ADPRS

Summary

ADPRS (ADP-ribosylserine hydrolase, HGNC:21304) is a protein-coding gene on chromosome 1p34.3, encoding ADP-ribosylhydrolase ARH3 (Q9NX46). ADP-ribosylhydrolase that preferentially hydrolyzes the scissile alpha-O-linkage attached to the anomeric C1’’ position of ADP-ribose and acts on different substrates, such as proteins ADP-ribosylated on serine and threonine, free poly(ADP-ribose) and O-acetyl-ADP-D-ribose.

This gene encodes a member of the ADP-ribosylglycohydrolase family. The encoded enzyme catalyzes the removal of ADP-ribose from ADP-ribosylated proteins. This enzyme localizes to the mitochondria, in addition to the nucleus and cytoplasm.

Source: NCBI Gene 54936 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures (Strong, GenCC)
• Clinical variants (ClinVar): 135 total — 14 pathogenic, 9 likely-pathogenic
• GTEx eGene: eQTL in 6 tissues, sQTL in 0 (q < 0.05)
• Phenotypes (HPO): 29
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.16 (unconstrained)
• MANE Select transcript: NM_017825

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21304
Approved symbol	ADPRS
Name	ADP-ribosylserine hydrolase
Location	1p34.3
Locus type	gene with protein product
Status	Approved
Aliases	ARH3, FLJ20446
Ensembl gene	ENSG00000116863
Ensembl biotype	protein_coding
OMIM	610624
Entrez	54936

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 8 protein_coding, 1 nonsense_mediated_decay

MANE Select: ENST00000373178

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

ENST00000373178, ENST00000896939, ENST00000896940, ENST00000896941, ENST00000932449, ENST00000959573, ENST00000959574, ENST00001000108, ENST00001141956

RefSeq mRNA: 1 — MANE Select: NM_017825 NM_017825

CCDS: CCDS402

Canonical transcript exons

ENST00000373178 — 6 exons

Exon	Start	End
ENSE00000766217	36091244	36091340
ENSE00000766220	36092422	36092522
ENSE00000861244	36093097	36093932
ENSE00001399758	36088892	36089115
ENSE00003398258	36091910	36092094
ENSE00003398800	36091618	36091825

Expression profiles

Bgee: expression breadth ubiquitous, 251 present calls, max score 98.22.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.9898 / max 205.5660, expressed in 1815 samples.

Highest expression (Bgee): oviduct epithelium, uterine tube, endothelial cell, gingival epithelium, esophagus squamous epithelium.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ADPRS is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 6 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

6 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Thyroid	eqtl	2.9e-03	+0.14	1:36142201:CT:C
Adipose Subcutaneous	eqtl	5.3e-03	-0.47	1:36391018:G:C
Artery Tibial	eqtl	1.4e-02	-0.40	1:36459908:A:G
Testis	eqtl	1.5e-02	+0.69	1:36018073:C:T
Colon Sigmoid	eqtl	2.2e-02	-0.43	1:36122651:C:G
Skin Sun Exposed Lower leg	eqtl	4.1e-02	-0.32	1:35874488:C:T

FANTOM5 promoters

1 alternative TSS:

Promoter ID	TPM avg	Samples expressed
2147	17.9898	1815

Top tissues by expression

showing 100 of 255 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
oviduct epithelium	UBERON:0004804	98.22	gold quality
right uterine tube	UBERON:0001302	97.79	gold quality
endothelial cell	CL:0000115	97.78	silver quality
gingival epithelium	UBERON:0001949	95.26	gold quality
esophagus squamous epithelium	UBERON:0006920	94.64	gold quality
middle temporal gyrus	UBERON:0002771	94.44	gold quality
gingiva	UBERON:0001828	93.59	gold quality
bronchial epithelial cell	CL:0002328	93.58	gold quality
bronchus	UBERON:0002185	93.19	gold quality
sperm	CL:0000019	93.05	gold quality
Brodmann (1909) area 23	UBERON:0013554	92.83	gold quality
nasal cavity epithelium	UBERON:0005384	92.64	gold quality
epithelial cell of pancreas	CL:0000083	92.48	silver quality
pancreatic ductal cell	CL:0002079	92.02	silver quality
fallopian tube	UBERON:0003889	91.88	gold quality
lower esophagus mucosa	UBERON:0035834	91.76	gold quality
right adrenal gland	UBERON:0001233	91.66	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	91.66	gold quality
right adrenal gland cortex	UBERON:0035827	91.46	gold quality
left adrenal gland	UBERON:0001234	91.38	gold quality
ventricular zone	UBERON:0003053	91.16	gold quality
apex of heart	UBERON:0002098	91.07	gold quality
left adrenal gland cortex	UBERON:0035825	91.05	gold quality
medial globus pallidus	UBERON:0002477	90.96	gold quality
adrenal cortex	UBERON:0001235	90.85	gold quality
esophagus mucosa	UBERON:0002469	90.62	gold quality
amniotic fluid	UBERON:0000173	90.45	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.30	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	90.29	gold quality
epithelium of nasopharynx	UBERON:0001951	90.16	gold quality
granulocyte	CL:0000094	90.13	gold quality
visceral pleura	UBERON:0002401	90.04	gold quality
gastrocnemius	UBERON:0001388	89.96	gold quality
tendon of biceps brachii	UBERON:0008188	89.94	silver quality
skin of leg	UBERON:0001511	89.93	gold quality
spinal cord	UBERON:0002240	89.79	gold quality
germinal epithelium of ovary	UBERON:0001304	89.72	gold quality
adrenal gland	UBERON:0002369	89.70	gold quality
ileal mucosa	UBERON:0000331	89.67	gold quality
muscle of leg	UBERON:0001383	89.63	gold quality
parietal pleura	UBERON:0002400	89.58	gold quality
globus pallidus	UBERON:0001875	89.53	gold quality
tibialis anterior	UBERON:0001385	89.11	gold quality
cartilage tissue	UBERON:0002418	88.84	gold quality
skin of abdomen	UBERON:0001416	88.78	gold quality
zone of skin	UBERON:0000014	88.77	gold quality
right testis	UBERON:0004534	88.53	gold quality
esophagus	UBERON:0001043	88.40	gold quality
left testis	UBERON:0004533	88.39	gold quality
mucosa of transverse colon	UBERON:0004991	88.38	gold quality
upper arm skin	UBERON:0004263	88.34	silver quality
nipple	UBERON:0002030	88.20	gold quality
testis	UBERON:0000473	88.13	gold quality
prefrontal cortex	UBERON:0000451	88.09	gold quality
hindlimb stylopod muscle	UBERON:0004252	87.95	gold quality
hypothalamus	UBERON:0001898	87.84	gold quality
deltoid	UBERON:0001476	87.82	silver quality
decidua	UBERON:0002450	87.82	gold quality
inferior vagus X ganglion	UBERON:0005363	87.58	gold quality
metanephros	UBERON:0000081	87.55	gold quality
kidney epithelium	UBERON:0004819	87.50	silver quality
cortical plate	UBERON:0005343	87.48	gold quality
substantia nigra	UBERON:0002038	87.40	gold quality
palpebral conjunctiva	UBERON:0001812	87.34	gold quality
right coronary artery	UBERON:0001625	87.25	gold quality
vagina	UBERON:0000996	87.24	gold quality
stromal cell of endometrium	CL:0002255	87.19	gold quality
upper lobe of left lung	UBERON:0008952	87.19	gold quality
midbrain	UBERON:0001891	87.17	gold quality
adult mammalian kidney	UBERON:0000082	87.15	gold quality
Ammon’s horn	UBERON:0001954	87.14	gold quality
endocervix	UBERON:0000458	87.05	gold quality
ganglionic eminence	UBERON:0004023	87.05	gold quality
blood	UBERON:0000178	87.04	gold quality
primary visual cortex	UBERON:0002436	87.04	gold quality
pharyngeal mucosa	UBERON:0000355	86.97	gold quality
metanephros cortex	UBERON:0010533	86.82	gold quality
amygdala	UBERON:0001876	86.64	gold quality
upper lobe of lung	UBERON:0008948	86.59	gold quality
mouth mucosa	UBERON:0003729	86.58	gold quality
spleen	UBERON:0002106	86.51	gold quality
tibia	UBERON:0000979	86.49	gold quality
caudate nucleus	UBERON:0001873	86.48	gold quality
popliteal artery	UBERON:0002250	86.40	gold quality
lymph node	UBERON:0000029	86.38	gold quality
tibial artery	UBERON:0007610	86.38	gold quality
temporal lobe	UBERON:0001871	86.34	gold quality
neocortex	UBERON:0001950	86.33	gold quality
nucleus accumbens	UBERON:0001882	86.32	gold quality
lower esophagus	UBERON:0013473	86.29	gold quality
frontal cortex	UBERON:0001870	86.27	gold quality
putamen	UBERON:0001874	86.26	gold quality
lower esophagus muscularis layer	UBERON:0035833	86.25	gold quality
ectocervix	UBERON:0012249	86.23	gold quality
Brodmann (1909) area 9	UBERON:0013540	86.21	gold quality
cerebral cortex	UBERON:0000956	86.20	gold quality
aorta	UBERON:0000947	86.17	gold quality
forebrain	UBERON:0001890	86.16	gold quality
nasal cavity mucosa	UBERON:0001826	86.11	gold quality
anterior cingulate cortex	UBERON:0009835	86.08	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.75
E-MTAB-6379	no	97.53

