ENDOG

Summary

ENDOG (endonuclease G, HGNC:3346) is a protein-coding gene on chromosome 9q34.11, encoding Endonuclease G, mitochondrial (Q14249). Endonuclease that preferentially catalyzes the cleavage of double-stranded 5-hydroxymethylcytosine (5hmC)-modified DNA.

The protein encoded by this gene is a nuclear encoded endonuclease that is localized in the mitochondrion. The encoded protein is widely distributed among animals and cleaves DNA at GC tracts. This protein is capable of generating the RNA primers required by DNA polymerase gamma to initiate replication of mitochondrial DNA.

Source: NCBI Gene 2021 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 59 total
• GTEx eGene: eQTL in 44 tissues, sQTL in 31 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.85 (unconstrained)
• MANE Select transcript: NM_004435
• Notable: 59 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3346
Approved symbol	ENDOG
Name	endonuclease G
Location	9q34.11
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000167136
Ensembl biotype	protein_coding
OMIM	600440
Entrez	2021

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 14 protein_coding

MANE Select: ENST00000372642

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1

ENST00000372642, ENST00000854121, ENST00001119128, ENST00001119129, ENST00001119130, ENST00001119131, ENST00001119132, ENST00001119133, ENST00001119134, ENST00001119135, ENST00001124821, ENST00001124822, ENST00001124823, ENST00001138934

RefSeq mRNA: 1 — MANE Select: NM_004435 NM_004435

CCDS: CCDS6912

Canonical transcript exons

ENST00000372642 — 3 exons

Exon	Start	End
ENSE00001110217	128820739	128820848
ENSE00001458288	128822328	128822676
ENSE00001458291	128818500	128819185

Expression profiles

Bgee: expression breadth ubiquitous, 255 present calls, max score 96.38.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.1457 / max 91.3627, expressed in 1743 samples.

Highest expression (Bgee): hindlimb stylopod muscle, apex of heart, gastrocnemius, triceps brachii, body of tongue.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ENDOG is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 44 tissues and its splicing (sQTL) in 31 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 75 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Nerve Tibial	eqtl	3.9e-76	+0.53	9:128824961:G:A
Skin Sun Exposed Lower leg	eqtl	5.1e-64	+0.53	9:128837832:T:C
Adipose Subcutaneous	eqtl	4.9e-47	+0.43	9:128818465:C:T
Thyroid	eqtl	6.1e-45	+0.42	9:128854888:G:A
Skin Not Sun Exposed Suprapubic	eqtl	5.3e-41	+0.48	9:128814275:T:C
Muscle Skeletal	sqtl	2.2e-40	-1.51	9:128821236:C:G
Cells Cultured fibroblasts	eqtl	2.0e-36	+0.35	9:128818465:C:T
Artery Tibial	eqtl	4.2e-33	+0.35	9:128816903:C:T
Cells EBV-transformed lymphocytes	eqtl	2.6e-32	+0.61	9:128813838:G:A
Testis	eqtl	3.2e-26	+0.38	9:128824961:G:A
Colon Transverse	eqtl	1.3e-22	+0.25	9:128837832:T:C
Adipose Visceral Omentum	eqtl	2.1e-21	-0.34	9:128798831:G:A
Heart Atrial Appendage	sqtl	5.7e-21	-1.47	9:128816929:A:G
Esophagus Mucosa	eqtl	7.7e-20	+0.29	9:128807899:T:C
Breast Mammary Tissue	eqtl	8.6e-20	+0.35	9:128816903:C:T
Brain Cerebellum	eqtl	2.5e-19	+0.56	9:128813622:A:G
Muscle Skeletal	eqtl	7.0e-19	+0.21	9:128850285:T:G
Brain Cerebellar Hemisphere	eqtl	4.0e-18	+0.49	9:128849531:T:C
Nerve Tibial	sqtl	4.5e-18	-1.17	9:128816242:A:AAT
Artery Aorta	eqtl	2.8e-17	+0.37	9:128813838:G:A

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
98842	6.4816	1647
98841	3.6641	1536

