DPH3

Summary

DPH3 (diphthamide biosynthesis 3, HGNC:27717) is a protein-coding gene on chromosome 3p25.1, encoding Diphthamide biosynthesis protein 3 (Q96FX2). Required for the first step of diphthamide biosynthesis, a post-translational modification of histidine which occurs in elongation factor 2. It is a common-essential gene (DepMap: required in 94.2% of cancer cell lines).

This gene encodes a CSL zinc finger-containing protein that is required for dipthamide biosynthesis. The encoded protein is necessary for the initial step in the modification of a histidine residue in elongation factor-2 to diphthamide. This modified residue is a target for ADP ribosylation by the bacterial toxins diphtheria toxin and Pseudomonas exotoxin A. Alternative splicing results in multiple transcript variants that encode the same isoform.

Source: NCBI Gene 285381 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 17 total
• Cancer dependency (DepMap): dependent in 94.2% of screened cell lines (common-essential)
• MANE Select transcript: NM_206831

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:27717
Approved symbol	DPH3
Name	diphthamide biosynthesis 3
Location	3p25.1
Locus type	gene with protein product
Status	Approved
Aliases	DESR1, DELGIP1, MGC20197, KTI11, DELGIP, DPH3A
Ensembl gene	ENSG00000154813
Ensembl biotype	protein_coding
OMIM	608959
Entrez	285381

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000285082, ENST00000383775, ENST00000462982, ENST00000488423, ENST00000858183, ENST00000953358

RefSeq mRNA: 2 — MANE Select: NM_206831 NM_001047434, NM_206831

CCDS: CCDS2629, CCDS43058

Canonical transcript exons

ENST00000488423 — 3 exons

Exon	Start	End
ENSE00001904327	16257061	16260829
ENSE00001930878	16264769	16264943
ENSE00003542850	16264155	16264229

Expression profiles

Bgee: expression breadth ubiquitous, 260 present calls, max score 94.29.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.9387 / max 421.0361, expressed in 1809 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
41325	20.7357	1807
41324	4.6448	1620
202693	0.3060	117
41323	0.2522	115

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	94.29	gold quality
deltoid	UBERON:0001476	93.99	gold quality
left ventricle myocardium	UBERON:0006566	93.74	gold quality
tibialis anterior	UBERON:0001385	92.61	gold quality
sperm	CL:0000019	92.60	gold quality
biceps brachii	UBERON:0001507	91.43	gold quality
epithelial cell of pancreas	CL:0000083	90.90	gold quality
endothelial cell	CL:0000115	90.73	gold quality
vastus lateralis	UBERON:0001379	90.32	gold quality
decidua	UBERON:0002450	90.27	gold quality
skeletal muscle tissue	UBERON:0001134	90.11	gold quality
quadriceps femoris	UBERON:0001377	90.09	gold quality
gastrocnemius	UBERON:0001388	90.09	gold quality
islet of Langerhans	UBERON:0000006	90.03	gold quality
hindlimb stylopod muscle	UBERON:0004252	89.91	gold quality
skeletal muscle organ	UBERON:0014892	89.85	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.75	gold quality
muscle of leg	UBERON:0001383	89.71	gold quality
muscle tissue	UBERON:0002385	89.53	gold quality
palpebral conjunctiva	UBERON:0001812	89.52	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	89.44	gold quality
visceral pleura	UBERON:0002401	89.32	gold quality
cauda epididymis	UBERON:0004360	89.31	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	89.24	gold quality
eye	UBERON:0000970	89.20	gold quality
adrenal tissue	UBERON:0018303	89.04	gold quality
tibia	UBERON:0000979	88.83	gold quality
superficial temporal artery	UBERON:0001614	88.40	gold quality
myocardium	UBERON:0002349	88.28	gold quality
stromal cell of endometrium	CL:0002255	88.27	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

126 targeting DPH3, 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-5692A	100.00	74.40	6850
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-3617-3P	99.98	67.86	918
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-3658	99.96	73.87	4379
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-548J-3P	99.94	72.61	4881

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 94.2% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 3)

• DelGIP1is a binding partner of deafness locus putative guanine nucleotide exchange factor; downregulation of DelGIP1 induced increased extracellular secretion of proteoglycans indicating a possible role for DelGIP1 in the secretion process (PMID:14980502)
• Solution structure of human DESR1, a CSL zinc-binding protein. (PMID:18214955)
• The results from this study show occurrence of frequent somatic non-coding mutations adjacent to a pre-existing binding site for Ets transcription factors within the directional promoter of DPH3 and OXNAD1 genes in three major skin cancers. (PMID:26416425)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	dph3	ENSDARG00000043360
mus_musculus	Dph3	ENSMUSG00000021905
rattus_norvegicus	Dph3	ENSRNOG00000019727