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Skeletal muscle	tissue	27.5	medium
Choroid plexus	tissue	26.1
Fallopian tube	tissue	24.3	medium
Vagina	tissue	21.6	medium
Skin 1	tissue	21.0	medium
Esophagus	tissue	21.0	medium
Tongue	tissue	20.3
Lymph node	tissue	20.1	medium
Adrenal gland	tissue	20.1	high
Placenta	tissue	19.5	high
Thymus	tissue	19.5
Ovary	tissue	19.4	low
Lung	tissue	19.2	medium
Tonsil	tissue	18.9	medium
Urinary bladder	tissue	18.7	high
Bone marrow	tissue	18.6	low
Caudate putamen	tissue	18.1
Frontal cortex	tissue	17.7
Locus coeruleus	tissue	17.6
Pituitary gland	tissue	17.2
Parathyroid gland	tissue	16.5	medium
Salivary gland	tissue	15.8	medium
Testis	tissue	15.7	medium
Seminal vesicle	tissue	15.4	medium
Pancreas	tissue	15.4	medium
Smooth muscle	tissue	15.3	medium
Breast	tissue	15.2	medium
Spleen	tissue	15.2	low
Nucleus accumbens	tissue	15.1
Appendix	tissue	15.1	medium
Thyroid gland	tissue	14.7	medium
Duodenum	tissue	14.7	high
Heart muscle	tissue	14.3	medium
Prostate	tissue	14.3	medium
Epididymis	tissue	14.2	medium
Hippocampus	tissue	14.1	low
Liver	tissue	14.0	medium
Kidney	tissue	14.0	medium
Cervix	tissue	13.7	medium
Colon	tissue	13.7	medium
Stomach 1	tissue	13.6	medium
Small intestine	tissue	13.5	medium
Adipose tissue	tissue	13.1	medium
Endometrium 1	tissue	12.7	medium
Gallbladder	tissue	12.5	high
Rectum	tissue	11.7	medium
Postcentral gyrus	tissue	9.9
Retina	tissue	8.4
Superior colliculi	tissue	7.8
Spinal cord	tissue	7.8
Hippocampal formation	tissue	7.8
Pons	tissue	7.3
Putamen	tissue	7.3
Thalamus	tissue	7.3
Midbrain	tissue	7.2
Cerebral cortex	tissue	7.0	medium
Medulla oblongata	tissue	7.0
Somatosensory cortex	tissue	7.0
Basal ganglia	tissue	6.9	medium
Motor cortex	tissue	6.6

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Dorsal funiculus (white matter) (26.6), Lateral funiculus (white matter) (26.4), Corpus callosum, splenium (white matter) (24.8), Corpus callosum, genu (white matter) (24.3), Parieto-temporal junction (white matter) (24.3).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting ADPRS by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

17 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-452-5P	99.65	69.63	1762
HSA-MIR-4676-3P	99.65	69.31	1733
HSA-MIR-892C-3P	99.65	69.38	1745
HSA-MIR-671-5P	99.52	67.11	1277
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-548G-3P	99.48	68.67	2159
HSA-MIR-548AS-3P	99.12	69.12	2294
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-1207-3P	98.99	66.22	1532
HSA-MIR-6754-5P	98.60	65.54	1627
HSA-MIR-6878-5P	98.49	67.91	2142
HSA-MIR-892B	98.00	67.11	821
HSA-MIR-6810-3P	97.96	64.57	1023
HSA-MIR-6736-3P	96.98	65.22	1342
HSA-MIR-6874-5P	95.73	64.94	545

Functional genomics

gnomAD constraint: pLI 3.37e-08, LOEUF 1.16, missense Z -0.295 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000373178 — one region, missense o/e 1.00.

Literature-anchored findings (GeneRIF, showing 17)

