INO80

Summary

INO80 (INO80 complex ATPase subunit, HGNC:26956) is a protein-coding gene on chromosome 15q15.1, encoding Chromatin-remodeling ATPase INO80 (Q9ULG1). ATPase component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and DNA repair. It is a selective cancer dependency (DepMap: 75.2% of cell lines).

This gene encodes a subunit of the chromatin remodeling complex, which is classified into subfamilies depending on sequence features apart from the conserved ATPase domain. This protein is the catalytic ATPase subunit of the INO80 chromatin remodeling complex, which is characterized by a DNA-binding domain. This protein is proposed to bind DNA and be recruited by the YY1 transcription factor to activate certain genes. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 54617 — RefSeq curated summary.

At a glance

• Gene–disease (curated): inborn error of immunity (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 22
• Clinical variants (ClinVar): 239 total — 2 likely-pathogenic
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 75.2% of screened cell lines
• MANE Select transcript: NM_017553

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26956
Approved symbol	INO80
Name	INO80 complex ATPase subunit
Location	15q15.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1259, hINO80, INO80A
Ensembl gene	ENSG00000128908
Ensembl biotype	protein_coding
OMIM	610169
Entrez	54617

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 11 retained_intron, 8 protein_coding, 4 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000557849, ENST00000558270, ENST00000558357, ENST00000559995, ENST00000560689, ENST00000560799, ENST00000561172, ENST00000561244, ENST00000648947, ENST00000696947, ENST00000696948, ENST00000696949, ENST00000696950, ENST00000696951, ENST00000696952, ENST00000696953, ENST00000696954, ENST00000865125, ENST00000933333, ENST00000933334, ENST00000933335, ENST00000933336, ENST00000933337, ENST00000970644

RefSeq mRNA: 1 — MANE Select: NM_017553 NM_017553

CCDS: CCDS10071

Canonical transcript exons

ENST00000648947 — 36 exons

Exon	Start	End
ENSE00001384493	40978880	40980440
ENSE00001595730	41081020	41081073
ENSE00001605608	41047408	41047501
ENSE00001614888	41092027	41092182
ENSE00001634351	41027596	41027736
ENSE00001639548	41085369	41085583
ENSE00001651818	41048212	41048276
ENSE00001668840	41074370	41074565
ENSE00001689527	41087562	41087682
ENSE00001702201	41049287	41049420
ENSE00001702218	41049935	41050102
ENSE00001704813	41071849	41072058
ENSE00001705869	41095601	41095668
ENSE00001726046	41058639	41058781
ENSE00001727093	41095759	41095928
ENSE00001739888	41073428	41073495
ENSE00001748356	41059867	41059926
ENSE00001754791	41044904	41045075
ENSE00001787273	41079701	41079904
ENSE00001801424	41069570	41069665
ENSE00002244371	41096168	41096353
ENSE00003467448	41005593	41005687
ENSE00003481622	41070467	41070547
ENSE00003494960	41053929	41054014
ENSE00003526678	41016088	41016215
ENSE00003541023	40985338	40985426
ENSE00003551858	40987091	40987193
ENSE00003570204	41055247	41055364
ENSE00003601266	40987816	40987974
ENSE00003604770	40997529	40997601
ENSE00003609980	40983762	40983921
ENSE00003647927	40984197	40984352
ENSE00003666418	41020900	41021125
ENSE00003678238	40982862	40983077
ENSE00003678273	41056622	41056706
ENSE00003837389	41115973	41116280

Expression profiles

Bgee: expression breadth ubiquitous, 253 present calls, max score 97.77.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.4235 / max 166.7885, expressed in 1780 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
149520	8.4655	1753
149521	2.5158	1193
149519	0.4423	253

