284604 (7:107572872 G>A), RS1002599507 (7:107575756 A>G)

Disease associations

OMIM: gene `` | disease phenotypes: MIM:613612

GenCC curated gene-disease

Mondo (1): COG5-congenital disorder of glycosylation (MONDO:0013325)

Orphanet (1): COG5-CDG (Orphanet:263487)

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST000869_1	Osteoarthritis	6.000000e-08
GCST005956_26	Waist-to-hip ratio adjusted for BMI	2.000000e-08
GCST005962_48	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	2.000000e-06
GCST010866_125	Coronary artery disease	8.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	increases expression, affects cotreatment, decreases expression, increases abundance	2
Valproic Acid	decreases expression, increases expression	2
Cyclosporine	increases expression	2
GSK-J4	decreases expression	1
alpha-pinene	increases abundance, affects cotreatment, decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	increases expression	1
(+)-JQ1 compound	decreases expression	1
Temozolomide	decreases expression	1
Acrolein	affects cotreatment, decreases expression, increases abundance	1
Atrazine	decreases expression	1
Doxorubicin	decreases expression	1
Hydrogen Peroxide	increases expression	1
Ozone	affects cotreatment, decreases expression, increases abundance	1
Silicon Dioxide	decreases expression	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Tunicamycin	increases expression	1
Asbestos, Crocidolite	decreases expression	1
Copper Sulfate	decreases expression	1
Particulate Matter	increases abundance, increases expression	1
Volatile Organic Compounds	affects cotreatment, decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E0U2	Ubigene Hep G2 DUS4L KO	Cancer cell line	Male
CVCL_E1EC	Ubigene U-87 MG DUS4L KO	Cancer cell line	Male

Clinical trials (associated diseases)

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