• ARH3 has poly(ADP-ribose) glycohydrolase activity but is structurally unrelated to poly(ADP-ribose) glycohydrolase (PMID:16278211)
• cloning, recombinant production, purification and crystallization of ARH3 consisting of 347 amino-acid residues (PMID:16511307)
• The molecular architecture of human ARH3 constitutes the archetype of an all-alpha-helical protein fold and suggests reversibility mechanisms of protein ADP-ribosylation. (PMID:17015823)
• poly(ADP-ribose) glycohydrolase ARH3 hydrolyzed O-acetyl-ADP-ribose to produce ADP-ribose in a time- and Mg(2+)-dependent reaction and thus could participate in two signaling pathways (PMID:17075046)
• ADP-ribosylhydrolase 3 (ARH3), not poly(ADP-ribose) glycohydrolase (PARG) isoforms, is responsible for degradation of mitochondrial matrix-associated poly(ADP-ribose). (PMID:22433848)
• By screening for the hydrolase that is responsible for the reversal of Ser-ADP ribosilation, the authors identified ARH3/ADPRHL2 as capable of efficiently and specifically removing Ser-ADP ribosilation of histones and other proteins. (PMID:28650317)
• Study results establish ARH3 as a serine mono-ADP-ribosylhydrolase and as an important regulator of the basal and stress-induced ADP-ribosylome. (PMID:29234005)
• Here, the authors show that serine ADP-ribosylation represents the major fraction of ADP-ribosylation synthesized after DNA damage in mammalian cells and that globally serine ADP-ribosylation is dependent on HPF1, PARP1 and ARH3. In the absence of HPF1, glutamate/aspartate becomes the main target residues for ADP-ribosylation. (PMID:29480802)
• study provides structural and functional insights into the molecular mechanism by which ARH3 hydrolyzes the ADP-ribosyl group from serine and contributes to DNA damage repair (PMID:30045870)
• ADPRHL2 was virtually absent in available affected individuals’ fibroblasts. (PMID:30401461)
• Study identified a family with an ARH3 gene mutation that resulted in a truncated, inactive protein. The 8-year-old proband exhibited a progressive neurodegeneration phenotype. Parthanatos was observed in neurons of the patient’s deceased sibling, and an older sibling exhibited a mild behavioral phenotype. Patient’s fibroblasts were more sensitive to H2O2 stress-induced poly(ADP-ribose) accumulation and cell death. (PMID:30830864)
• Pathogenic ARH3 mutations result in ADP-ribose chromatin scars during DNA strand break repair. (PMID:32636369)
• AI26 inhibits the ADP-ribosylhydrolase ARH3 and suppresses DNA damage repair. (PMID:32753484)
• Structural and biochemical analysis of human ADP-ribosyl-acceptor hydrolase 3 reveals the basis of metal selectivity and different roles for the two magnesium ions. (PMID:33894202)
• Unrestrained poly-ADP-ribosylation provides insights into chromatin regulation and human disease. (PMID:34019811)
• The regulatory landscape of the human HPF1- and ARH3-dependent ADP-ribosylome. (PMID:34625544)
• Delineation of ADPRHL2 Variants: Report of Two New Patients with Review of the Literature. (PMID:38365196)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	adprs	ENSDARG00000019338
mus_musculus	Adprs	ENSMUSG00000042558
rattus_norvegicus	Adprs	ENSRNOG00000010849

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:2140364) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 8 distinct phenotype terms.

Mouse phenotype (MP)	Records
increased bone mineral density	1
increased body length	1
increased circulating alkaline phosphatase level	1
increased susceptibility to ischemic brain injury	1
increased lean body mass	1
decreased total body fat amount	1
increased bone mineral content	1
abnormal susceptibility to injury induced morbidity/mortality	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	Q3SYV9	93.7%	Diamond
Gallus gallus	Q5ZI51	69.6%	Diamond
Latimeria chalumnae	H3BCW1	68.6%	Diamond
Xenopus tropicalis	Q28FQ6	56.1%	Diamond
Rhodospirillum rubrum	P14300	35.7%	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
AGO3	protein-coding	192669
AGO1	protein-coding	26523
TEKT2	protein-coding	27285
COL8A2	protein-coding	1296
TRAPPC3	protein-coding	27095
MAP7D1	protein-coding	55700
THRAP3	protein-coding	9967

Protein

Protein identifiers

ADP-ribosylhydrolase ARH3 — Q9NX46 (reviewed: Q9NX46)

Alternative names: ADP-ribose glycohydrolase ARH3, ADP-ribosylhydrolase 3, O-acetyl-ADP-ribose deacetylase ARH3, Poly(ADP-ribose) glycohydrolase ARH3, [Protein ADP-ribosylarginine] hydrolase-like protein 2, [Protein ADP-ribosylserine] hydrolase

All UniProt accessions (1): Q9NX46

UniProt curated annotations — full annotation on UniProt →

Function. ADP-ribosylhydrolase that preferentially hydrolyzes the scissile alpha-O-linkage attached to the anomeric C1’’ position of ADP-ribose and acts on different substrates, such as proteins ADP-ribosylated on serine and threonine, free poly(ADP-ribose) and O-acetyl-ADP-D-ribose. Specifically acts as a serine mono-ADP-ribosylhydrolase by mediating the removal of mono-ADP-ribose attached to serine residues on proteins, thereby playing a key role in DNA damage response. Serine ADP-ribosylation of proteins constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage. Does not hydrolyze ADP-ribosyl-arginine, -cysteine, -diphthamide, or -asparagine bonds. Also able to degrade protein free poly(ADP-ribose), which is synthesized in response to DNA damage: free poly(ADP-ribose) acts as a potent cell death signal and its degradation by ADPRHL2 protects cells from poly(ADP-ribose)-dependent cell death, a process named parthanatos. Also hydrolyzes free poly(ADP-ribose) in mitochondria. Specifically digests O-acetyl-ADP-D-ribose, a product of deacetylation reactions catalyzed by sirtuins. Specifically degrades 1’’-O-acetyl-ADP-D-ribose isomer, rather than 2’’-O-acetyl-ADP-D-ribose or 3’’-O-acetyl-ADP-D-ribose isomers.