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cardiac muscle of right atrium	UBERON:0003379	97.77	gold quality
pancreatic ductal cell	CL:0002079	97.23	gold quality
left ventricle myocardium	UBERON:0006566	96.69	gold quality
tibialis anterior	UBERON:0001385	95.91	gold quality
ileal mucosa	UBERON:0000331	94.80	gold quality
epithelial cell of pancreas	CL:0000083	93.64	silver quality
nasal cavity epithelium	UBERON:0005384	93.46	silver quality
kidney epithelium	UBERON:0004819	93.44	gold quality
sural nerve	UBERON:0015488	93.42	gold quality
upper arm skin	UBERON:0004263	92.77	gold quality
calcaneal tendon	UBERON:0003701	92.28	gold quality
gingival epithelium	UBERON:0001949	91.99	gold quality
deltoid	UBERON:0001476	91.01	silver quality
epithelium of nasopharynx	UBERON:0001951	90.94	gold quality
myocardium	UBERON:0002349	90.26	gold quality
gingiva	UBERON:0001828	90.03	gold quality
quadriceps femoris	UBERON:0001377	89.00	silver quality
gastrocnemius	UBERON:0001388	88.55	gold quality
muscle tissue	UBERON:0002385	88.52	gold quality
granulocyte	CL:0000094	88.33	gold quality
mammalian vulva	UBERON:0000997	88.27	gold quality
muscle of leg	UBERON:0001383	88.25	gold quality
skeletal muscle tissue	UBERON:0001134	88.15	gold quality
vastus lateralis	UBERON:0001379	88.15	silver quality
cerebellar vermis	UBERON:0004720	88.01	gold quality
tendon	UBERON:0000043	87.97	gold quality
superficial temporal artery	UBERON:0001614	87.55	gold quality
epithelium of mammary gland	UBERON:0003244	87.45	gold quality
mammary duct	UBERON:0001765	87.38	gold quality
cardia of stomach	UBERON:0001162	87.21	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.87

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SMARCA1, SMARCA5, STAT1, YY1

miRNA regulators (miRDB)

147 targeting INO80, 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-1252-5P	100.00	69.80	2774
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3163	100.00	77.23	8605
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-6768-5P	99.92	67.36	1942

