OARD1

Summary

OARD1 (O-acyl-ADP-ribose deacylase 1, HGNC:21257) is a protein-coding gene on chromosome 6p21.1, encoding ADP-ribose glycohydrolase OARD1 (Q9Y530). ADP-ribose glycohydrolase that hydrolyzes ADP-ribose and acts on different substrates, such as proteins ADP-ribosylated on glutamate and O-acetyl-ADP-D-ribose.

The protein encoded by this gene is a deacylase that can convert O-acetyl-ADP-ribose to ADP-ribose and acetate, O-propionyl-ADP-ribose to ADP-ribose and propionate, and O-butyryl-ADP-ribose to ADP-ribose and butyrate. The ADP-ribose product is able to inhibit these reactions through a competitive feedback loop.

Source: NCBI Gene 221443 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 34 total
• Druggable target: yes
• MANE Select transcript: NM_001329686

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21257
Approved symbol	OARD1
Name	O-acyl-ADP-ribose deacylase 1
Location	6p21.1
Locus type	gene with protein product
Status	Approved
Aliases	MGC19570, dJ34B21.3, TARG1
Ensembl gene	ENSG00000124596
Ensembl biotype	protein_coding
OMIM	614393
Entrez	221443

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 14 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000373154, ENST00000424266, ENST00000463088, ENST00000464633, ENST00000465893, ENST00000467234, ENST00000468811, ENST00000469104, ENST00000471367, ENST00000479950, ENST00000480585, ENST00000482515, ENST00000482853, ENST00000486443, ENST00000488238, ENST00000628419, ENST00000903172

RefSeq mRNA: 13 — MANE Select: NM_001329686 NM_001329684, NM_001329685, NM_001329686, NM_001329688, NM_001329689, NM_001329690, NM_001329691, NM_001329692, NM_001329693, NM_001329694, NM_001329695, NM_001329696, NM_145063

CCDS: CCDS34445, CCDS87395, CCDS87396, CCDS87397

Canonical transcript exons

ENST00000424266 — 6 exons

Exon	Start	End
ENSE00001504677	41068841	41068953
ENSE00001916087	41072236	41072356
ENSE00001927993	41064772	41067437
ENSE00003639139	41071596	41071675
ENSE00003655766	41071132	41071276
ENSE00003678313	41070076	41070134

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 97.58.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.7287 / max 393.6424, expressed in 1800 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
73519	9.3837	1746
73520	3.4619	1444
73521	1.1982	719
73518	0.9309	575
73517	0.3882	201
73516	0.3658	173

Top tissues by expression

293 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	97.58	gold quality
sperm	CL:0000019	96.53	gold quality
right testis	UBERON:0004534	96.08	gold quality
left testis	UBERON:0004533	95.88	gold quality
body of pancreas	UBERON:0001150	95.31	gold quality
testis	UBERON:0000473	95.30	gold quality
esophagus squamous epithelium	UBERON:0006920	94.97	gold quality
ventricular zone	UBERON:0003053	94.28	gold quality
buccal mucosa cell	CL:0002336	94.03	gold quality
ganglionic eminence	UBERON:0004023	93.97	gold quality
male germ cell	CL:0000015	93.83	gold quality
metanephros cortex	UBERON:0010533	93.73	gold quality
secondary oocyte	CL:0000655	93.44	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	93.28	gold quality
oocyte	CL:0000023	93.17	gold quality
right lobe of liver	UBERON:0001114	93.00	gold quality
palpebral conjunctiva	UBERON:0001812	92.73	gold quality
body of stomach	UBERON:0001161	92.70	gold quality
pancreas	UBERON:0001264	92.70	gold quality
rectum	UBERON:0001052	92.57	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	92.06	gold quality
calcaneal tendon	UBERON:0003701	91.86	gold quality
right adrenal gland	UBERON:0001233	91.72	gold quality
embryo	UBERON:0000922	91.55	gold quality
right adrenal gland cortex	UBERON:0035827	91.40	gold quality
islet of Langerhans	UBERON:0000006	91.39	gold quality
right uterine tube	UBERON:0001302	91.26	gold quality
epithelium of esophagus	UBERON:0001976	91.11	gold quality
left ovary	UBERON:0002119	90.97	gold quality
left adrenal gland	UBERON:0001234	90.84	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.11
E-CURD-135	no	695.46
E-MTAB-6142	no	206.86

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

17 targeting OARD1, 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-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-4502	99.65	66.99	1021
HSA-MIR-122B-3P	99.21	68.90	1333
HSA-MIR-21-3P	99.21	68.95	1312
HSA-MIR-5001-3P	98.91	67.28	1394
HSA-MIR-3668	98.52	68.76	951
HSA-MIR-4768-3P	98.16	66.02	2330
HSA-MIR-197-3P	98.09	69.23	1004