Subunit / interactions. Monomer.

Subcellular location. Nucleus. Cytoplasm. Chromosome. Mitochondrion matrix.

Tissue specificity. Ubiquitous. Expressed in skin fibroblasts.

Disease relevance. Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures (CONDSIAS) [MIM:618170] An autosomal recessive neurodegenerative disorder characterized by pediatric onset of progressive brain atrophy, developmental regression, and seizures in association with periods of stress, such as infections. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. The protein undergoes a dramatic conformational switch from closed to open states upon substrate-binding, which enables specific substrate recognition for the 1’’-O-linkage. The glutamate flap (Glu-41) blocks substrate entrance to Mg(2+) in the unliganded closed state. In presence of substrate, Glu-41 is ejected from the active site: this closed-to-open transition significantly widens the substrate-binding channel and precisely positions the scissile 1’’-O-linkage for cleavage while securing tightly 2’- and 3’-hydroxyls of ADP-ribose.

Cofactor. Binds 2 magnesium ions per subunit.

Similarity. Belongs to the ADP-ribosylglycohydrolase family.

RefSeq proteins (1): NP_060295* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005502	Ribosyl_crysJ1	Family
IPR036705	Ribosyl_crysJ1_sf	Homologous_superfamily
IPR050792	ADP-ribosylglycohydrolase	Family

Pfam: PF03747

Enzyme classification (BRENDA)

• EC 3.2.1.143 — poly(ADP-ribose) glycohydrolase (BRENDA: 15 organisms, 83 substrates, 316 inhibitors, 21 Km, 4 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
(ADP-RIBOSE)N	0.0006–0.0066	10
POLY(ADP-RIBOSE)	0.0003–0.0111	7
(ADP-D-RIBOSE)15	0.0054–0.0058	2
ALPHA-NAD+	0.0006	1

Catalyzed reactions (Rhea)

• (1’’->2’)-ADP-alpha-D-ribose + H2O = (1’’->2’)-ADP-alpha-D-ribose + ADP-D-ribose (RHEA:52216)
• 1’’-O-acetyl-ADP-alpha-D-ribose + H2O = ADP-D-ribose + acetate + H(+) (RHEA:58112)
• O-(ADP-D-ribosyl)-L-seryl-[protein] + H2O = ADP-D-ribose + L-seryl-[protein] (RHEA:58256)
• alpha-NAD(+) + H2O = ADP-D-ribose + nicotinamide + H(+) (RHEA:68792)

UniProt features (84 total): mutagenesis site 28, helix 23, binding site 14, sequence variant 10, strand 3, turn 2, chain 1, site 1, modified residue 1, sequence conflict 1

Structure

Experimental structures (PDB)

14 structures by resolution:

PDB	Title	Method	Resolution (Å)
7ARW	Structure of human ARH3 E41A bound to alpha-NAD+ and magnesium	X-RAY DIFFRACTION	1.31
5ZQY	Crystal structure of a poly(ADP-ribose) glycohydrolase	X-RAY DIFFRACTION	1.58
2FOZ	human ADP-ribosylhydrolase 3	X-RAY DIFFRACTION	1.6
6D3A	Structure of human ARH3 D314E bound to ADP-ribose and magnesium	X-RAY DIFFRACTION	1.6
6D36	Structure of human ARH3 bound to ADP-ribose and magnesium	X-RAY DIFFRACTION	1.7
7L9F	Crystal structure of human ARH3 bound to calcium and ADP-ribose	X-RAY DIFFRACTION	1.75
7L9I	Crystal structure of human ARH3-D314A bound to magnesium and ADP-ribose	X-RAY DIFFRACTION	1.8
2G4K	Anomalous substructure of human ADP-ribosylhydrolase 3	X-RAY DIFFRACTION	1.82
7L9H	Crystal structure of human ARH3-D77A bound to magnesium and ADP-ribose	X-RAY DIFFRACTION	1.85
9RFD	Human ADP-ribosylhydrolase 3 (ARH3) in complex with ADP	X-RAY DIFFRACTION	1.85
9RFE	Human ADP-ribosylhydrolase 3 (ARH3) in complex with an inhibitor	X-RAY DIFFRACTION	1.85
7AKS	Human ADP-ribosylserine hydrolase ARH3 mutant E41A in complex with H2B-S7-mar peptide	X-RAY DIFFRACTION	1.86
7AKR	Human ADP-ribosylserine hydrolase ARH3 mutant E41A in complex with ADP-ribose dimer	X-RAY DIFFRACTION	1.95
2FP0	human ADP-ribosylhydrolase 3	X-RAY DIFFRACTION	2.05