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 75.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Identifies INOC1 gene product as a SNF2-like helicase associated with human INO80 chromatin remodeling complex (hINO80). hINO80 includes orthologs of 8 subunits of the yeast INO80 complex, as well as additional, metazoan-specific proteins. (PMID:16230350)
• report the cloning, expression, and functional activity of the domains from hINO80 gene both in terms of the DNA dependent ATPase as well as DNA binding activity (PMID:16298340)
• Methods for purification and assay of the INO80 chromatin remodeling complexes are described. (PMID:17101442)
• Binding of YY1 to its DNA sites in target genes requires INO80, suggesting that YY1 uses the INO80 complex not only to activate transcription but also to gain access to target promoters (PMID:17721549)
• Ino80 has a crucial role in stabilizing a stalled replisome to ensure proper restart of DNA replication (PMID:18376411)
• INO80 is an important new player in DNA replication to help safeguard the integrity of the genome (PMID:18388905)
• In the nucleus Uch37 is also associated with the human Ino80 chromatin-remodeling complex (hINO80). (PMID:18922472)
• hINO80 associates with spindle microtubule during mitosis, and its deficiency leads to defective microtubule assembly and abnormal chromosome segregation. (PMID:20237820)
• These results suggest that hINO80 assists double-strand break repair by positively regulating the expression of the Rad54B and XRCC3 genes. (PMID:20687897)
• Subunit organization of the human INO80 chromatin remodeling complex: an evolutionarily conserved core complex catalyzes ATP-dependent nucleosome remodeling. (PMID:21303910)
• Ino80 mediates double-strand break repair through its role in DNA end strand resection (PMID:21947284)
• These results suggest that hIno80 can play a direct role in the spindle assembly independent of its chromatin remodeling activity. (PMID:22133677)
• These results suggest that the human INO80 complex, like the yeast complex, was involved in the DNA damage tolerance pathway and that phosphorylation of human INO80 was involved in the DNA damage tolerance pathway. (PMID:22166198)
• human Inositol auxotrophy 80 (Ino80) SNF2 ATPase is subject to regulation at multiple levels in the INO80 chromatin-remodeling complex. (PMID:24297934)
• Mutations in INO80D is associated with translocation renal cell carcinoma. (PMID:24899691)
• The data indicate that under conditions of replication stress INO80 protects stalled forks from collapsing and allows their subsequent restart. (PMID:25016522)
• INO80 is stabilized and targeted to replication forks by BAP1 during normal DNA synthesis but downregulated in BAP1 defective cancer cells (PMID:25283999)
• INO80 complex negatively regulates p21 expression in a p53-mediated mechanism and is implicated in cell cycle phase G2/M arrest and abnormal chromosome stability. (PMID:26340092)
• The inositol hexaphosphate binding site is located within the C-terminal region of the Ino80 subunit. (PMID:27257055)
• The expression of Ino80, the SWI/SNF ATPase, is elevated in melanoma cells and patient melanomas compared with normal melanocytes and benign nevi. (PMID:27340176)
• Interactions of the chromatin remodeling protein INO80 with DNA, and the role of YY1 in this process have been described. (PMID:27428271)
• the existence of both INO80 and YY1 is required for recruiting the INO80/YY1 complex to BCCIP promoter region. Our findings strongly indicate that BCCIP is a potential target gene of the INO80/YY1 complex. (PMID:27535137)
• our study defines a critical role of INO80 in promoting oncogenic transcription and NSCLC tumorigenesis, and reveals a potential treatment strategy for inhibiting the cancer transcription network by targeting the INO80 chromatin remodeling complex. (PMID:27641337)
• Ino80 was upregulated in cervical cancer and promoted cell proliferation and tumorigenesis by binding to the Nanog transcription start site and enhancing its expression. (PMID:27750218)
• Overexpression of miRNA-148a and knockdown of INO80 acted synergistically to decrease the expression of stem cell marker genes as well as to attenuate stem cell-specific properties including the ability to form tumors. (PMID:27779717)
• INO80-silencing MSC cultured in osteogenic condition expressed lower mRNA levels of osteoblast-specific genes, including Runx2, Osx, Col1alpha1 and OCN. INO80 can interact with Wdr5 in MSC and positively regulates the canonical Wnt signaling transduction. (PMID:27804957)
• Our work defines SETD2 as a tumor suppressor gene in Hepatosplenic T-cell lymphoma (HSTL)and implicates genes including INO80 and PIK3CD in the disease (PMID:28122867)
• By demonstrating a key role for SUMOylation in regulating the INO80 chromatin remodeling complex, this work illustrates the power of bioinformatics analysis of large data sets in predicting novel biological phenomena. (PMID:28254775)
• Instead nucleosome sliding requires cooperativity between two INO80 complexes that monitor DNA length simultaneously on either side of the nucleosome during sliding. The C-terminal domain of the human Ino80 subunit (Ino80CTD) binds cooperatively to DNA and dimerisation of these domains provides crosstalk between complexes. (PMID:28585918)
• the INO80 complex, including Ino80 and actin-related proteins, is assembled around a single RUVBL1 (Tip49a) and RUVBL2 (Tip49b) AAA+ heterohexamer (PMID:29323271)
• Data report a single-molecule level assay for INO80, based on the relative movement of FRET labels on the nucleosome. Results found that while binding wild-type and all tailless nucleosomes with equal affinity, the bound state of INO80 in the presence of ADP is homogenous for wild-type nucleosomes and heterogeneous for all tailless nucleosomes. (PMID:29331030)
• human INO80 chromatin remodeling complex is more compositionally heterogenous at its genomic targets than anticipated. (PMID:29432129)
• LncRNA PTCSC3 was low-expressed in anaplastic thyroid cancer (ATC) tissues and cells. Over-expressed PTCSC3 inhibited the drug resistance of ATC to doxorubicin. PTCSC3 negatively regulated STAT3, and STAT3 promoted expression of INO80. PTCSC3 regulated INO80 through STAT3. PTCSC3 suppressed stem cells properties and drug resistance of ATC to doxorubicin. (PMID:29561707)
• structure of the human INO80 chromatin remodeller with a bound nucleosome, which reveals that INO80 interacts with nucleosomes in a previously undescribed manner (PMID:29643506)
• Here, the authors show that ARP8, a subunit of the INO80 chromatin remodeling complex, is phosphorylated after etoposide treatment. The etoposide-induced phosphorylation of ARP8 is regulated by ATM and ATR, and attenuates its interaction with INO80. (PMID:29759113)
• INO80 chromatin remodeler cooperates with FANCM to mediate DNA interstrand crosslink-induced checkpoint activation and repair (PMID:30606611)
• Resolution of R-loops by INO80 promotes DNA replication and maintains cancer cell proliferation and viability. (PMID:32913330)
• Linc-MYH configures INO80 to regulate muscle stem cell numbers and skeletal muscle hypertrophy. (PMID:32960481)
• CHIP and BAP1 Act in Concert to Regulate INO80 Ubiquitination and Stability for DNA Replication. (PMID:33658435)
• INO80 participates in the pathogenesis of recurrent miscarriage by epigenetically regulating trophoblast migration and invasion. (PMID:33724648)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ino80	ENSDARG00000070432
mus_musculus	Ino80	ENSMUSG00000034154
rattus_norvegicus	Ino80	ENSRNOG00000014483
drosophila_melanogaster	Ino80	FBGN0289122