Literature-anchored findings (GeneRIF, showing 5)

• Orphan macrodomain protein (human C6orf130) is an O-acyl-ADP-ribose deacylase: solution structure and catalytic properties. (PMID:21849506)
• C6orf130 enzymatic activity has a role in the turnover and recycling of protein ADP-ribosylation in neurodegenerative disease. (PMID:23481255)
• Studies indicate that poly (ADP-ribose) glycohydrolase (PARG) and terminal ADP-ribose glycohydrolase 1 (TARG1) are key enzymes in poly(ADP-ribose) polymerases (PARPs)-mediated ADP-ribosylation. (PMID:26091342)
• Comparative analysis of MACROD1, MACROD2 and TARG1 expression, localisation and interactome. (PMID:32427867)
• TARG1 protects against toxic DNA ADP-ribosylation. (PMID:34508355)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	oard1	ENSDARG00000057426
mus_musculus	Oard1	ENSMUSG00000040771
rattus_norvegicus	Oard1	ENSRNOG00000012679
drosophila_melanogaster	Targ1	FBGN0053054
drosophila_melanogaster	Targ2	FBGN0053056
drosophila_melanogaster	Targ3	FBGN0085290

Protein

Protein identifiers

ADP-ribose glycohydrolase OARD1 — Q9Y530 (reviewed: Q9Y530)

Alternative names: O-acetyl-ADP-ribose deacetylase 1, Terminal ADP-ribose protein glycohydrolase 1, [Protein ADP-ribosylglutamate] hydrolase OARD1

All UniProt accessions (7): C9IZY1, C9J5P1, C9JA90, C9JNE2, C9JXC3, Q9Y530, H7C5Q1

UniProt curated annotations — full annotation on UniProt →

Function. ADP-ribose glycohydrolase that hydrolyzes ADP-ribose and acts on different substrates, such as proteins ADP-ribosylated on glutamate and O-acetyl-ADP-D-ribose. Specifically acts as a glutamate mono-ADP-ribosylhydrolase by mediating the removal of mono-ADP-ribose attached to glutamate residues on proteins. Does not act on poly-ADP-ribosylated proteins: the poly-ADP-ribose chain of poly-ADP-ribosylated glutamate residues must by hydrolyzed into mono-ADP-ribosylated glutamate by PARG to become a substrate for OARD1. Deacetylates O-acetyl-ADP ribose, a signaling molecule generated by the deacetylation of acetylated lysine residues in histones and other proteins. Catalyzes the deacylation of O-acetyl-ADP-ribose, O-propionyl-ADP-ribose and O-butyryl-ADP-ribose, yielding ADP-ribose plus acetate, propionate and butyrate, respectively.

Subcellular location. Nucleus. Nucleoplasm. Nucleolus. Chromosome.

Tissue specificity. Ubiquitous.

Disease relevance. Defects in OARD1 are found in patients with severe neurodegeneration. Defects were found in an extended consanguineous family with several affected cases in two generations.

Activity regulation. Subject to competitive inhibition by the product ADP-ribose.

RefSeq proteins (13): NP_001316613, NP_001316614, NP_001316615, NP_001316617, NP_001316618, NP_001316619, NP_001316620, NP_001316621, NP_001316622, NP_001316623, NP_001316624, NP_001316625, NP_659500 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002589	Macro_dom	Domain
IPR043472	Macro_dom-like	Homologous_superfamily
IPR050892	ADP-ribose_metab_enzymes	Family

Pfam: PF01661

Catalyzed reactions (Rhea), 3 shown:

• 2’’-O-acetyl-ADP-D-ribose + H2O = ADP-D-ribose + acetate + H(+) (RHEA:57060)
• 5-O-(ADP-D-ribosyl)-L-glutamyl-[protein] + H2O = L-glutamyl-[protein] + ADP-D-ribose + H(+) (RHEA:58248)
• alpha-NAD(+) + H2O = ADP-D-ribose + nicotinamide + H(+) (RHEA:68792)

UniProt features (31 total): mutagenesis site 7, strand 7, helix 6, binding site 3, active site 2, modified residue 2, initiator methionine 1, chain 1, sequence variant 1, domain 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
4J5R	X-RAY DIFFRACTION	1.25
4J5Q	X-RAY DIFFRACTION	1.35
4J5S	X-RAY DIFFRACTION	1.55
2EEE	SOLUTION NMR
2L8R	SOLUTION NMR
2LGR	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y530-F1	93.87	0.91

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): 84 (nucleophile); 125 (proton acceptor)