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NX46-F1	95.70	0.95

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Predicted intracellular proteins, Disease related genes, Potential drug targets, Human disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm

Antibody reliability (HPA): IH approved · IF enhanced

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)

Position	Role
41	glutamate flap

Ligand- & substrate-binding residues (14)

Position	Role
41	Mg(2+)
271	substrate
314	Mg(2+)
316	Mg(2+)
317	Mg(2+)
76	Mg(2+)
77	Mg(2+)
77	substrate
78	Mg(2+)
146–152	substrate
182	substrate
235	substrate

Post-translational modifications (1)

Type	Positions
Phosphothreonine	64

Mutagenesis-validated functional residues (28)

Position	Phenotype
34	reduces hydrolase activity.
41	significant loss of activity. does not affect recruitment to dna lesion regions following dna damage. strongly reduced ability to hydrolyze …
76	abolishes hydrolase activity.
77–78	retains ability to bind proteins adp-ribosylated on serine but is unable to hydrolyze them.
77–78	complete loss of activity.
77	complete loss of activity. abolishes mg(2+) binding. retains ability to bind adp-ribose. does not affect recruitment to dna lesion regions …
78	abolishes hydrolase activity.
78	complete loss of activity.
115	abolished ability to bind and hydrolyze proteins adp-ribosylated on serine. no effect on hydrolase activity.
143	abolishes hydrolase activity.
148	complete loss of activity. abolished recruitment to dna lesion regions following dna damage. abolished ability to hydrolyze proteins …
149	significant loss of activity. abolished recruitment to dna lesion regions following dna damage. abolished ability to hydrolyze proteins …
149	no effect on hydrolase activity.
150	reduces hydrolase activity.
151	partial loss of activity.
182	complete loss of activity. abolished recruitment to dna lesion regions following dna damage. abolished ability to hydrolyze proteins …
185	no effect on hydrolase activity.
186	no effect on hydrolase activity.
238–239	slight reduction in activity toward poly(adp-ribose). does not affect ability to degrade o-acetyl-adp-d-ribose.
261–262	slight reduction in activity toward poly(adp-ribose). does not affect ability to degrade o-acetyl-adp-d-ribose.
269	no effect on hydrolase activity.
270	no effect on hydrolase activity.
271	no effect on hydrolase activity.
314	complete loss of activity. abolishes mg(2+) and adp-ribose binding. does not affect recruitment to dna lesion regions following dna damage …
314	significant loss of activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 5; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

5 pathways:

ID	Pathway	Evidence
R-HSA-110362	POLB-Dependent Long Patch Base Excision Repair	curated
R-HSA-73884	Base Excision Repair	—
R-HSA-73894	DNA Repair	—
R-HSA-110373	Resolution of AP sites via the multiple-nucleotide patch replacement pathway	—
R-HSA-73933	Resolution of Abasic Sites (AP sites)	—

MSigDB gene sets: 157 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, chr1p34, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_DNA_DAMAGE_RESPONSE, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, GCM_NF2, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_RADICAL, REACTOME_DNA_REPAIR, GOBP_RESPONSE_TO_OXYGEN_RADICAL, GOBP_CELLULAR_RESPONSE_TO_REACTIVE_OXYGEN_SPECIES, GOBP_RESPONSE_TO_REACTIVE_OXYGEN_SPECIES, GOCC_MITOCHONDRIAL_MATRIX, GOBP_DNA_METABOLIC_PROCESS, GOMF_MAGNESIUM_ION_BINDING

GO Biological Process (6): DNA repair (GO:0006281), base-excision repair, gap-filling (GO:0006287), negative regulation of necroptotic process (GO:0060546), cellular response to superoxide (GO:0071451), peptidyl-serine ADP-deribosylation (GO:0140290), DNA damage response (GO:0006974)

GO Molecular Function (8): magnesium ion binding (GO:0000287), hydrolase activity, hydrolyzing O-glycosyl compounds (GO:0004553), poly(ADP-ribose) glycohydrolase activity (GO:0004649), O-acetyl-ADP-ribose deacetylase activity (GO:0061463), ADP-ribosylserine-[protein] hydrolase activity (GO:0140292), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), site of DNA damage (GO:0090734), chromosome (GO:0005694)

Reactome top-level categories

4 top-level categories:

Category	Pathways
Resolution of AP sites via the multiple-nucleotide patch replacement pathway	1
Resolution of Abasic Sites (AP sites)	1
DNA Repair	1
Base Excision Repair	1