Paralogs (30): HLTF (ENSG00000071794), SMARCA2 (ENSG00000080503), SRCAP (ENSG00000080603), ATRX (ENSG00000085224), RAD54L (ENSG00000085999), BTAF1 (ENSG00000095564), CHD8 (ENSG00000100888), SMARCA1 (ENSG00000102038), CHD4 (ENSG00000111642), CHD5 (ENSG00000116254), TTF2 (ENSG00000116830), HELLS (ENSG00000119969), ZRANB3 (ENSG00000121988), CHD6 (ENSG00000124177), SMARCA4 (ENSG00000127616), CHD1L (ENSG00000131778), SMARCAL1 (ENSG00000138375), SHPRH (ENSG00000146414), SMARCA5 (ENSG00000153147), CHD1 (ENSG00000153922), SMARCAD1 (ENSG00000163104), RAD54L2 (ENSG00000164080), CHD3 (ENSG00000170004), CHD7 (ENSG00000171316), CHD2 (ENSG00000173575), CHD9 (ENSG00000177200), EP400 (ENSG00000183495), ERCC6L (ENSG00000186871), RAD54B (ENSG00000197275), ERCC6 (ENSG00000225830)

Protein

Protein identifiers

Chromatin-remodeling ATPase INO80 — Q9ULG1 (reviewed: Q9ULG1)

Alternative names: DNA helicase-related INO80 complex homolog 1, DNA helicase-related protein INO80, INO80 complex subunit A

All UniProt accessions (5): Q9ULG1, A0A8V8TLQ3, H0YKH3, H0YMN5, H0YNL3

UniProt curated annotations — full annotation on UniProt →

Function. ATPase component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and DNA repair. Binds DNA. As part of the INO80 complex, remodels chromatin by shifting nucleosomes. Regulates transcription upon recruitment by YY1 to YY1-activated genes, where it acts as an essential coactivator. Involved in UV-damage excision DNA repair. The contribution to DNA double-strand break repair appears to be largely indirect through transcriptional regulation. Involved in DNA replication. Required for microtubule assembly during mitosis thereby regulating chromosome segregation cycle.

Subunit / interactions. Component of the chromatin remodeling INO80 complex; three different complex modules assemble on different domains of INO80. Interacts with DDB1. Interacts with transcriptional repressor protein YY1; the interaction recruits the INO80 complex to YY1 target genes. Interacts with YY1AP1. Interacts with tubulin alpha. (Microbial infection) Interacts with Epstein Barr virus (EBV) lytic switch protein BZLF1; this interaction participates to the activation of early lytic viral genes by BZLF1.

Subcellular location. Cytoplasm. Nucleus. Cytoskeleton. Spindle. Chromosome.

Tissue specificity. According to PubMed:10574462, widely expressed. According to PubMed:16298340, specifically expressed in brain, liver and pancreas.

Activity regulation. Activated upon binding to double stranded DNA or nucleosomes.

Domain organisation. The DBINO region is involved in binding to DNA.

Miscellaneous. Although the ATP-dependent helicase activity displayed by the INO80 complex requires INO80 ATPase activity, it is likely that the helicase function is carried out by the other components of the complex, RUVBL1 and RUVBL2, and not by INO80 itself.

Similarity. Belongs to the SNF2/RAD54 helicase family.

RefSeq proteins (1): NP_060023* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000330	SNF2_N	Domain
IPR001650	Helicase_C-like	Domain
IPR014001	Helicase_ATP-bd	Domain
IPR020838	DBINO	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR031047	DEXQc_INO80	Domain
IPR038718	SNF2-like_sf	Homologous_superfamily
IPR049730	SNF2/RAD54-like_C	Domain
IPR050520	INO80/SWR1_helicase	Family