Protein

Protein identifiers

Diphthamide biosynthesis protein 3 — Q96FX2 (reviewed: Q96FX2)

Alternative names: CSL-type zinc finger-containing protein 2, DelGEF-interacting protein 1

All UniProt accessions (1): Q96FX2

UniProt curated annotations — full annotation on UniProt →

Function. Required for the first step of diphthamide biosynthesis, a post-translational modification of histidine which occurs in elongation factor 2. DPH1 and DPH2 transfer a 3-amino-3-carboxypropyl (ACP) group from S-adenosyl-L-methionine (SAM) to a histidine residue, the reaction is assisted by a reduction system comprising DPH3 and a NADH-dependent reductase. Acts as an electron donor to reduce the Fe-S cluster in DPH1-DPH2 keeping the [4Fe-4S] clusters in the active and reduced state. Restores iron to DPH1-DPH2 iron-sulfur clusters which have degraded from [4Fe-4S] to [3Fe-4S] by donating an iron atom to reform [4Fe-4S] clusters, in a manner dependent on the presence of elongation factor 2 and SAM. Associates with the elongator complex and is required for tRNA Wobble base modifications mediated by the elongator complex. The elongator complex is required for multiple tRNA modifications, including mcm5U (5-methoxycarbonylmethyl uridine), mcm5s 2U (5-methoxycarbonylmethyl-2-thiouridine), and ncm5U (5-carbamoylmethyl uridine).

Subunit / interactions. Component of the 2-(3-amino-3-carboxypropyl)histidine synthase complex composed of DPH1, DPH2, DPH3 and a NADH-dependent reductase. Interacts with SERGEF.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Widely expressed with highest levels in small intestine, spleen, thymus, heart, liver and lung.

Domain organisation. The DPH-type metal-binding (MB) domain can also bind zinc. However, iron is the physiological binding partner as zinc binding impairs the protein electron donor function.

Pathway. Protein modification; peptidyl-diphthamide biosynthesis.

Similarity. Belongs to the DPH3 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96FX2-1	1	yes
Q96FX2-2	2

RefSeq proteins (2): NP_001040899, NP_996662* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007872	DPH_MB_dom	Domain
IPR036671	DPH_MB_sf	Homologous_superfamily
IPR044248	DPH3/4-like	Family

Pfam: PF05207

Catalyzed reactions (Rhea), 2 shown:

• 3Fe-4S-[protein] + Fe(2+)-[Dph3] = 3Fe-4S-[protein] + Fe(3+)-[Dph3] (RHEA:71235)
• 2 3Fe-4S-[protein] + 2 Fe(2+)-[Dph3] + NADH = 2 4Fe-4S-[protein] + 2 [Dph3] + NAD(+) + H(+) (RHEA:71239)

UniProt features (18 total): strand 6, binding site 4, turn 3, helix 2, chain 1, domain 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2JR7	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96FX2-F1	84.51	0.69

Functional residue map

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

Ligand- & substrate-binding residues (4): 26; 28; 48; 51

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5358493	Synthesis of diphthamide-EEF2

MSigDB gene sets: 132 (showing top): RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_TRNA_METABOLIC_PROCESS, CREBP1_Q2, CHANDRAN_METASTASIS_DN, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_LOCALIZATION, CREB_Q4, GOBP_POSITIVE_REGULATION_OF_BINDING, GOBP_REGULATION_OF_PROTEIN_SECRETION, CDP_01, GOBP_NEGATIVE_REGULATION_OF_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION, GOBP_RNA_MODIFICATION, WCTCNATGGY_UNKNOWN, GOBP_NEGATIVE_REGULATION_OF_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION, GOBP_NEGATIVE_REGULATION_OF_SECRETION

GO Biological Process (4): tRNA wobble base 5-methoxycarbonylmethyl-2-thiouridinylation (GO:0002926), protein histidyl modification to diphthamide (GO:0017183), negative regulation of protein secretion (GO:0050709), positive regulation of binding (GO:0051099)