GO top-level categories

29 GO namespaces:

Category	Terms
cellular anatomical structure	3
DNA metabolic process	2
intracellular membrane-bounded organelle	2
DNA damage response	1
base-excision repair	1
regulation of necroptotic process	1
negative regulation of programmed necrotic cell death	1
necroptotic process	1
response to superoxide	1
cellular response to oxygen radical	1
protein de-ADP-ribosylation	1
cellular response to stress	1
metal ion binding	1
hydrolase activity, acting on glycosyl bonds	1
hydrolase activity, hydrolyzing O-glycosyl compounds	1
deacetylase activity	1
carboxylic ester hydrolase activity	1
hydrolase activity, hydrolyzing N-glycosyl compounds	1
catalytic activity, acting on a protein	1
binding	1
catalytic activity	1
cation binding	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
mitochondrion	1
intracellular organelle lumen	1
chromosome	1
intracellular membraneless organelle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 13 of 21 annotations. The rest are phylogenetic / computational / electronic (IEA).

13 experimentally-supported GO terms:

GO term	NS	Evidence
DNA repair	BP	mutant phenotype
cellular response to superoxide	BP	mutant phenotype
peptidyl-serine ADP-deribosylation	BP	direct assay
cytoplasm	CC	direct assay
mitochondrion	CC	direct assay
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
site of DNA damage	CC	direct assay
ADP-ribosylserine-[protein] hydrolase activity	MF	direct assay
O-acetyl-ADP-ribose deacetylase activity	MF	direct assay
hydrolase activity, hydrolyzing O-glycosyl compounds	MF	direct assay
magnesium ion binding	MF	direct assay
poly(ADP-ribose) glycohydrolase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 526 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADPRS	PARG	Q86W56	880
ADPRS	PARP1	P09874	853
ADPRS	MACROD1	Q9BQ69	807
ADPRS	MACROD2	A1Z1Q3	767
ADPRS	OARD1	Q9Y530	751
ADPRS	HPF1	Q9NWY4	718
ADPRS	PARP2	Q9UGN5	676
ADPRS	NUDT16	Q96DE0	646
ADPRS	PARP10	Q53GL7	620
ADPRS	ADPRH	P54922	605
ADPRS	TRPT1	Q86TN4	589
ADPRS	PARP15	Q460N3	585
ADPRS	PARP3	Q9Y6F1	573
ADPRS	ZC3HAV1	Q7Z2W4	555
ADPRS	NUDT5	Q9UKK9	539

IntAct

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

6 partners by confidence:

Partner	Interaction type	MIscore	Records
PRDM5	physical association	0.560	3
TNKS	physical association	0.560	3
ISG15	physical association	0.400	1
HSPB1	physical association	0.370	1
FRA10AC1	physical association	0.000	1
HEXD	physical association	0.000	1

Disease & clinical

Genetic variants

Variant evidence for ADPRS: 135 ClinVar records (23 pathogenic / likely pathogenic). Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	9
Uncertain significance	77
Likely benign	22
Benign	2

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 23 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
590301	NM_017825.3(ADPRS):c.414_418del (p.Ala139fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
590302	NM_017825.3(ADPRS):c.530C>T (p.Ser177Leu)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	5
1339799	NM_017825.3(ADPRS):c.340_341del (p.Arg114fs)	Pathogenic	criteria provided, single submitter	2
852549	NM_017825.3(ADPRS):c.416_426del (p.Ala139fs)	Pathogenic	criteria provided, single submitter	1
2572385	NM_017825.3(ADPRS):c.146del (p.Thr49fs)	Pathogenic	criteria provided, single submitter	1
4819230	NM_017825.3(ADPRS):c.640C>T (p.Gln214Ter)	Pathogenic	criteria provided, single submitter	1
4819231	NM_017825.3(ADPRS):c.726C>A (p.Tyr242Ter)	Pathogenic	criteria provided, single submitter	1
4850194	NM_017825.3(ADPRS):c.429dup (p.Asn144Ter)	Pathogenic	criteria provided, single submitter	1
4854590	NM_017825.3(ADPRS):c.545_546del (p.His182fs)	Pathogenic	criteria provided, single submitter	1
4855864	NM_017825.3(ADPRS):c.580C>T (p.Gln194Ter)	Pathogenic	criteria provided, single submitter	1
599344	NM_017825.3(ADPRS):c.292del (p.Val98fs)	Likely pathogenic	criteria provided, single submitter	2
801466	NM_017825.3(ADPRS):c.485T>C (p.Leu162Pro)	Likely pathogenic	criteria provided, single submitter	1
804377	NM_017825.3(ADPRS):c.169_170del (p.Leu58fs)	Likely pathogenic	criteria provided, single submitter	1
1679337	NM_017825.3(ADPRS):c.564C>A (p.Tyr188Ter)	Likely pathogenic	criteria provided, single submitter	1
2583170	NM_017825.3(ADPRS):c.166C>T (p.Gln56Ter)	Likely pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore ADPRS’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 31 predictions of 557):

