AEN

Summary

AEN (apoptosis enhancing nuclease, HGNC:25722) is a protein-coding gene on chromosome 15q26.1, encoding Apoptosis-enhancing nuclease (Q8WTP8). Exonuclease with activity against single- and double-stranded DNA and RNA.

Enables DNA exonuclease activity. Involved in intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator and response to ionizing radiation. Located in nuclear membrane; nucleolus; and nucleoplasm.

Source: NCBI Gene 64782 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 72 total — 2 pathogenic
• MANE Select transcript: NM_022767

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25722
Approved symbol	AEN
Name	apoptosis enhancing nuclease
Location	15q26.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ12484, FLJ12562
Ensembl gene	ENSG00000181026
Ensembl biotype	protein_coding
OMIM	610177
Entrez	64782

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 10 protein_coding, 4 retained_intron

ENST00000332810, ENST00000557787, ENST00000557927, ENST00000558327, ENST00000559528, ENST00000560174, ENST00000937448, ENST00000937449, ENST00000937450, ENST00000937451, ENST00000937452, ENST00000937453, ENST00000944204, ENST00000944205

RefSeq mRNA: 1 — MANE Select: NM_022767 NM_022767

CCDS: CCDS10344

Canonical transcript exons

ENST00000332810 — 4 exons

Exon	Start	End
ENSE00001246505	88629226	88629426
ENSE00001253502	88626146	88626749
ENSE00001316794	88621340	88621382
ENSE00001361696	88630058	88632281

Expression profiles

Bgee: expression breadth ubiquitous, 212 present calls, max score 91.59.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.0237 / max 285.4989, expressed in 1803 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
148284	18.3615	1778
148283	4.7268	1683
148285	1.9355	878

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.59	gold quality
adenohypophysis	UBERON:0002196	88.43	gold quality
stromal cell of endometrium	CL:0002255	87.99	gold quality
secondary oocyte	CL:0000655	86.95	gold quality
pituitary gland	UBERON:0000007	86.86	gold quality
body of pancreas	UBERON:0001150	86.45	gold quality
cartilage tissue	UBERON:0002418	85.21	gold quality
pancreas	UBERON:0001264	84.99	gold quality
islet of Langerhans	UBERON:0000006	84.72	gold quality
gall bladder	UBERON:0002110	84.57	gold quality
body of stomach	UBERON:0001161	83.45	gold quality
mucosa of transverse colon	UBERON:0004991	83.14	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.31	gold quality
gastrocnemius	UBERON:0001388	82.26	gold quality
tendon of biceps brachii	UBERON:0008188	81.96	silver quality
spleen	UBERON:0002106	81.93	gold quality
right adrenal gland cortex	UBERON:0035827	81.44	gold quality
granulocyte	CL:0000094	81.22	gold quality
left lobe of thyroid gland	UBERON:0001120	81.00	gold quality
left adrenal gland cortex	UBERON:0035825	81.00	gold quality
lymph node	UBERON:0000029	80.89	gold quality
left adrenal gland	UBERON:0001234	80.88	gold quality
ascending aorta	UBERON:0001496	80.81	gold quality
thoracic aorta	UBERON:0001515	80.75	gold quality
right lobe of thyroid gland	UBERON:0001119	80.57	gold quality
muscle of leg	UBERON:0001383	80.42	gold quality
lower esophagus muscularis layer	UBERON:0035833	80.36	gold quality
lower esophagus	UBERON:0013473	80.34	gold quality
right adrenal gland	UBERON:0001233	80.33	gold quality
stomach	UBERON:0000945	80.31	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-93593	yes	8.91
E-ANND-3	yes	7.76

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

85 targeting AEN, 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-4283	100.00	66.42	2097
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-6077	99.99	68.04	2299
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-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-219A-5P	99.91	73.36	735
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665

Literature-anchored findings (GeneRIF, showing 2)

• AEN is an important downstream mediator of p53 in apoptosis induction in cancer. (PMID:18264133)
• identification of ISG20L1 as a p53 family target and discovery that modulation of this target can regulate autophagic processes further strengthens the connection between p53 signaling and autophagy (PMID:20429933)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	rexo1	ENSDARG00000026986
danio_rerio	zgc:152968	ENSDARG00000037002
mus_musculus	Aen	ENSMUSG00000030609
rattus_norvegicus	Aen	ENSRNOG00000018421
drosophila_melanogaster	CG12877	FBGN0039544
drosophila_melanogaster	prage	FBGN0283741
caenorhabditis_elegans		WBGENE00004095