Pfam: PF00176, PF00271, PF13892

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (24 total): region of interest 9, compositionally biased region 5, domain 3, modified residue 2, sequence variant 2, chain 1, binding site 1, mutagenesis site 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
7ZI4	ELECTRON MICROSCOPY	3.2
9GE5	ELECTRON MICROSCOPY	3.35
9GCG	ELECTRON MICROSCOPY	3.43
9GEV	ELECTRON MICROSCOPY	3.47
9GFB	ELECTRON MICROSCOPY	3.55
6HTS	ELECTRON MICROSCOPY	4.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9ULG1-F1	67.05	0.21

Functional residue map

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

Ligand- & substrate-binding residues (1): 543–550

Post-translational modifications (2): 118, 1512

Mutagenesis-validated functional residues (1):

Position	Phenotype
653	abolishes dna-dependent atpase and nucleosome remodeling activities.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-5689603	UCH proteinases
R-HSA-5696394	DNA Damage Recognition in GG-NER
R-HSA-392499	Metabolism of proteins
R-HSA-5688426	Deubiquitination
R-HSA-5696398	Nucleotide Excision Repair
R-HSA-5696399	Global Genome Nucleotide Excision Repair (GG-NER)
R-HSA-597592	Post-translational protein modification
R-HSA-73894	DNA Repair

MSigDB gene sets: 280 (showing top): RNGTGGGC_UNKNOWN, GOBP_CHROMOSOME_ORGANIZATION, GOBP_POSITIVE_REGULATION_OF_DNA_REPLICATION, GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_REGULATION_OF_DNA_TEMPLATED_DNA_REPLICATION, GOBP_CELLULAR_RESPONSE_TO_UV, GOBP_CELL_CYCLE_DNA_REPLICATION, GOBP_CELLULAR_RESPONSE_TO_LIGHT_STIMULUS, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_GROWTH, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP, GOBP_TELOMERE_ORGANIZATION, TGACCTY_ERR1_Q2, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, AATGGAG_MIR136

GO Biological Process (31): mitotic sister chromatid segregation (GO:0000070), telomere maintenance (GO:0000723), double-strand break repair via homologous recombination (GO:0000724), regulation of DNA replication (GO:0006275), DNA repair (GO:0006281), regulation of DNA repair (GO:0006282), double-strand break repair (GO:0006302), chromatin remodeling (GO:0006338), DNA-templated transcription (GO:0006351), positive regulation of nuclear cell cycle DNA replication (GO:0010571), positive regulation of cell growth (GO:0030307), regulation of chromosome organization (GO:0033044), cellular response to UV (GO:0034644), positive regulation of DNA repair (GO:0045739), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of embryonic development (GO:0045995), spindle assembly (GO:0051225), cell division (GO:0051301), regulation of cell cycle (GO:0051726), regulation of DNA strand elongation (GO:0060382), UV-damage excision repair (GO:0070914), cellular response to ionizing radiation (GO:0071479), positive regulation of telomere maintenance in response to DNA damage (GO:1904507), regulation of G1/S transition of mitotic cell cycle (GO:2000045), DNA metabolic process (GO:0006259), DNA recombination (GO:0006310), DNA damage response (GO:0006974), positive regulation of DNA metabolic process (GO:0051054), chromosome organization (GO:0051276), regulation of macromolecule metabolic process (GO:0060255)

GO Molecular Function (11): DNA binding (GO:0003677), actin binding (GO:0003779), ATP binding (GO:0005524), ATP-dependent activity, acting on DNA (GO:0008094), ATP hydrolysis activity (GO:0016887), histone binding (GO:0042393), alpha-tubulin binding (GO:0043014), ATP-dependent chromatin remodeler activity (GO:0140658), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (10): nucleus (GO:0005634), nucleoplasm (GO:0005654), spindle (GO:0005819), cytosol (GO:0005829), microtubule (GO:0005874), nuclear body (GO:0016604), Ino80 complex (GO:0031011), chromosome (GO:0005694), cytoplasm (GO:0005737), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Deubiquitination	1
Global Genome Nucleotide Excision Repair (GG-NER)	1
Post-translational protein modification	1
DNA Repair	1
Nucleotide Excision Repair	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membraneless organelle	4
DNA repair	3
cellular anatomical structure	3
DNA metabolic process	2
regulation of DNA metabolic process	2
ATP-dependent activity	2
microtubule cytoskeleton	2
sister chromatid segregation	1
mitotic nuclear division	1
mitotic cell cycle process	1
telomere organization	1
recombinational repair	1
double-strand break repair	1
DNA replication	1
DNA damage response	1
regulation of cellular response to stress	1
chromatin organization	1
gene expression	1
RNA biosynthetic process	1
nuclear DNA replication	1
regulation of nuclear cell cycle DNA replication	1
positive regulation of cell cycle process	1
positive regulation of DNA-templated DNA replication	1
regulation of cell growth	1
cell growth	1
positive regulation of growth	1
positive regulation of cellular process	1
regulation of organelle organization	1
chromosome organization	1
response to UV	1
cellular response to light stimulus	1
regulation of DNA repair	1
positive regulation of response to stimulus	1
positive regulation of DNA metabolic process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1