Ligand- & substrate-binding residues (3): 21; 119–125; 152

Post-translational modifications (2): 2, 4

Mutagenesis-validated functional residues (7):

Position	Phenotype
32	abolishes enzyme activity.
33	no effect.
35	reduced catalytic activity. no effect on affinity towards substrate.
83	reduced catalytic activity. no effect on affinity towards substrate.
84	abolishes enzyme activity and ability to form a stable covalent adduct with the adp-ribosylated substrate.
123	abolishes enzyme activity.
125	abolishes enzyme activity without affecting ability to form a stable covalent adduct with the adp-ribosylated substrate.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 177 (showing top): MYAATNNNNNNNGGC_UNKNOWN, TGCGCANK_UNKNOWN, RORA1_01, CMYB_01, MORF_ATRX, TGACCTY_ERR1_Q2, LHX3_01, FOXO1_01, GGCNKCCATNK_UNKNOWN, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, MCAATNNNNNGCG_UNKNOWN, GATA3_01, MORF_PPP5C, MORF_FANCG

GO Biological Process (4): DNA damage response (GO:0006974), purine nucleoside metabolic process (GO:0042278), protein de-ADP-ribosylation (GO:0051725), peptidyl-glutamate ADP-deribosylation (GO:0140291)

GO Molecular Function (6): purine nucleoside binding (GO:0001883), obsolete ADP-ribosyl-[dinitrogen reductase] hydrolase activity (GO:0047407), O-acetyl-ADP-ribose deacetylase activity (GO:0061463), ADP-ribosylglutamate-[protein] hydrolase activity (GO:0140293), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (5): nucleoplasm (GO:0005654), nucleolus (GO:0005730), site of DNA damage (GO:0090734), nucleus (GO:0005634), chromosome (GO:0005694)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nuclear lumen	2
cellular anatomical structure	2
intracellular membraneless organelle	2
cellular response to stress	1
nucleoside metabolic process	1
purine-containing compound metabolic process	1
protein modification process	1
protein de-ADP-ribosylation	1
nucleoside binding	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
chromosome	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

408 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
OARD1	MACROD1	Q9BQ69	847
OARD1	MACROD2	A1Z1Q3	811
OARD1	PARG	Q86W56	777
OARD1	ADPRS	Q9NX46	773
OARD1	PARP10	Q53GL7	608
OARD1	PARP15	Q460N3	601
OARD1	GDAP2	Q9NXN4	597
OARD1	XRCC1	P18887	573
OARD1	PARP14	Q460N5	544
OARD1	NUDT16	Q96DE0	544
OARD1	PARP9	Q8IXQ6	516
OARD1	PARP16	Q8N5Y8	495
OARD1	PARP2	Q9UGN5	489
OARD1	CHD1L	Q86WJ1	480
OARD1	PARP12	Q9H0J9	476

IntAct

21 interactions, top by confidence:

A	B	Type	Score
PARP1	OARD1	psi-mi:“MI:0414”(enzymatic reaction)	0.600
OARD1	PARP1	psi-mi:“MI:0414”(enzymatic reaction)	0.600
OARD1	PARP1	psi-mi:“MI:0915”(physical association)	0.600
PARP1	OARD1	psi-mi:“MI:0915”(physical association)	0.600
TNKS	OARD1	psi-mi:“MI:0915”(physical association)	0.560
PICK1	OARD1	psi-mi:“MI:0915”(physical association)	0.560
	OARD1	psi-mi:“MI:0915”(physical association)	0.560
OARD1	PARP10	psi-mi:“MI:0414”(enzymatic reaction)	0.440
PARP10	OARD1	psi-mi:“MI:0414”(enzymatic reaction)	0.440
OARD1	dacD	psi-mi:“MI:0915”(physical association)	0.370
INSR	BLTP3B	psi-mi:“MI:0914”(association)	0.350
OARD1	TNKS	psi-mi:“MI:0915”(physical association)	0.000
OARD1	PICK1	psi-mi:“MI:0915”(physical association)	0.000
OARD1		psi-mi:“MI:0915”(physical association)	0.000

BioGRID (24): OXSR1 (Co-fractionation), OARD1 (Affinity Capture-MS), OARD1 (Affinity Capture-MS), OARD1 (Affinity Capture-MS), OARD1 (Affinity Capture-MS), OARD1 (Affinity Capture-MS), OARD1 (Affinity Capture-MS), OARD1 (Two-hybrid), OARD1 (Two-hybrid), TNKS (Two-hybrid), OARD1 (Proximity Label-MS), OARD1 (Proximity Label-MS), OARD1 (Proximity Label-MS), OARD1 (Proximity Label-MS), OARD1 (Affinity Capture-RNA)