Paralogs (5): REXO5 (ENSG00000005189), REXO1 (ENSG00000079313), ISG20L2 (ENSG00000143319), REXO4 (ENSG00000148300), ISG20 (ENSG00000172183)

Protein

Protein identifiers

Apoptosis-enhancing nuclease — Q8WTP8 (reviewed: Q8WTP8)

Alternative names: Interferon-stimulated 20 kDa exonuclease-like 1

All UniProt accessions (2): Q8WTP8, H0YMJ6

UniProt curated annotations — full annotation on UniProt →

Function. Exonuclease with activity against single- and double-stranded DNA and RNA. Mediates p53-induced apoptosis. When induced by p53 following DNA damage, digests double-stranded DNA to form single-stranded DNA and amplifies DNA damage signals, leading to enhancement of apoptosis.

Subcellular location. Nucleus. Nucleolus.

Induction. Up-regulated by p53/TP53 in response to ionizing radiation and DNA-damaging agents such as adriamycin. Phosphorylation of p53/TP53 at ‘Ser-15’ is required for effective induction.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8WTP8-1	1	yes
Q8WTP8-2	2

RefSeq proteins (1): NP_073604* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR012337	RNaseH-like_sf	Homologous_superfamily
IPR013520	Ribonucl_H	Domain
IPR036397	RNaseH_sf	Homologous_superfamily
IPR047021	REXO1/3/4-like	Family

Pfam: PF00929

UniProt features (14 total): sequence variant 3, mutagenesis site 3, region of interest 2, short sequence motif 2, chain 1, domain 1, compositionally biased region 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WTP8-F1	75.19	0.48

Functional residue map

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

Mutagenesis-validated functional residues (3):

Position	Phenotype
114	abolishes exonuclease activity; when associated with a-116 and a-258.
116	abolishes exonuclease activity; when associated with a-114 and a-258.
258	abolishes exonuclease activity; when associated with a-114 and a-116.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 185 (showing top): MODULE_97, GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_INTRINSIC_APOPTOTIC_SIGNALING_PATHWAY_IN_RESPONSE_TO_DNA_DAMAGE_BY_P53_CLASS_MEDIATOR, GOMF_NUCLEASE_ACTIVITY, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, MODULE_182, NAGASHIMA_NRG1_SIGNALING_UP, USF_C, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, GOBP_APOPTOTIC_SIGNALING_PATHWAY, GOBP_INTRINSIC_APOPTOTIC_SIGNALING_PATHWAY_IN_RESPONSE_TO_DNA_DAMAGE, GOBP_DNA_DAMAGE_RESPONSE, GOBP_RESPONSE_TO_RADIATION, GOBP_INTRINSIC_APOPTOTIC_SIGNALING_PATHWAY

GO Biological Process (6): RNA processing (GO:0006396), response to ionizing radiation (GO:0010212), intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator (GO:0042771), DNA metabolic process (GO:0006259), apoptotic process (GO:0006915), DNA damage response (GO:0006974)

GO Molecular Function (6): nucleic acid binding (GO:0003676), exonuclease activity (GO:0004527), DNA exonuclease activity (GO:0004529), nuclease activity (GO:0004518), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (4): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), nuclear membrane (GO:0031965)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
nuclear lumen	2
gene expression	1
RNA biosynthetic process	1
primary metabolic process	1
response to radiation	1
intrinsic apoptotic signaling pathway in response to DNA damage	1
intrinsic apoptotic signaling pathway by p53 class mediator	1
nucleic acid metabolic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cellular response to stress	1
nuclease activity	1
hydrolase activity, acting on ester bonds	1
exonuclease activity	1
DNA nuclease activity	1
catalytic activity, acting on a nucleic acid	1
catalytic activity	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1
intracellular membraneless organelle	1
nucleus	1
nuclear envelope	1
organelle membrane	1

Protein interactions and networks

STRING

1488 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AEN	PHLDA3	Q9Y5J5	688
AEN	DFFB	O76075	485
AEN	ZMAT3	Q9HA38	466
AEN	CCNG1	P51959	464
AEN	EI24	O14681	444
AEN	DRAM1	Q8N682	435
AEN	PLK2	Q9NYY3	422
AEN	DCXR	Q7Z4W1	412
AEN	DHRS3	O75911	390
AEN	BBC3	Q96PG8	387
AEN	PLS1	Q14651	386
AEN	SUSD6	Q92537	371
AEN	SESN1	Q9Y6P5	368
AEN	CDKN1A	P38936	367
AEN	PLTP	P55058	366