GO Molecular Function (4): ferrous iron binding (GO:0008198), iron chaperone activity (GO:0034986), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
binding	2
iron ion binding	2
tRNA wobble uridine modification	1
peptidyl-histidine modification	1
protein secretion	1
regulation of protein secretion	1
negative regulation of protein transport	1
negative regulation of secretion by cell	1
positive regulation of molecular function	1
regulation of binding	1
metallochaperone activity	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
cellular_component	1

Protein interactions and networks

STRING

790 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DPH3	SERGEF	Q9UGK8	968
DPH3	DPH2	Q9BQC3	914
DPH3	DPH1	Q9BZG8	914
DPH3	EEF2	P13639	898
DPH3	DNAJC24	Q6P3W2	887
DPH3	DPH5	Q9H2P9	856
DPH3	DPH7	Q9BTV6	845
DPH3	ELP3	Q9H9T3	835
DPH3	DPH6	Q7L8W6	811
DPH3	KTI12	Q96EK9	798
DPH3	EXOC2	Q96KP1	788
DPH3	ELP4	Q96EB1	780
DPH3	OXNAD1	Q96HP4	719
DPH3	PPP6R1	Q9UPN7	683
DPH3	PPP6R2	O75170	682

IntAct

23 interactions, top by confidence:

A	B	Type	Score
DPH3	SERGEF	psi-mi:“MI:0915”(physical association)	0.820
SERGEF	DPH3	psi-mi:“MI:0915”(physical association)	0.820
PIH1D2	DPH3	psi-mi:“MI:0915”(physical association)	0.720
MEOX2	DPH3	psi-mi:“MI:0915”(physical association)	0.560
ZNF438	DPH3	psi-mi:“MI:0915”(physical association)	0.560
DPH3	ATE1	psi-mi:“MI:0914”(association)	0.530
RPL8	DPH3	psi-mi:“MI:0915”(physical association)	0.370
ADIPOR1	DPH3	psi-mi:“MI:0915”(physical association)	0.370
DPH3	PIH1D2	psi-mi:“MI:0915”(physical association)	0.000
DPH3	MEOX2	psi-mi:“MI:0915”(physical association)	0.000
DPH3	ZNF438	psi-mi:“MI:0915”(physical association)	0.000
DPH3	SERGEF	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (20): DPH3 (Two-hybrid), DPH3 (Co-fractionation), SERGEF (Affinity Capture-MS), DPH2 (Affinity Capture-MS), ATE1 (Affinity Capture-MS), NEK7 (Affinity Capture-MS), DPH3 (Two-hybrid), DPH3 (Two-hybrid), DPH3 (Two-hybrid), ZNF438 (Two-hybrid), DPH2 (Affinity Capture-MS), ATE1 (Affinity Capture-MS), SERGEF (Affinity Capture-MS), DPH3 (Negative Genetic), DPH3 (Negative Genetic)

ESM2 similar proteins: A6H767, A9CB27, O75312, P0C0V4, P24534, P28656, P29412, P29522, P34826, P55209, Q17QC0, Q17QF2, Q1EBV4, Q1LZC9, Q20168, Q21102, Q2TBX0, Q3E840, Q4I9U7, Q4P8G2, Q4R312, Q4WPU8, Q5E983, Q5R4D4, Q5R7N8, Q5RED0, Q5ZIN1, Q62384, Q6BTW5, Q6C0G3, Q6CMG4, Q6DET9, Q6FXS6, Q6GN98, Q6NPL9, Q6VUC1, Q74Z32, Q7SC15, Q7ZY81, Q8K0W9

Diamond homologs: P0C0V4, P0CN22, P0CN23, Q1LZC9, Q21102, Q3E840, Q4I9U7, Q4P8G2, Q4R312, Q4WPU8, Q54CI5, Q5R7N8, Q6BTW5, Q6C0G3, Q6CMG4, Q6FXS6, Q6VUC1, Q74Z32, Q7SC15, Q8K0W9, Q8STR6, Q96FX2, Q9H4G8, Q9UT33, Q9VGQ9, Q4I7G0, P0C0V5, P47138, Q4WPF7, Q6BPC1, Q6C6T1, Q6CUQ9, Q6FWM1, Q752D7, Q7SEK8, Q9UUG3, A4SFR5, A5ITA7, A6QHC2, A6U251

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	12
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

216 predictions. Top by Δscore:

Variant	Effect	Δscore
3:16264153:A:AC	donor_gain	1.0000
3:16264154:C:CC	donor_gain	1.0000
3:16264767:ACCT:A	donor_loss	1.0000
3:16264168:A:AC	donor_gain	0.9900
3:16264169:C:CC	donor_gain	0.9900
3:16260828:TCC:T	acceptor_loss	0.9800
3:16260829:CCTAA:C	acceptor_loss	0.9800
3:16260830:C:CC	acceptor_gain	0.9800
3:16260831:T:C	acceptor_loss	0.9800
3:16264165:A:C	donor_gain	0.9800
3:16264767:A:AC	donor_gain	0.9800
3:16264768:C:CC	donor_gain	0.9800
3:16260828:TC:T	acceptor_gain	0.9700
3:16260829:CC:C	acceptor_gain	0.9700
3:16264816:T:TA	donor_gain	0.9700
3:16260825:TGATC:T	acceptor_gain	0.9600
3:16264170:T:C	donor_gain	0.9600
3:16260826:GATC:G	acceptor_gain	0.9500
3:16260836:CAGAG:C	acceptor_gain	0.9300
3:16260830:C:T	acceptor_gain	0.9200
3:16260840:G:GC	acceptor_gain	0.9100
3:16264788:T:C	donor_gain	0.9100
3:16260837:A:T	acceptor_gain	0.9000
3:16260840:G:C	acceptor_gain	0.9000
3:16264148:CCCTT:C	donor_loss	0.8900
3:16264149:CCTTA:C	donor_loss	0.8900
3:16264150:CTTAC:C	donor_loss	0.8900
3:16264151:T:TA	donor_loss	0.8900
3:16264152:TA:T	donor_loss	0.8900
3:16264153:ACTTT:A	donor_loss	0.8900

AlphaMissense

546 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:16264781:G:C	F32L	1.000
3:16264781:G:T	F32L	1.000
3:16264782:A:G	F32S	1.000
3:16264783:A:G	F32L	1.000
3:16264180:A:G	L53P	0.999
3:16264180:A:T	L53H	0.999
3:16264186:C:G	C51S	0.999
3:16264186:C:T	C51Y	0.999
3:16264187:A:G	C51R	0.999
3:16264187:A:T	C51S	0.999
3:16264194:A:C	C48W	0.999
3:16264195:C:G	C48S	0.999
3:16264195:C:T	C48Y	0.999
3:16264196:A:G	C48R	0.999
3:16264196:A:T	C48S	0.999
3:16264201:G:T	A46E	0.999
3:16264222:A:G	L39S	0.999
3:16264791:C:A	G29V	0.999
3:16264791:C:T	G29E	0.999
3:16264794:C:T	C28Y	0.999
3:16264795:A:G	C28R	0.999
3:16264800:C:G	C26S	0.999
3:16264801:A:G	C26R	0.999
3:16264801:A:T	C26S	0.999
3:16264185:G:C	C51W	0.998
3:16264186:C:A	C51F	0.998
3:16264195:C:A	C48F	0.998
3:16264776:A:T	I34N	0.998
3:16264782:A:C	F32C	0.998
3:16264788:T:A	D30V	0.998

dbSNP variants (sampled 300 via entrez): RS1000098686 (3:16257485 C>A), RS1000151271 (3:16265024 C>T), RS1000418511 (3:16264897 G>A), RS1000446373 (3:16264396 A>G), RS1001021740 (3:16262677 T>C), RS1001689030 (3:16265054 G>A,C), RS1002315951 (3:16257303 C>T), RS1002362069 (3:16263796 A>C,G), RS1002450030 (3:16259036 T>C), RS1002476891 (3:16266305 A>G), RS1002612775 (3:16266627 G>A,T), RS1003148867 (3:16261972 A>T), RS1003486574 (3:16260095 C>T), RS1003588446 (3:16266430 C>T), RS1003775564 (3:16262238 T>C,G)

Disease associations

OMIM: gene MIM:608959 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, increases expression	3
sodium arsenite	decreases expression, increases expression	2
Copper	affects binding, decreases expression, increases expression	2
aristolochic acid I	increases expression	1
dicrotophos	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
perfluoro-n-nonanoic acid	increases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
NSC 689534	increases expression, affects binding	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Sunitinib	increases expression	1
Vorinostat	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Disulfiram	affects binding, decreases expression	1
Quercetin	increases expression	1
Smoke	decreases expression	1
Testosterone	decreases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Cyclosporine	increases expression	1
Sodium Selenite	increases expression	1
Cadmium Chloride	increases expression	1
Copper Sulfate	increases expression	1
Vitamin K 3	affects expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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