EXO5

Summary

EXO5 (exonuclease 5, HGNC:26115) is a protein-coding gene on chromosome 1p34.2, encoding Exonuclease V (Q9H790). Single-stranded DNA (ssDNA) bidirectional exonuclease involved in DNA repair.

The protein encoded by this gene is a single-stranded DNA (ssDNA)-specific exonuclease that can slide along the DNA before cutting it. However, human replication protein A binds ssDNA and restricts sliding of the encoded protein, providing a 5’-directionality to the enzyme. This protein localizes to nuclear repair loci after DNA damage.

Source: NCBI Gene 64789 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 76 total
• Dosage sensitivity (ClinGen): haploinsufficiency dosage sensitivity unlikely, triplosensitivity no evidence
• MANE Select transcript: NM_001346953

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26115
Approved symbol	EXO5
Name	exonuclease 5
Location	1p34.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ21144
Ensembl gene	ENSG00000164002
Ensembl biotype	protein_coding
OMIM	618601
Entrez	64789

Gene structure

Transcript identifiers

Ensembl transcripts: 37 — 36 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000296380, ENST00000358527, ENST00000372703, ENST00000415550, ENST00000418186, ENST00000419161, ENST00000420209, ENST00000432259, ENST00000443729, ENST00000471429, ENST00000682383, ENST00000905580, ENST00000905581, ENST00000905582, ENST00000905583, ENST00000905584, ENST00000905585, ENST00000905586, ENST00000905587, ENST00000905588, ENST00000905589, ENST00000905590, ENST00000905591, ENST00000905592, ENST00000905593, ENST00000905594, ENST00000905595, ENST00000925740, ENST00000925741, ENST00000925742, ENST00000925743, ENST00000925744, ENST00000925745, ENST00000925746, ENST00000925747, ENST00000941503, ENST00000941504

RefSeq mRNA: 12 — MANE Select: NM_001346953 NM_001346946, NM_001346947, NM_001346948, NM_001346949, NM_001346950, NM_001346951, NM_001346952, NM_001346953, NM_001346954, NM_001346955, NM_001346956, NM_022774

CCDS: CCDS453

Canonical transcript exons

ENST00000415550 — 4 exons

Exon	Start	End
ENSE00001080399	40514515	40516038
ENSE00001235054	40509733	40509790
ENSE00001429985	40509451	40509625
ENSE00001674726	40508767	40508908

Expression profiles

Bgee: expression breadth ubiquitous, 203 present calls, max score 98.10.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.1706 / max 178.3381, expressed in 1694 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
2391	3.2864	1557
2390	1.4099	963
2392	0.4743	198

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	98.10	gold quality
oocyte	CL:0000023	91.83	gold quality
buccal mucosa cell	CL:0002336	89.77	gold quality
tendon of biceps brachii	UBERON:0008188	84.23	gold quality
cortical plate	UBERON:0005343	83.31	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.42	gold quality
granulocyte	CL:0000094	79.85	gold quality
ganglionic eminence	UBERON:0004023	79.41	gold quality
tendon	UBERON:0000043	78.39	gold quality
stromal cell of endometrium	CL:0002255	78.05	gold quality
ventricular zone	UBERON:0003053	77.43	gold quality
islet of Langerhans	UBERON:0000006	77.39	gold quality
leukocyte	CL:0000738	76.20	gold quality
monocyte	CL:0000576	76.04	gold quality
esophagus squamous epithelium	UBERON:0006920	75.87	silver quality
right adrenal gland cortex	UBERON:0035827	75.86	gold quality
mononuclear cell	CL:0000842	75.80	gold quality
calcaneal tendon	UBERON:0003701	75.78	gold quality
medial globus pallidus	UBERON:0002477	75.14	silver quality
smooth muscle tissue	UBERON:0001135	75.10	gold quality
rectum	UBERON:0001052	74.97	gold quality
right adrenal gland	UBERON:0001233	74.86	gold quality
amniotic fluid	UBERON:0000173	74.80	silver quality
lymph node	UBERON:0000029	74.36	gold quality
palpebral conjunctiva	UBERON:0001812	74.31	gold quality
spleen	UBERON:0002106	74.11	gold quality
right coronary artery	UBERON:0001625	74.03	gold quality
left adrenal gland	UBERON:0001234	74.01	gold quality
body of uterus	UBERON:0009853	73.95	gold quality
muscle layer of sigmoid colon	UBERON:0035805	73.87	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.88