Top tissues by expression

showing 100 of 280 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	96.38	gold quality
apex of heart	UBERON:0002098	96.25	gold quality
gastrocnemius	UBERON:0001388	95.87	gold quality
triceps brachii	UBERON:0001509	95.17	gold quality
body of tongue	UBERON:0011876	94.98	gold quality
muscle of leg	UBERON:0001383	94.90	gold quality
muscle organ	UBERON:0001630	94.54	gold quality
vastus lateralis	UBERON:0001379	94.15	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	93.85	gold quality
quadriceps femoris	UBERON:0001377	93.82	gold quality
skeletal muscle tissue	UBERON:0001134	93.04	gold quality
diaphragm	UBERON:0001103	93.02	silver quality
biceps brachii	UBERON:0001507	92.86	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	92.78	gold quality
mucosa of transverse colon	UBERON:0004991	92.23	gold quality
heart left ventricle	UBERON:0002084	92.17	gold quality
cardiac ventricle	UBERON:0002082	92.01	gold quality
gluteal muscle	UBERON:0002000	91.73	gold quality
right lobe of liver	UBERON:0001114	91.36	gold quality
epithelium of bronchus	UBERON:0002031	90.94	gold quality
right atrium auricular region	UBERON:0006631	90.66	gold quality
bronchus	UBERON:0002185	90.49	gold quality
bronchial epithelial cell	CL:0002328	90.47	gold quality
muscle tissue	UBERON:0002385	89.72	gold quality
cardiac atrium	UBERON:0002081	89.42	gold quality
heart	UBERON:0000948	89.05	gold quality
deltoid	UBERON:0001476	89.04	gold quality
Brodmann (1909) area 9	UBERON:0013540	88.74	gold quality
heart right ventricle	UBERON:0002080	88.29	gold quality
tongue	UBERON:0001723	88.19	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	87.76	gold quality
anterior cingulate cortex	UBERON:0009835	87.59	gold quality
cingulate cortex	UBERON:0003027	87.57	gold quality
right frontal lobe	UBERON:0002810	87.37	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	87.32	gold quality
lateral nuclear group of thalamus	UBERON:0002736	86.87	gold quality
adult mammalian kidney	UBERON:0000082	86.73	gold quality
adult organism	UBERON:0007023	86.65	gold quality
pharyngeal mucosa	UBERON:0000355	86.26	gold quality
renal medulla	UBERON:0000362	85.96	gold quality
amygdala	UBERON:0001876	85.96	gold quality
middle temporal gyrus	UBERON:0002771	85.94	gold quality
lateral globus pallidus	UBERON:0002476	85.50	silver quality
putamen	UBERON:0001874	85.49	gold quality
liver	UBERON:0002107	85.43	gold quality
nucleus accumbens	UBERON:0001882	85.37	gold quality
right uterine tube	UBERON:0001302	85.26	gold quality
right adrenal gland	UBERON:0001233	85.19	gold quality
left adrenal gland	UBERON:0001234	85.19	gold quality
left adrenal gland cortex	UBERON:0035825	84.96	gold quality
neocortex	UBERON:0001950	84.88	gold quality
right adrenal gland cortex	UBERON:0035827	84.86	gold quality
caudate nucleus	UBERON:0001873	84.79	gold quality
type B pancreatic cell	CL:0000169	84.72	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.62	gold quality
primary visual cortex	UBERON:0002436	84.59	gold quality
prefrontal cortex	UBERON:0000451	84.56	gold quality
cerebral cortex	UBERON:0000956	84.40	gold quality
frontal cortex	UBERON:0001870	84.37	gold quality
adrenal cortex	UBERON:0001235	84.35	gold quality
metanephros cortex	UBERON:0010533	84.30	gold quality
telencephalon	UBERON:0001893	84.26	gold quality
occipital lobe	UBERON:0002021	84.26	gold quality
body of stomach	UBERON:0001161	84.15	gold quality
body of pancreas	UBERON:0001150	83.89	gold quality
forebrain	UBERON:0001890	83.89	gold quality
transverse colon	UBERON:0001157	83.82	gold quality
hypothalamus	UBERON:0001898	83.69	gold quality
superior surface of tongue	UBERON:0007371	83.69	gold quality
tendon of biceps brachii	UBERON:0008188	83.64	silver quality
cortical plate	UBERON:0005343	83.41	gold quality
right testis	UBERON:0004534	83.25	gold quality
brain	UBERON:0000955	83.11	gold quality
substantia nigra	UBERON:0002038	82.90	gold quality
substantia nigra pars reticulata	UBERON:0001966	82.76	silver quality
temporal lobe	UBERON:0001871	82.67	gold quality
midbrain	UBERON:0001891	82.65	gold quality
lower esophagus muscularis layer	UBERON:0035833	82.47	gold quality
esophagus mucosa	UBERON:0002469	82.46	gold quality
lower esophagus	UBERON:0013473	82.43	gold quality
Brodmann (1909) area 23	UBERON:0013554	82.39	gold quality
duodenum	UBERON:0002114	82.34	gold quality
Ammon’s horn	UBERON:0001954	82.28	gold quality
left testis	UBERON:0004533	82.19	gold quality
esophagus	UBERON:0001043	81.94	gold quality
nasal cavity epithelium	UBERON:0005384	81.90	silver quality
jejunum	UBERON:0002115	81.75	gold quality
ventral tegmental area	UBERON:0002691	81.72	silver quality
esophagogastric junction muscularis propria	UBERON:0035841	81.71	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	81.65	gold quality
substantia nigra pars compacta	UBERON:0001965	81.58	silver quality
granulocyte	CL:0000094	81.56	gold quality
monocyte	CL:0000576	81.48	gold quality
adenohypophysis	UBERON:0002196	81.46	gold quality
cortex of kidney	UBERON:0001225	81.37	gold quality
popliteal artery	UBERON:0002250	81.12	gold quality
adrenal gland	UBERON:0002369	81.12	gold quality
tibial artery	UBERON:0007610	81.09	gold quality
tibialis anterior	UBERON:0001385	81.05	silver quality
testis	UBERON:0000473	81.02	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.69