Position(s)	Effect	Δscore	Sites
1:36091242–36091243	acceptor_loss	1.0000	6
1:36091608	acceptor_gain	1.0000
1:36091616–36091617	acceptor_loss	1.0000	5
1:36091745	donor_gain	1.0000
1:36091823	donor_gain	1.0000
1:36091826–36091827	donor_loss	1.0000	5
1:36091908–36091909	acceptor_loss	1.0000	5
1:36091951	acceptor_gain	1.0000
1:36092095–36092096	donor_loss	1.0000	5
1:36092414	acceptor_gain	1.0000

AlphaMissense

834 missense substitutions predicted likely pathogenic (of 2,355 scored), across 220 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
M155	9	0.965	0.994
M321	9	0.925	0.991
D77	8	0.997	0.999
D78	8	0.997	0.999
D314	8	0.997	0.999
D316	8	0.997	0.999
D34	8	0.993	0.998
H182	8	0.991	0.998
N151	8	0.989	0.999
F124	8	0.931	0.990
F104	8	0.928	0.993
F284	8	0.878	0.991
D99	8	0.809	0.882
F143	7	0.990	0.999
R114	7	0.966	0.996
E41	7	0.958	0.989
W339	7	0.956	0.997
M81	7	0.952	0.989
F95	7	0.928	0.978
C343	7	0.917	0.988

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
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	9.01e-09

Disease associations

OMIM: gene MIM:610624 | disease phenotypes: MIM:618170

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures	Strong	Autosomal recessive	3

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (12 panels, 6 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

12 panels:

Panel	Rating
Ataxia and cerebellar anomalies - childhood onset	green
DDG2P	green
Early onset or syndromic epilepsy	green
Hereditary ataxia and cerebellar anomalies, childhood onset	green
Hereditary neuropathy or pain disorder	green
Unexplained death in infancy and sudden unexplained death in childhood	green
Adult-onset neurological disorders	amber
Hereditary ataxia, adult onset	amber
Hypotonic infant	amber
Intellectual disability	amber
Leukodystrophy, childhood onset	amber
Paediatric disorders	amber

Mondo (1): neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures (MONDO:0100095)

Orphanet (1): Childhood-onset stress-induced neurodegenerative ataxia-seizure syndrome (Orphanet:694922)

HPO phenotypes

29 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000407	Sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000602	Ophthalmoplegia
HP:0000639	Nystagmus
HP:0000651	Diplopia
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001308	Tongue fasciculations
HP:0001310	Dysmetria
HP:0001324	Muscle weakness
HP:0001761	Pes cavus
HP:0002059	Cerebral atrophy
HP:0002069	Bilateral tonic-clonic seizure
HP:0002080	Intention tremor
HP:0002093	Respiratory insufficiency
HP:0002121	Generalized non-motor (absence) seizure
HP:0002376	Developmental regression
HP:0002465	Poor speech
HP:0003447	Axonal loss
HP:0003487	Babinski sign
HP:0006855	Cerebellar vermis atrophy
HP:0011463	Childhood onset
HP:0031165	Multifocal seizures

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295963 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 52 human assays (52 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
1-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-N-(1-methylcyclopropyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxobenzimidazole-5-sulfonamide	IC50	76700 nM	US-10995073: PARG inhibitory compounds

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Leflunomide	decreases expression	2
Cyclosporine	decreases expression, increases expression	2
Cadmium Chloride	decreases expression, increases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
bisphenol A	decreases expression	1
sodium arsenite	increases expression	1
cylindrospermopsin	increases expression	1
2-palmitoylglycerol	increases expression	1
abrine	increases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	decreases expression	1
jinfukang	increases expression	1
bisphenol AF	increases expression	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
Sunitinib	increases expression	1
Adenosine Diphosphate Ribose	decreases reaction, increases hydrolysis	1
Air Pollutants	decreases expression, increases abundance	1
Benzene	increases expression	1
Benzo(a)pyrene	increases methylation	1
Estradiol	affects expression	1
Lead	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1
Asbestos, Crocidolite	increases expression	1
Copper Sulfate	decreases expression	1
O-Acetyl-ADP-Ribose	decreases reaction, increases hydrolysis	1
Particulate Matter	increases abundance, decreases expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4265327	Binding	Inhibition of human full length C-terminus His-tagged ARH3 expressed in Escherichia coli using Bt-NAD ribosylated PARP1 substrate after 30 mins by TR-FRET assay	Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. — *J Med Chem*

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7JP	Ubigene A-549 ADPRS KO	Cancer cell line	Male
CVCL_D8GW	Ubigene HCC1806 ADPRS KO	Cancer cell line	Female
CVCL_E1PL	HAP1 ADPRHL2 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for ADPRS across ~30M SureChEMBL compounds — explore on Sugi Predict.