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

38 targeting EXO5, 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-3924	100.00	72.09	2394
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-6505-5P	99.73	69.25	1595
HSA-MIR-580-3P	99.67	69.23	1841
HSA-MIR-4527	99.66	67.43	714
HSA-MIR-6512-3P	99.65	66.07	1468
HSA-MIR-6720-5P	99.65	66.22	1459
HSA-MIR-17-3P	99.55	66.77	1311
HSA-MIR-6833-5P	99.50	68.93	1161
HSA-MIR-6740-3P	99.48	68.49	1392
HSA-MIR-548B-3P	99.38	67.26	1000
HSA-MIR-2115-3P	99.31	69.68	2026
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-520E-5P	99.27	68.90	1513
HSA-MIR-7151-3P	99.04	69.72	2370
HSA-MIR-4738-3P	98.98	67.98	1846
HSA-MIR-361-5P	98.95	70.16	1340
HSA-MIR-4742-5P	98.89	68.41	1542
HSA-MIR-767-3P	98.61	67.69	1192
HSA-MIR-323A-5P	98.59	65.13	651
HSA-MIR-6818-3P	98.56	68.23	1307

Functional genomics

ClinGen dosage: haploinsufficiency 40 (dosage sensitivity unlikely), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 4)

• The human homolog (C1orf176; EXO5) that functions in the repair of nuclear DNA damage. (PMID:23095756)
• Three of them [PLEC (OR = 6.28, p = 6.42 x 10(-23) ) (p.Arg2016Trp), EXO5 (OR = 3.37, p = 4.82 x 10(-09) ) (p.Arg344AlafsTer10) and DNAH7 (OR = 1.64, p = 0.048)] were replicated as potential candidates. (PMID:29761480)
• Functional deficiency of DNA repair gene EXO5 results in androgen-induced genomic instability and prostate tumorigenesis. (PMID:31616062)
• EXO5-DNA structure and BLM interactions direct DNA resection critical for ATR-dependent replication restart. (PMID:34197737)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	exo5	ENSDARG00000042727
mus_musculus	Exo5	ENSMUSG00000028629
rattus_norvegicus	Exo5	ENSRNOG00000037432

Protein

Protein identifiers

Exonuclease V — Q9H790 (reviewed: Q9H790)

Alternative names: Defects in morphology protein 1 homolog

All UniProt accessions (6): Q9H790, X6RCL8, X6RCY3, X6RF29, X6RK18, X6RLK1

UniProt curated annotations — full annotation on UniProt →

Function. Single-stranded DNA (ssDNA) bidirectional exonuclease involved in DNA repair. Probably involved in DNA repair following ultraviolet (UV) irradiation and interstrand cross-links (ICLs) damage. Has both 5’-3’ and 3’-5’ exonuclease activities with a strong preference for 5’-ends. Acts as a sliding exonuclease that loads at ssDNA ends and then slides along the ssDNA prior to cutting; however the sliding and the 3’-5’ exonuclease activities are abolished upon binding to the replication protein A (RPA) complex that enforces 5’-directionality activity.

Subunit / interactions. Monomer; monomeric form has weak exonuclease activity. Homodimer; homodimeric form is unsure but has much higher exonuclease activity, suggesting that it could homodimerize upon DNA-binding. Interacts with the replication protein A (RPA) complex.

Subcellular location. Nucleus. Cytoplasm. Cytosol.

Cofactor. Binds 1 [4Fe-4S] cluster.

Similarity. Belongs to the EXO5 family.

RefSeq proteins (12): NP_001333875, NP_001333876, NP_001333877, NP_001333878, NP_001333879, NP_001333880, NP_001333881, NP_001333882, NP_001333883, NP_001333884, NP_001333885, NP_073611 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011604	PDDEXK-like_dom_sf	Homologous_superfamily
IPR019190	EXOV	Family

Pfam: PF09810

UniProt features (34 total): helix 12, strand 7, binding site 6, mutagenesis site 3, turn 3, sequence variant 2, chain 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
7LW7	X-RAY DIFFRACTION	2.5
7LW9	X-RAY DIFFRACTION	2.71
7LWA	X-RAY DIFFRACTION	2.85
7LW8	X-RAY DIFFRACTION	2.88

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H790-F1	80.65	0.63

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 (6): 92; 182; 196; 343; 346; 352

Mutagenesis-validated functional residues (3):