IntAct

109 interactions, top by confidence:

A	B	Type	Score
AEN	ZNF473	psi-mi:“MI:0915”(physical association)	0.670
AEN	ZNF317	psi-mi:“MI:0915”(physical association)	0.670
AEN	ZFP64	psi-mi:“MI:0915”(physical association)	0.670
ZFP64	AEN	psi-mi:“MI:0915”(physical association)	0.670
ZNF473	AEN	psi-mi:“MI:0915”(physical association)	0.670
ZNF317	AEN	psi-mi:“MI:0915”(physical association)	0.670
AEN	AAMP	psi-mi:“MI:0915”(physical association)	0.570
AEN		psi-mi:“MI:0915”(physical association)	0.560
	AEN	psi-mi:“MI:0915”(physical association)	0.560
AAMP	AEN	psi-mi:“MI:0915”(physical association)	0.560
AEN	ZBTB43	psi-mi:“MI:0915”(physical association)	0.560
AEN	RBMY1A1	psi-mi:“MI:0915”(physical association)	0.560
AEN	TRIM27	psi-mi:“MI:0915”(physical association)	0.560
AEN	EMD	psi-mi:“MI:0915”(physical association)	0.560
AEN	KRTAP10-5	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-7	AEN	psi-mi:“MI:0915”(physical association)	0.560
AEN	KRTAP10-8	psi-mi:“MI:0915”(physical association)	0.560
TLE5	AEN	psi-mi:“MI:0915”(physical association)	0.560
AEN	IKZF1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (57): AEN (Two-hybrid), AEN (Two-hybrid), AEN (Two-hybrid), AEN (Two-hybrid), AEN (Two-hybrid), AEN (Two-hybrid), AEN (Two-hybrid), AEN (Two-hybrid), AEN (Two-hybrid), AEN (Two-hybrid), AEN (Two-hybrid), AEN (Two-hybrid), AEN (Two-hybrid), AEN (Two-hybrid), AEN (Two-hybrid)

ESM2 similar proteins: A0JPN4, A2AKB4, A2APT9, A4Q9E8, A4Q9F6, A6NNM8, A6QQJ8, A8CVX7, B2GUW6, D2H8V8, O88866, O94761, P48778, Q14154, Q2YDK1, Q3TYG6, Q49AM3, Q4KLY6, Q4QQS0, Q4R747, Q5D1E7, Q5D1E8, Q5NC05, Q5RA67, Q5REE2, Q5SXM2, Q60953, Q6ZQM0, Q6ZUX3, Q6ZW76, Q75NR7, Q7TSG2, Q8BIY3, Q8BP86, Q8C7W7, Q8IX06, Q8N841, Q8R2S1, Q8VCU0, Q8WTP8

Diamond homologs: A1A5R7, A1Z7K9, A3KPE8, A3LRV8, A4RF51, A5DAD0, A5E1W0, B2GUW6, G0SAK8, O94375, O94443, P0C581, P0CQ08, P0CQ09, P0CQ44, P0CQ45, P48778, P53010, P53015, P53331, Q08237, Q09798, Q0CJU7, Q10124, Q2GSV2, Q2T9U5, Q2YDK1, Q3U1G5, Q4PER6, Q4R9F7, Q4WYA1, Q504Q3, Q54U94, Q5AL29, Q5APK0, Q5B367, Q5F450, Q5REE2, Q6AXU3, Q6C462

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	60
Likely benign	6
Benign	0

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
2498631	GRCh37/hg19 15q25.2-26.3(chr15:84228005-102264590)x3	Pathogenic
625751	GRCh37/hg19 15q25.2-26.1(chr15:83883823-92165844)	Pathogenic

SpliceAI

528 predictions. Top by Δscore:

Variant	Effect	Δscore
15:88626144:A:AG	acceptor_gain	1.0000
15:88626145:G:GG	acceptor_gain	1.0000
15:88626145:GGCT:G	acceptor_gain	1.0000
15:88626747:GAG:G	donor_gain	1.0000
15:88626750:GTAAG:G	donor_loss	1.0000
15:88626751:T:A	donor_loss	1.0000
15:88629217:T:A	acceptor_gain	1.0000
15:88629221:CACA:C	acceptor_loss	1.0000
15:88629223:CA:C	acceptor_loss	1.0000
15:88629224:A:AG	acceptor_gain	1.0000
15:88629225:G:GT	acceptor_gain	1.0000
15:88629225:GATC:G	acceptor_gain	1.0000
15:88629425:AGGTG:A	donor_loss	1.0000
15:88629427:G:GA	donor_loss	1.0000
15:88629427:G:GG	donor_gain	1.0000
15:88621381:AGGTG:A	donor_loss	0.9900
15:88621383:G:GC	donor_loss	0.9900
15:88621384:T:A	donor_loss	0.9900
15:88626141:TTCA:T	acceptor_loss	0.9900
15:88626142:TCA:T	acceptor_loss	0.9900
15:88626144:AG:A	acceptor_gain	0.9900
15:88626144:AGGCT:A	acceptor_gain	0.9900
15:88626145:GG:G	acceptor_gain	0.9900
15:88626145:GGC:G	acceptor_gain	0.9900
15:88626145:GGCTG:G	acceptor_gain	0.9900
15:88626750:G:GG	donor_gain	0.9900
15:88629221:CACAG:C	acceptor_gain	0.9900
15:88629222:ACAG:A	acceptor_gain	0.9900
15:88629223:CAGA:C	acceptor_gain	0.9900
15:88629225:GA:G	acceptor_gain	0.9900

AlphaMissense

2117 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:88626607:C:T	S133F	0.997
15:88626605:T:G	C132W	0.996
15:88626551:C:A	D114E	0.995
15:88626551:C:G	D114E	0.995
15:88626598:C:A	A130D	0.995
15:88626603:T:C	C132R	0.995
15:88626607:C:A	S133Y	0.995
15:88629290:T:A	L202H	0.995
15:88626544:C:A	A112D	0.994
15:88626553:G:A	C115Y	0.994
15:88626554:T:G	C115W	0.994
15:88626557:G:C	E116D	0.994
15:88626557:G:T	E116D	0.994
15:88626606:T:C	S133P	0.994
15:88629260:G:A	G192E	0.994
15:88630088:G:C	D258H	0.994
15:88630090:T:A	D258E	0.994
15:88630090:T:G	D258E	0.994
15:88630112:T:G	Y266D	0.994
15:88626543:G:C	A112P	0.993
15:88626610:T:A	I134N	0.993
15:88626678:C:A	R157S	0.993
15:88629254:T:A	V190E	0.993
15:88629320:G:C	R212P	0.993
15:88626601:G:C	R131P	0.992
15:88626655:C:A	P149H	0.992
15:88626739:C:A	A177D	0.992
15:88629265:G:C	A194P	0.992
15:88629278:A:C	D198A	0.992
15:88629278:A:G	D198G	0.992

dbSNP variants (sampled 300 via entrez): RS1000116081 (15:88629433 G>A,C), RS1000122387 (15:88621469 C>T), RS1000202059 (15:88625408 C>T), RS1000211939 (15:88610249 A>T), RS1000300613 (15:88615182 G>A), RS1000355738 (15:88630436 T>G), RS1000552009 (15:88625505 A>C,T), RS1000554185 (15:88625642 A>G), RS1000586377 (15:88629735 C>G), RS1000640169 (15:88629517 A>G), RS1000709408 (15:88610476 G>C), RS1001011801 (15:88620889 C>T), RS1001074432 (15:88610439 G>A), RS1001104287 (15:88631085 A>G), RS1001333505 (15:88630634 C>A)

Disease associations

OMIM: gene MIM:610177 | 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
GCST003542_130	Night sleep phenotypes	9.000000e-06
GCST004858_21	Dupuytren’s disease	7.000000e-17

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004229	Dupuytren Contracture

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1470108	AEN, MIR7-2		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	5
Aflatoxin B1	affects expression, increases expression	4
(+)-JQ1 compound	decreases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, increases expression	2
Estradiol	increases expression	2
Nickel	increases expression	2
Ozone	affects cotreatment, increases oxidation, increases abundance, increases expression	2
Valproic Acid	increases expression, affects expression	2
Cyclosporine	increases expression	2
Cadmium Chloride	decreases expression	2
aristolochic acid I	increases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
afuresertib	decreases expression	1
beauvericin	decreases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
trichostatin A	affects expression	1
diethyl maleate	increases expression	1
beta-lapachone	increases expression	1
sodium arsenite	increases expression, affects cotreatment, increases abundance	1
butyraldehyde	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
hydroquinone	increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
polyhexamethyleneguanidine	affects expression	1
buprofezin	increases expression	1
azoxystrobin	increases expression	1
cylindrospermopsin	increases expression	1
deguelin	increases expression	1
abrine	increases expression	1

Clinical trials (associated diseases)

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