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Skeletal muscle	tissue	126.7	low
Tongue	tissue	55.2
Choroid plexus	tissue	38.6
Postcentral gyrus	tissue	32.2
Locus coeruleus	tissue	21.1
Nucleus accumbens	tissue	20.1
Hippocampus	tissue	19.7	high
Heart muscle	tissue	15.5	medium
Liver	tissue	15.2	medium
Pituitary gland	tissue	12.9
Frontal cortex	tissue	12.5
Duodenum	tissue	11.7	low
Parathyroid gland	tissue	11.3	low
Caudate putamen	tissue	10.5
Vagina	tissue	10.1	low
Kidney	tissue	9.9	medium
Pons	tissue	9.7
Colon	tissue	9.2	medium
Pancreas	tissue	9.2	medium
Superior colliculi	tissue	9.0
Stomach 1	tissue	8.6	medium
Small intestine	tissue	8.5	medium
Thalamus	tissue	8.1
Fallopian tube	tissue	8.0	low
Medulla oblongata	tissue	7.8
Substantia nigra	tissue	7.6
Hypothalamus	tissue	7.3
Prostate	tissue	7.1	low
Periaqueductal gray	tissue	6.9
Midbrain	tissue	6.8
Seminal vesicle	tissue	6.6	low
Cerebral cortex	tissue	6.4	high
Somatosensory cortex	tissue	6.4
Adrenal gland	tissue	6.3	high
Adipose tissue	tissue	6.2	low
Spinal cord	tissue	6.1
Salivary gland	tissue	6.0	medium
Cerebellum	tissue	6.0	high
Septum	tissue	5.9
Hippocampal formation	tissue	5.7
Testis	tissue	5.4	medium
Rectum	tissue	5.3	medium
Motor cortex	tissue	5.3
Skin 1	tissue	5.2	medium
Temporal cortex	tissue	5.0
Occipital cortex	tissue	5.0
Ventral forebrain	tissue	4.9
Putamen	tissue	4.8
Entorhinal cortex	tissue	4.7
Retrosplenial and cingulate cortex	tissue	4.7
Olfactory bulb	tissue	4.7
Prefrontal cortex	tissue	4.5
Retrosplenial cortex	tissue	4.5
Breast	tissue	4.1	medium
Bone marrow	tissue	4.1	medium
Amygdala	tissue	4.0
Insular cortex	tissue	4.0
Basal ganglia	tissue	3.9	medium
Ovary	tissue	3.8	medium
Cervix	tissue	3.7	medium

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Precentral gyrus (33.5), Cerebellar nuclei (31.5), Precentral gyrus, middle (31.5), Nucleus ambiguus (30.5), Supplementary motor cortex (29.7).

Regulation

Is transcription factor: no

Functional genomics

gnomAD constraint: pLI 5.22e-10, LOEUF 1.85, missense Z -1.54 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000372642 — one region, missense o/e 0.93.