Position	Phenotype
343	abolishes iron-sulfur-binding and affects exonuclease activity; when associated with a-346.
346	abolishes iron-sulfur-binding and affects exonuclease activity; when associated with a-343.
196	nearly abolishes exonuclease activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 103 (showing top): GOMF_NUCLEASE_ACTIVITY, chr1p34, GOBP_DNA_DAMAGE_RESPONSE, GOBP_INTERSTRAND_CROSS_LINK_REPAIR, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, GOMF_EXONUCLEASE_ACTIVITY, PARENT_MTOR_SIGNALING_DN, GAL_LEUKEMIC_STEM_CELL_UP, GOBP_DNA_METABOLIC_PROCESS, GOMF_5_3_EXONUCLEASE_ACTIVITY, GOBP_DNA_REPAIR, GOMF_HYDROLASE_ACTIVITY_ACTING_ON_ESTER_BONDS, GOMF_3_5_EXONUCLEASE_ACTIVITY, GOMF_METAL_CLUSTER_BINDING, GOMF_DNA_EXONUCLEASE_ACTIVITY

GO Biological Process (4): interstrand cross-link repair (GO:0036297), DNA metabolic process (GO:0006259), DNA repair (GO:0006281), DNA damage response (GO:0006974)

GO Molecular Function (9): DNA binding (GO:0003677), single-stranded DNA 3’-5’ DNA exonuclease activity (GO:0008310), single-stranded DNA 5’-3’ DNA exonuclease activity (GO:0045145), metal ion binding (GO:0046872), 4 iron, 4 sulfur cluster binding (GO:0051539), nuclease activity (GO:0004518), exonuclease activity (GO:0004527), hydrolase activity (GO:0016787), iron-sulfur cluster binding (GO:0051536)

GO Cellular Component (4): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
single-stranded DNA exodeoxyribonuclease activity	2
DNA repair	1
nucleic acid metabolic process	1
DNA metabolic process	1
DNA damage response	1
cellular response to stress	1
nucleic acid binding	1
3’-5’-DNA exonuclease activity	1
5’-3’ DNA exonuclease activity	1
cation binding	1
iron-sulfur cluster binding	1
catalytic activity, acting on a nucleic acid	1
nuclease activity	1
hydrolase activity, acting on ester bonds	1
catalytic activity	1
metal cluster binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

464 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EXO5	DDX39B	Q13838	489
EXO5	RAD51	Q06609	469
EXO5	EEPD1	Q7L9B9	456
EXO5	EXO1	Q9UQ84	414
EXO5	REXO2	Q9Y3B8	394
EXO5	UGDH	O60701	375
EXO5	C9JR48	C9JR48	370
EXO5	PISD	Q9UG56	366
EXO5	DNA2	P51530	348
EXO5	IQCF6	A8MYZ5	348
EXO5	RFESD	Q8TAC1	348
EXO5	ENDOV	Q8N8Q3	347
EXO5	JHY	Q6NUN7	345
EXO5	EXOG	Q9Y2C4	343
EXO5	ESR2	Q92731	335

IntAct

0 interactions, top by confidence:

BioGRID (28): EXO5 (Positive Genetic), EXO5 (Reconstituted Complex), RPA1 (Affinity Capture-MS), CANX (Affinity Capture-MS), SSBP1 (Affinity Capture-MS), ENAH (Affinity Capture-MS), BAG2 (Affinity Capture-MS), BLM (Affinity Capture-MS), MCM3 (Affinity Capture-MS), DNAJC7 (Affinity Capture-MS), SFXN3 (Affinity Capture-MS), ACTR3 (Affinity Capture-MS), TOP3A (Affinity Capture-MS), ECD (Affinity Capture-MS), GPS1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1P8ASY1, A1YVX4, A2VDX7, A3KMI0, A3LNL5, C5DIF1, C5DXZ1, F1Q514, O13836, O89042, P09543, P09884, P13233, P16330, P29375, P41229, P41230, Q29FC1, Q2KHZ2, Q30DN6, Q38JA7, Q3UXZ9, Q58DC8, Q5F3R2, Q5RFD0, Q5XI06, Q5XUN4, Q62240, Q69ZS7, Q6CVT0, Q6FJK6, Q6IQX0, Q6PGC1, Q75A64, Q7Z478, Q80Y84, Q8BJL0, Q8LI34, Q99MK2, Q9BY66

Diamond homologs: A2VDX7, F1Q514, Q9CXP9, Q9H790, Q9FKK6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	56
Likely benign	5
Benign	13

Top pathogenic / likely-pathogenic (0)

SpliceAI

568 predictions. Top by Δscore:

Variant	Effect	Δscore
1:40508897:G:GT	donor_gain	0.9900
1:40509732:GCCTT:G	acceptor_gain	0.9900
1:40514504:A:AG	acceptor_gain	0.9900
1:40514505:T:G	acceptor_gain	0.9900
1:40514513:AG:A	acceptor_gain	0.9900
1:40514514:GG:G	acceptor_gain	0.9900
1:40509153:G:GT	donor_gain	0.9800
1:40509731:A:AG	acceptor_gain	0.9800
1:40509732:G:GG	acceptor_gain	0.9800
1:40514504:AT:A	acceptor_gain	0.9800
1:40514510:TGCAG:T	acceptor_loss	0.9800
1:40514511:GCAGG:G	acceptor_loss	0.9800
1:40514512:CAG:C	acceptor_loss	0.9800
1:40514513:A:AT	acceptor_loss	0.9800
1:40508906:GAG:G	donor_gain	0.9700
1:40514501:AACAT:A	acceptor_gain	0.9700
1:40514513:A:AG	acceptor_gain	0.9700
1:40514514:G:GG	acceptor_gain	0.9700
1:40514514:GGGCC:G	acceptor_gain	0.9700
1:40508905:AGAG:A	donor_loss	0.9600
1:40508906:GAGG:G	donor_loss	0.9600
1:40508907:AG:A	donor_loss	0.9600
1:40508908:GG:G	donor_loss	0.9600
1:40508909:GTTAG:G	donor_loss	0.9600
1:40508910:T:A	donor_loss	0.9600
1:40514513:AGG:A	acceptor_gain	0.9600
1:40514514:GGG:G	acceptor_gain	0.9600
1:40514514:GGGC:G	acceptor_gain	0.9600
1:40508916:G:T	donor_gain	0.9500
1:40509527:A:T	donor_gain	0.9500

AlphaMissense

1027 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:40514818:T:A	C92S	0.949
1:40514819:G:C	C92S	0.949
1:40514974:G:C	A144P	0.931
1:40514905:C:G	H121D	0.916
1:40514818:T:C	C92R	0.914
1:40514907:C:A	H121Q	0.899
1:40514907:C:G	H121Q	0.899
1:40514817:G:C	W91C	0.895
1:40514817:G:T	W91C	0.895
1:40514815:T:A	W91R	0.891
1:40514815:T:C	W91R	0.891
1:40514795:C:T	T84I	0.878
1:40514820:T:G	C92W	0.874
1:40514792:T:A	V83D	0.871
1:40514965:G:C	D141H	0.862
1:40514819:G:A	C92Y	0.855
1:40514819:G:T	C92F	0.853
1:40514811:G:C	Q89H	0.850
1:40514811:G:T	Q89H	0.850
1:40514822:A:T	E93V	0.849
1:40514905:C:A	H121N	0.841
1:40514801:T:A	L86Q	0.839
1:40514975:C:A	A144E	0.839
1:40514593:T:C	F17L	0.838
1:40514595:C:A	F17L	0.838
1:40514595:C:G	F17L	0.838
1:40514786:T:C	L81S	0.835
1:40514825:T:C	L94P	0.827
1:40514801:T:G	L86R	0.821
1:40514987:T:C	L148P	0.819

dbSNP variants (sampled 300 via entrez): RS1000165673 (1:40514646 C>G), RS1000365921 (1:40508699 G>C), RS1000501087 (1:40513196 T>G), RS1000552022 (1:40513489 C>G), RS1000714705 (1:40507464 C>A), RS1000779357 (1:40508802 A>C,G,T), RS1000813284 (1:40513813 T>G), RS1001106130 (1:40507098 T>C), RS1001618539 (1:40508663 C>T), RS1001659184 (1:40514489 A>G), RS1001919076 (1:40511960 G>A,C,T), RS1001991153 (1:40511844 T>A,C), RS1002830431 (1:40507176 CT>C), RS1003267102 (1:40506793 T>A), RS1003662147 (1:40511527 T>C,G)

Disease associations

OMIM: gene MIM:618601 | 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

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, increases expression	4
Benzo(a)pyrene	decreases methylation, increases expression, affects methylation	2
Cisplatin	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	affects expression, affects cotreatment, decreases expression	2
aristolochic acid I	increases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
GSK-J4	decreases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
butyraldehyde	increases expression	1
ferrous chloride	decreases expression	1
di-n-butylphosphoric acid	affects 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	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	affects cotreatment, decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
bisphenol S	affects cotreatment, decreases methylation	1
jinfukang	increases expression, affects cotreatment	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	increases expression	1
Temozolomide	decreases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation, decreases methylation	1
Leflunomide	decreases expression	1
Acetaminophen	increases expression	1
Atrazine	decreases expression	1
Calcitriol	decreases expression, affects cotreatment	1
Niclosamide	decreases expression	1
Silver	decreases expression	1
Smoke	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_SM59	HAP1 EXO5 (-) 1	Cancer cell line	Male
CVCL_XN58	HAP1 EXO5 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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