ESM2 similar proteins: A0A314KSQ4, A2RU49, D3ZLY0, O08848, O80526, P11172, P13439, P31754, P42700, Q0V8R7, Q1LZ74, Q28DB5, Q28DS0, Q2KIX2, Q3U2J5, Q498R1, Q4JIJ2, Q4R678, Q4V9J0, Q5IH14, Q5R514, Q5R962, Q5RF32, Q5XGM5, Q66H63, Q68FT5, Q6DJF8, Q6GM82, Q6GQ33, Q6IQS6, Q6NYU2, Q7SXM0, Q7TNK6, Q7Z4G4, Q80SY6, Q80YV4, Q8BGT5, Q8C1A3, Q8JGT5, Q8R5F3

Diamond homologs: Q1LZ74, Q8R5F3, Q91G65, Q9Y530

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	22
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3469 predictions. Top by Δscore:

Variant	Effect	Δscore
6:41039158:TTA:T	donor_loss	1.0000
6:41039159:TA:T	donor_loss	1.0000
6:41039160:A:AC	donor_gain	1.0000
6:41039160:A:T	donor_loss	1.0000
6:41039160:AC:A	donor_gain	1.0000
6:41039161:C:CA	donor_gain	1.0000
6:41039161:CC:C	donor_gain	1.0000
6:41039161:CCG:C	donor_gain	1.0000
6:41039161:CCGT:C	donor_gain	1.0000
6:41053475:CAGG:C	donor_gain	1.0000
6:41053476:AGG:A	donor_gain	1.0000
6:41053477:GG:G	donor_gain	1.0000
6:41053477:GGG:G	donor_gain	1.0000
6:41053478:GG:G	donor_gain	1.0000
6:41053479:G:GC	donor_loss	1.0000
6:41053479:G:GG	donor_gain	1.0000
6:41053480:T:A	donor_loss	1.0000
6:41061318:T:A	acceptor_gain	1.0000
6:41061326:A:AG	acceptor_gain	1.0000
6:41061327:G:GG	acceptor_gain	1.0000
6:41061327:GA:G	acceptor_gain	1.0000
6:41061865:G:GT	donor_gain	1.0000
6:41061868:G:GG	donor_gain	1.0000
6:41061893:G:GG	donor_gain	1.0000
6:41064099:A:G	acceptor_gain	1.0000
6:41071124:AAACT:A	donor_loss	1.0000
6:41071125:AACT:A	donor_loss	1.0000
6:41071126:ACTCA:A	donor_loss	1.0000
6:41071127:CT:C	donor_loss	1.0000
6:41071128:T:TC	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000074411 (6:41089112 T>C), RS1000128522 (6:41096700 G>A,T), RS1000191526 (6:41064989 C>T), RS1000201091 (6:41094838 T>C), RS1000225000 (6:41086060 A>C,G), RS1000247557 (6:41093466 CCTTT>C), RS1000353546 (6:41075797 C>T), RS1000511812 (6:41086398 T>A), RS1000597301 (6:41064361 G>T), RS1000653778 (6:41070328 A>C), RS1000686367 (6:41077323 A>C,G), RS1000717191 (6:41077010 G>A,C), RS1000768007 (6:41071007 G>A), RS1000834089 (6:41074450 C>A,T), RS1000928374 (6:41064573 G>A)

Disease associations

OMIM: gene MIM:614393 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST004610_19	White blood cell count	2.000000e-10
GCST007511_10	Alzheimer’s disease (late onset)	2.000000e-13
GCST010988_362	Adult body size	7.000000e-09
GCST90002397_131	Mean spheric corpuscular volume	2.000000e-13

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:1001870	late-onset Alzheimers disease

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295991 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	decreases expression, affects expression, increases abundance	3
Smoke	decreases expression, increases abundance	2
Valproic Acid	affects expression, decreases expression	2
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
cobaltous chloride	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
Resveratrol	increases expression, affects cotreatment	1
Acetaminophen	decreases expression	1
Coumestrol	increases expression	1
Dexamethasone	decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Ozone	affects expression, increases abundance	1
Plant Extracts	affects cotreatment, increases expression	1
Potassium Dichromate	increases expression	1
Quercetin	decreases expression	1
Rotenone	decreases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	decreases methylation	1
Okadaic Acid	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118614	Binding	Binding affinity to OARD1 in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg 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_E2FF	HAP1 OARD1 (-) 1	Cancer cell line	Male
CVCL_E2FG	HAP1 OARD1 (-) 2	Cancer cell line	Male
CVCL_E2FH	HAP1 OARD1 (-) 3	Cancer cell line	Male
CVCL_E2FI	HAP1 OARD1 (-) 4	Cancer cell line	Male

Clinical trials (associated diseases)

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