Literature-anchored findings (GeneRIF, showing 39)

• examination of submitochondrial localization and its ability to cleave R-loops in order to clarify role in mtDNA replication (PMID:12444964)
• endonuclease G and apoptosis-inducing factor are relocated and have roles in calcium induced signaling and oxidative stress-related impairment of mitochondria (PMID:15182854)
• EndoG forms complexes with AIF and FEN-1 but not with PCNA. Heat shock proteins 70 interact with EndoG and are involved in the regulation of its activity. (PMID:16133872)
• Our findings suggest that the presence of EndoG in non-invasive breast cancer cells determines their sensitivity to apoptosis, which may be taken into consideration for developing the chemotherapeutic strategy for cancer treatment. (PMID:17046751)
• Hypochlorous acid induced Bax-dependent mitochondrial permeability which led to cell death without caspase activity by processes involving AIF/EndoG-dependent pathways. (PMID:17107772)
• study of cellular localization of the endonuclease G, AIF & AMID during apoptosis using bioinformatics and image analysis (PMID:17347867)
• EndoG inactivation by loss of expression may not occur in colorectal and gastric cancers. Rather, neo-expression of EndoG may play a role in both colorectal and gastric tumorigenesis. (PMID:18705403)
• data showed that loss of EndoG expression is a feature of hepatocellular carcinomas (PMID:18754329)
• These results suggest that Bim, Bcl-xL, FAK and endonuclease G are involved in safingol-induced apoptosis of detached oral squamous cell carcinoma. (PMID:19199036)
• Results suggest that human Endonuclease G shares a similar catalytic mechanism with nuclease A from Anabaena. (PMID:19272175)
• nuclear translocation of apoptosis-inducing factor and endonuclease G play a crucial role in (-)-Epigallocatechin-3-gallate -induced apoptosis of human laryngeal epidermoid carcinoma Hep2 cells (PMID:19781850)
• When EndoG gene expression was downregulated by lentiviral shRNA vectors, we found a significant reduction in the replicative life span and a corresponding increase in cell death. (PMID:20211237)
• ENDOG might contribute to cancer pathogenesis by expressional alterations, but not by somatic mutations (PMID:21080888)
• Benzyl isothiocyanate induces apoptosis in DU 145 cells through the release of AIF and Endo G from the mitochondria and also promotes caspase-3 activation. (PMID:21206973)
• Data show that among the 13 SNPs in the 3 genes, only 3 were found to be polymorphic: R196K and K277R in the DFFB gene, and S12L in the EndoG gene, and all 6 SNPs in the FEN-1 gene were entirely monoallelic. (PMID:22011247)
• Conclude that EndoG and TOPO2a may actively participate in apoptotic chromatin degradation. (PMID:22160858)
• Ethyl gallate induces apoptosis of HL-60 cells by promoting the expression of caspases-8, -9, -3, apoptosis-inducing factor and endonuclease G. (PMID:23109891)
• CHIP overexpression reduces EndoG levels, and results in reduced or no oxidative stress-induced cell death in cultured cancer cells. (PMID:23764847)
• These data indicate that HSV-1 UL12.5 deploys cellular proteins, including ENDOG and EXOG, to destroy mtDNA and contribute to a growing body of literature highlighting roles for ENDOG and EXOG in mtDNA maintenance. (PMID:23986585)
• Using gene reporter assays, we show that promoter variations in 11 intrinsic apoptosis genes, including ADPRT, APAF1, BCL2, BAD, BID, MCL1, BIRC4, BCL2L1, ENDOG, YWHAB, and YWHAQ, influence promoter activity in an allele-specific manner. (PMID:24038028)
• Endonuclease G mediates alpha-synuclein cytotoxicity during Parkinson’s disease. (PMID:24129513)
• Data indicate that older muscles showed a 3-fold greater fraction of endonuclease G (a mitochondrial proapoptotic factor)-positive myonuclei. (PMID:24371120)
• Endonuclease G (EndoG), an apoptotic nuclease, as an essential factor for MLLbcr-specific DNA recombination after induction of replication stress. (PMID:25132265)
• study demonstrate EndoG interacts with cellular Inhibitor of Apoptosis Protein 1 (cIAP1); results indicate IAPs interact and ubiquitinate EndoG via K63-mediated isopeptide linkages without affecting EndoG levels and EndoG-mediated cell death, suggesting EndoG ubiquitination by IAPs may serve as a regulatory signal independent of proteasomal degradation (PMID:25139236)
• Data suggest that endonuclease G (EndoG) inhibitors have the potential to be utilized for amelioration of cell injuries in which participation of EndoG is essential. (PMID:25401220)
• Results show that BNIP3 interacts with the voltage-dependent anion channel (VDAC) to directly induce mitochondrial release and nuclear translocation of EndoG. (PMID:25436615)
• our study established a link between Endo G and mitochondrial function during cardiac hypertrophy (PMID:26492643)
• These findings suggest that non-viral DNA vectors are also substrates for EndoG in its role in homologous recombination (PMID:27239850)
• EndoG is not a mediator of exogenous DNA clearance, but in non-physiological circumstances, it may nonspecifically cleave intracellular DNA regardless of its origin. (PMID:27260396)
• Overexpression of EndoG in capital ES, Cyrillicsmall a, Cyrilliccapital ES, Cyrillicsmall o, Cyrillic-2 cells downregulated the expression of active full-length hTERT variant and upregulated non-active spliced variant. (PMID:27420614)
• ndoG digests long non-coding RNA and produces 47-mer RNA oligonucleotide complementary to hTERT pre-mRNA exon 8 and intron 8 junction place. Interaction of 47-mer RNA oligonucleotide and hTERT pre-mRNA causes alternative splicing. (PMID:27797329)
• Galectin-3-induced cell death in HIV-1-infected macrophages is most likely related to the translocation of Endo G from the cytoplasm to the nucleus. (PMID:27981746)
• Overexpression of EndoG in CD4+ T cells downregulated the expression of the active full-length hTERT variant and upregulated the inactive alternatively spliced variant. (PMID:28320284)
• EndoG is an endonuclease with the unique ability to inactivate another endonuclease, DNase I, and to modulate the development of apoptosis. (PMID:30521874)
• Autophagy restricts mitochondrial DNA damage-induced release of ENDOG (endonuclease G) to regulate genome stability. (PMID:33465003)
• Assessment of the Role of Nuclear ENDOG Gene and mtDNA Variations on Paternal Mitochondrial Elimination (PME) in Infertile Men: An Experimental Study. (PMID:35477840)
• Unleashing a novel function of Endonuclease G in mitochondrial genome instability. (PMID:36394256)
• Endonuclease G promotes preeclampsia by regulating the Wnt signaling pathway. (PMID:36852641)
• Apoptotic endonuclease EndoG induces alternative splicing of Caspase-2. (PMID:39239896)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	endog	ENSDARG00000058865
mus_musculus	Endog	ENSMUSG00000015337
rattus_norvegicus	Endog	ENSRNOG00000016033
drosophila_melanogaster	EndoG	FBGN0033690
drosophila_melanogaster	Tengl4	FBGN0037857
drosophila_melanogaster	Tengl2	FBGN0052463
caenorhabditis_elegans	cps-6	WBGENE00000787