Protein interactions and networks

STRING

2941 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
INO80	ATP1A1	P05023	763
INO80	ATP1A2	P50993	670
INO80	ATP1A4	Q13733	670
INO80	INO80C	Q6PI98	666
INO80	K7ENP7	K7ENP7	666
INO80	NDUFS6	O75380	658
INO80	ATP1A3	P13637	651
INO80	RUVBL1	P82276	571
INO80	INO80B	Q9C086	550
INO80	ADRM1	Q16186	544
INO80	NFRKB	Q6P4R8	543
INO80	ENTPD2	Q9Y5L3	542
INO80	ACTL6A	O96019	527
INO80	ALPG	P10696	512
INO80	RUVBL2	Q9Y230	497

IntAct

105 interactions, top by confidence:

A	B	Type	Score
YY1	INO80	psi-mi:“MI:0915”(physical association)	0.900
YY1	INO80	psi-mi:“MI:0407”(direct interaction)	0.900
INO80E	YY1	psi-mi:“MI:0914”(association)	0.900
INO80	ACTR5	psi-mi:“MI:0915”(physical association)	0.880
ACTR5	INO80	psi-mi:“MI:0915”(physical association)	0.880
RUVBL1	ZNHIT1	psi-mi:“MI:0914”(association)	0.860
UCHL5	PSMD11	psi-mi:“MI:0914”(association)	0.840
UCHL5	PSMD12	psi-mi:“MI:0914”(association)	0.840
YY1	ACTL6A	psi-mi:“MI:0914”(association)	0.830
ACTL6A	YY1	psi-mi:“MI:0915”(physical association)	0.830
RUVBL2	ZNHIT1	psi-mi:“MI:0914”(association)	0.810
INO80E	TFPT	psi-mi:“MI:0914”(association)	0.790
YY1	TFPT	psi-mi:“MI:0914”(association)	0.740
INO80C	YY1	psi-mi:“MI:0914”(association)	0.740
RUVBL2	POLR3A	psi-mi:“MI:0914”(association)	0.640
RUVBL1	POLR3A	psi-mi:“MI:0914”(association)	0.640
CA10	WDHD1	psi-mi:“MI:0914”(association)	0.640
INO80E	ACTL6A	psi-mi:“MI:0914”(association)	0.640
BCL7A	ARID1A	psi-mi:“MI:0914”(association)	0.640
BCL7C	ARID1A	psi-mi:“MI:0914”(association)	0.640

BioGRID (191): BAP1 (Affinity Capture-Western), HIST2H2AC (Affinity Capture-Western), INO80 (Affinity Capture-MS), INO80 (Affinity Capture-MS), INO80 (Affinity Capture-Western), INO80 (Co-fractionation), INO80 (Co-fractionation), INO80 (Co-fractionation), INO80 (Co-fractionation), INO80 (Synthetic Growth Defect), INO80 (Affinity Capture-MS), INO80 (Affinity Capture-MS), INO80 (Affinity Capture-MS), INO80 (Affinity Capture-MS), INO80 (Affinity Capture-MS)

ESM2 similar proteins: A8WW61, A8XJZ8, A8XLS0, G5ED39, G5EE01, G5EED4, G5EG51, O01914, O04407, O13682, O17514, O61766, O94324, P24349, P33802, P34441, P34491, P34544, P52344, P91868, Q03564, Q08119, Q08964, Q10573, Q11107, Q18508, Q20497, Q20646, Q21733, Q23238, Q54IS0, Q5K6N0, Q6BER5, Q6ZPV2, Q74ZM2, Q75D88, Q8I8W7, Q8RWS4, Q8RXS6, Q95QK3