Paralogs (1): EXOG (ENSG00000157036)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1261433) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 7 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal testis morphology	1
small testis	1
abnormal skin morphology	1
abnormal coat/hair pigmentation	1
abnormal male germ cell apoptosis	1
decreased sensitivity to induced cell death	1
embryonic lethality before implantation, complete penetrance	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Bos taurus	P38447	88.6%	Diamond
Xenopus laevis	Q0IH72	61.1%	Diamond
Cunninghamella echinulata var. echinulata	P81203	60.5%	Diamond
Syncephalastrum racemosum	P81204	60.5%	Diamond
Schizosaccharomyces pombe 972h-	Q10480	49.2%	Diamond
Saccharomyces cerevisiae S288C	P08466	48.0%	Diamond
Nostoc sp. PCC 7120 = FACHB-418	P38446	36.5%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
KYAT1-SPOUT1	protein-coding	127739546
DOLK	protein-coding	22845
PHYHD1	protein-coding	254295
SPOUT1	protein-coding	51490
LRRC8A	protein-coding	56262
KYAT1	protein-coding	883
ZDHHC12-DT	ncRNA	100506100
PKN3	protein-coding	29941
TBC1D13	protein-coding	54662
ZDHHC12	protein-coding	84885
ZER1	protein-coding	10444

Protein

Protein identifiers

Endonuclease G, mitochondrial — Q14249 (reviewed: Q14249)

All UniProt accessions (2): E5KNL5, Q14249

UniProt curated annotations — full annotation on UniProt →

Function. Endonuclease that preferentially catalyzes the cleavage of double-stranded 5-hydroxymethylcytosine (5hmC)-modified DNA. The 5hmC-modified nucleotide does not increase the binding affinity, but instead increases the efficiency of cutting and specifies the site of cleavage for the modified DNAs. Shows significantly higher affinity for four-stranded Holliday junction over duplex and single-stranded DNAs. Promotes conservative recombination when the DNA is 5hmC-modified. Promotes autophagy through the suppression of mTOR by its phosphorylation-mediated interaction with YWHAG and its endonuclease activity-mediated DNA damage response. GSK3-beta mediated phosphorylation of ENDOG enhances its interaction with YWHAG, leading to the release of TSC2 and PIK3C3 from YWHAG resulting in mTOR pathway suppression and autophagy initiation. Promotes cleavage of mtDNA in response to oxidative and nitrosative stress, in turn inducing compensatory mtDNA replication.

Subunit / interactions. Homodimer; disulfide-linked. Homodimerization is essential for enzyme activity. Interacts with YWHAG.

Subcellular location. Mitochondrion.

Post-translational modifications. GSK3-beta-mediated dual phosphorylations at Thr-128 and Ser-288 is necessary for its interaction with YWHAG and the induction of autophagy.

Similarity. Belongs to the DNA/RNA non-specific endonuclease family.

RefSeq proteins (1): NP_004426* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001604	Endo_G_ENPP1-like_dom	Domain
IPR018524	DNA/RNA_endonuclease_AS	Active_site
IPR020821	ENPP1-3/EXOG-like_nuc-like	Domain
IPR040255	Non-specific_endonuclease	Family
IPR044925	His-Me_finger_sf	Homologous_superfamily
IPR044929	DNA/RNA_non-sp_Endonuclease_sf	Homologous_superfamily

Pfam: PF01223

UniProt features (16 total): mutagenesis site 4, sequence conflict 2, modified residue 2, transit peptide 1, chain 1, region of interest 1, active site 1, binding site 1, site 1, disulfide bond 1, sequence variant 1

Structure

Experimental structures (PDB)

2 structures by resolution:

PDB	Title	Method	Resolution (Å)
9M0H	Crystal structure of human endonuclease G mutant C113A/H141A	X-RAY DIFFRACTION	1.85
9M0G	Crystal structure of human endonuclease G mutant C113A/H141A bound with trans-Resveratrol	X-RAY DIFFRACTION	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14249-F1	85.67	0.74

Human Protein Atlas

Protein class: Predicted intracellular proteins, Plasma proteins

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH approved

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 (2)

Position	Role
141	proton acceptor
110	essential for catalytic activity

Ligand- & substrate-binding residues (1)

Position	Role
172	Mg(2+)

Post-translational modifications (2)

Type	Positions
Phosphothreonine	128
Phosphoserine	288

Disulfide bonds (1)

Type	Positions
Interchain	113

Mutagenesis-validated functional residues (4)

Position	Phenotype
128	loss of phosphorylation. suppresses interaction with ywhag and induction of autophagy; when associated with a-288.
128	phosphomimetic mutant. no effect on its interaction with ywhag. enhances interaction with ywhag; when associated with t-288.
288	loss of phosphorylation. suppresses interaction with ywhag and induction of autophagy; when associated with a-128.
288	phosphomimetic mutant. no effect on its interaction with ywhag. enhances interaction with ywhag; when associated with t-128.

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

MSigDB gene sets: 201 (showing top): GOBP_POSITIVE_REGULATION_OF_DNA_REPLICATION, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_REGULATION_OF_AUTOPHAGY, GOMF_ENDONUCLEASE_ACTIVITY, GOMF_RNA_NUCLEASE_ACTIVITY, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_RESPONSE_TO_ESTRADIOL, GOBP_REGULATION_OF_DNA_TEMPLATED_DNA_REPLICATION, GOBP_RESPONSE_TO_PEPTIDE, GOMF_NUCLEASE_ACTIVITY, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_MITOCHONDRIAL_DNA_METABOLIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_CARBOHYDRATE_STIMULUS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP

GO Biological Process (16): apoptotic DNA fragmentation (GO:0006309), DNA recombination (GO:0006310), DNA damage response (GO:0006974), response to mechanical stimulus (GO:0009612), positive regulation of autophagy (GO:0010508), negative regulation of TOR signaling (GO:0032007), mitochondrial DNA catabolic process (GO:0032043), response to estradiol (GO:0032355), cellular response to oxidative stress (GO:0034599), cellular response to calcium ion (GO:0071277), cellular response to glucose stimulus (GO:0071333), cellular response to hypoxia (GO:0071456), positive regulation of mitochondrial DNA replication (GO:0090297), positive regulation of hydrogen peroxide-mediated programmed cell death (GO:1901300), positive regulation of apoptotic DNA fragmentation (GO:1902512), DNA catabolic process (GO:0006308)

GO Molecular Function (12): single-stranded DNA endonuclease activity (GO:0000014), magnesium ion binding (GO:0000287), nucleic acid binding (GO:0003676), DNA endonuclease activity (GO:0004520), RNA endonuclease activity (GO:0004521), protein homodimerization activity (GO:0042803), nuclease activity (GO:0004518), endonuclease activity (GO:0004519), DNA nuclease activity (GO:0004536), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (5): nucleus (GO:0005634), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), perikaryon (GO:0043204), perinuclear region of cytoplasm (GO:0048471)

GO top-level categories

56 GO namespaces:

Category	Terms
DNA catabolic process	2
DNA metabolic process	2
cellular response to stress	2
DNA nuclease activity	2
binding	2
endonuclease activity	2
nuclease activity	2
intracellular membrane-bounded organelle	2
cytoplasm	2
cellular anatomical structure	2
apoptotic nuclear changes	1
response to external stimulus	1
response to abiotic stimulus	1
autophagy	1
positive regulation of catabolic process	1
regulation of autophagy	1
TOR signaling	1
regulation of TOR signaling	1
negative regulation of intracellular signal transduction	1
mitochondrion	1
mitochondrial DNA metabolic process	1
response to lipid	1
response to oxygen-containing compound	1
response to oxidative stress	1
cellular response to chemical stress	1
response to calcium ion	1
cellular response to metal ion	1
intracellular glucose homeostasis	1
response to glucose	1
cellular response to hexose stimulus	1
response to hypoxia	1
cellular response to decreased oxygen levels	1
mitochondrial DNA replication	1
regulation of mitochondrial DNA replication	1
positive regulation of mitochondrial DNA metabolic process	1
positive regulation of DNA-templated DNA replication	1
hydrogen peroxide-mediated programmed cell death	1
positive regulation of programmed cell death	1
regulation of hydrogen peroxide-mediated programmed cell death	1
apoptotic DNA fragmentation	1
regulation of apoptotic DNA fragmentation	1
positive regulation of DNA catabolic process	1
nucleic acid catabolic process	1
DNA endonuclease activity	1
hydrolase activity, acting on ester bonds	1
metal ion binding	1
RNA nuclease activity	1
identical protein binding	1
protein dimerization activity	1
catalytic activity, acting on a nucleic acid	1
catalytic activity, acting on DNA	1
catalytic activity	1
cation binding	1
organelle inner membrane	1
mitochondrial membrane	1
neuronal cell body	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 7 of 33 annotations. The rest are phylogenetic / computational / electronic (IEA).

7 experimentally-supported GO terms:

GO term	NS	Evidence
DNA damage response	BP	mutant phenotype
mitochondrial DNA catabolic process	BP	mutant phenotype
negative regulation of TOR signaling	BP	mutant phenotype
positive regulation of autophagy	BP	mutant phenotype
positive regulation of mitochondrial DNA replication	BP	mutant phenotype
mitochondrion	CC	direct assay
DNA endonuclease activity	MF	mutant phenotype

Protein interactions and networks

STRING

showing 15 of 1,538 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ENDOG	CYCS	P00001	852
ENDOG	SPOUT1	Q5T280	852
ENDOG	AIFM1	O95831	842
ENDOG	TBC1D13	Q9NVG8	839
ENDOG	DIABLO	Q9NR28	770
ENDOG	KYAT1	Q16773	768
ENDOG	HTRA2	O43464	767
ENDOG	DFFA	O00273	765
ENDOG	CASP9	P55211	726
ENDOG	APAF1	O14727	715
ENDOG	DFFB	O76075	685
ENDOG	RASSF6	Q6ZTQ3	685
ENDOG	CASP3	P42574	676
ENDOG	BAX	P55269	638
ENDOG	BCL2	P10415	638

IntAct

Human interaction partners of ENDOG in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

5 partners by confidence:

Partner	Interaction type	MIscore	Records
ITLN2	physical association	0.640	2
DNAJA4	physical association	0.500	1
TNKS	direct interaction	0.440	1
CPA4	physical association	0.400	1
GRK6	association	0.350	1

BioGRID (104 interactions; top human partners by supporting records): DNAJA1 (Affinity Capture-MS; 6 records), DNAJA4 (Affinity Capture-MS; 4 records), AIFM1 (Proximity Label-MS; 3 records), DNAJA2 (Affinity Capture-MS; 3 records), HSPA4 (Affinity Capture-Western; 3 records), ITLN1 (Affinity Capture-MS; 3 records), ITLN2 (Affinity Capture-MS; 3 records), TPM1 (Affinity Capture-MS; 3 records), BAG4 (Affinity Capture-MS; 2 records), CPA4 (Affinity Capture-MS; 2 records), EPHA8 (Affinity Capture-MS; 2 records), EVL (Affinity Capture-MS; 2 records), GRK6 (Affinity Capture-MS; 2 records), HSPA2 (Affinity Capture-MS; 2 records), HSPA8 (Affinity Capture-MS; 2 records)

SIGNOR signaling

3 signaling interactions:

A	Effect	B	Mechanism
ENDOG	up-regulates	BAX
BIRC2	“up-regulates activity”	ENDOG	ubiquitination
BAK1	up-regulates	ENDOG

Disease & clinical

Genetic variants

Variant evidence for ENDOG: 59 ClinVar records (0 pathogenic / likely pathogenic); 7 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	47
Likely benign	3
Benign	3

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 30 predictions of 400):

Position(s)	Effect	Δscore	Sites
9:128820737–128820738	acceptor_loss	1.0000	6
9:128820849–128820850	donor_loss	1.0000	5
9:128819186–128819187	donor_loss	0.9900	6
9:128820735	acceptor_gain	0.9600
9:128822325–128822327	acceptor_loss	0.9400	7
9:128822314	acceptor_gain	0.9300
9:128820278	donor_gain	0.9200
9:128819185	donor_loss	0.9000
9:128819296	donor_gain	0.8900
9:128819185	donor_loss	0.8700

AlphaMissense

796 missense substitutions predicted likely pathogenic (of 1,889 scored), across 190 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
H141	8	0.992	0.997
N172	8	0.982	0.996
F115	8	0.977	0.998
D118	8	0.975	0.996
D131	8	0.975	0.986
D138	8	0.970	0.980
H228	8	0.970	0.990
F159	8	0.961	0.999
N163	8	0.931	0.999
N251	8	0.925	0.998
H148	8	0.922	0.989
F278	8	0.922	0.993
D86	8	0.900	0.974
W176	7	0.995	0.999
F263	7	0.992	0.997
E180	7	0.989	0.998
F230	7	0.986	0.995
F137	7	0.972	0.991
W94	7	0.968	0.997
E97	7	0.968	0.990

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Papillary Cell Carcinoma (TCGA)	favorable	3.78e-05

Disease associations

OMIM: gene MIM:600440 | disease phenotypes:

GWAS associations

7 associations:

Study	Trait	p-value
GCST006879_19	Blood metabolite levels	4e-83
GCST006879_18	Blood metabolite levels	3e-43
GCST006879_21	Blood metabolite levels	2e-22
GCST006879_22	Blood metabolite levels	2e-20
GCST006879_2	Blood metabolite levels	2e-12
GCST006879_20	Blood metabolite levels	5e-12
GCST006879_1	Blood metabolite levels	1e-9

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3804749 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	4
Quercetin	affects cotreatment, increases expression	3
Valproic Acid	affects cotreatment, increases expression, decreases expression, increases methylation	3
Resveratrol	affects localization, decreases reaction	2
Acetylcysteine	decreases reaction, increases localization, affects cotreatment, affects localization	2
Air Pollutants	increases expression, decreases expression, increases abundance	2
Cisplatin	decreases expression, affects cotreatment, increases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
Cyclosporine	decreases expression	2
cationic amphipathic peptide RT2	increases expression	1
lupiwighteone	increases expression	1
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
danthron	increases expression, affects localization	1
naringin	increases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	increases expression	1
lead acetate	decreases expression	1
tetrandrine	decreases expression	1
perfosfamide	decreases reaction, increases localization, increases response to substance, increases expression	1
trichostatin A	increases expression	1
sulforaphane	increases expression	1
fisetin	increases localization	1
cobaltous chloride	decreases expression	1
bufalin	increases expression	1
boric acid	increases expression	1
3,3’,4,5’-tetrahydroxystilbene	affects localization, decreases reaction	1
beta-methylcholine	affects expression	1
celastrol	increases expression	1
casticin	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3807465	Binding	Activation of endonuclease G in human HL60 cells at 0.1 to 1 uM after 48 hrs by Western blot analysis	5-Ene-4-thiazolidinones induce apoptosis in mammalian leukemia cells. — *Eur J Med Chem*

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SM01	HAP1 ENDOG (-) 1	Cancer cell line	Male
CVCL_SM02	HAP1 ENDOG (-) 2	Cancer cell line	Male
CVCL_SM03	HAP1 ENDOG (-) 3	Cancer cell line	Male
CVCL_SM04	HAP1 ENDOG (-) 4	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.