Diamond homologs: A0A0P0WGX7, A1C9W6, A1CZE5, A2BGR3, A2R9H9, A4H7G5, A4HVU6, A4IHD2, A4PBL4, A4R227, A5E0W5, A6QQR4, A6ZL17, A6ZU34, A7EQA8, A7TJI3, A7Z019, B3LN76, B4F769, B5VE38, B6EU02, C0H4W3, C7GQI8, E7F1C4, F4HW51, O13682, O14148, P0CO16, P0CO17, P0CO18, P0CO19, P32863, P34739, P36607, P38086, P41410, P43610, P46100, P51532, P53115

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
INO80	“form complex”	“INO80 complex”	binding
STUB1	“up-regulates activity”	INO80	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 87 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Global Genome Nucleotide Excision Repair (GG-NER)	11	83.8×	2e-17
DNA Damage Recognition in GG-NER	15	71.4×	1e-22
Formation of the canonical BAF (cBAF) complex	6	63.4×	2e-08
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	7	53.3×	2e-09
Nucleotide Excision Repair	11	52.3×	7e-15
Formation of the embryonic stem cell BAF (esBAF) complex	5	50.1×	1e-06
Regulation of endogenous retroelements	6	36.8×	5e-07
UCH proteinases	17	35.2×	3e-20

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of telomere maintenance in response to DNA damage	14	201.7×	4e-30
regulation of DNA strand elongation	14	189.0×	2e-29
regulation of chromosome organization	14	168.0×	3e-28
positive regulation of DNA repair	16	73.5×	1e-24
regulation of DNA replication	14	65.8×	8e-21
regulation of embryonic development	15	63.5×	5e-22
DNA recombination	14	60.5×	2e-20
regulation of G0 to G1 transition	7	60.5×	5e-10

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	2
Uncertain significance	156
Likely benign	24
Benign	14

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
183320	NM_017553.3(INO80):c.3737G>A (p.Arg1246Gln)	Likely pathogenic
183321	NM_017553.3(INO80):c.1501T>C (p.Ser501Pro)	Likely pathogenic

SpliceAI

5479 predictions. Top by Δscore:

Variant	Effect	Δscore
15:40982857:TGTAC:T	donor_loss	1.0000
15:40982858:GTACC:G	donor_loss	1.0000
15:40982859:TAC:T	donor_loss	1.0000
15:40982860:A:AG	donor_loss	1.0000
15:40982861:C:G	donor_loss	1.0000
15:40983001:T:TA	donor_gain	1.0000
15:40983073:AATTC:A	acceptor_gain	1.0000
15:40983074:ATTC:A	acceptor_gain	1.0000
15:40983075:TTC:T	acceptor_gain	1.0000
15:40983076:TC:T	acceptor_gain	1.0000
15:40983077:CC:C	acceptor_gain	1.0000
15:40983078:C:A	acceptor_loss	1.0000
15:40983078:C:CC	acceptor_gain	1.0000
15:40983087:CAAA:C	acceptor_gain	1.0000
15:40983088:A:T	acceptor_gain	1.0000
15:40983090:A:AC	acceptor_gain	1.0000
15:40983090:A:C	acceptor_gain	1.0000
15:40983096:C:CT	acceptor_gain	1.0000
15:40983096:C:T	acceptor_gain	1.0000
15:40983097:A:T	acceptor_gain	1.0000
15:40983761:CCAT:C	donor_gain	1.0000
15:40983773:T:C	donor_gain	1.0000
15:40983917:GAGAT:G	acceptor_gain	1.0000
15:40983918:AGAT:A	acceptor_gain	1.0000
15:40983919:GAT:G	acceptor_gain	1.0000
15:40983919:GATC:G	acceptor_loss	1.0000
15:40983920:AT:A	acceptor_gain	1.0000
15:40983922:C:CC	acceptor_gain	1.0000
15:40984191:CCTCA:C	donor_loss	1.0000
15:40984192:CTCAC:C	donor_loss	1.0000

AlphaMissense

10250 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:40987117:A:G	L1269P	1.000
15:40987120:A:G	L1268P	1.000
15:40987120:A:T	L1268H	1.000
15:40987123:A:G	L1267P	1.000
15:40987129:A:T	V1265D	1.000
15:40987847:C:G	R1233P	1.000
15:40987877:C:G	R1223P	1.000
15:40987881:A:C	Y1222D	1.000
15:40987889:A:T	V1219D	1.000
15:40987904:C:T	G1214E	1.000
15:40987905:C:A	G1214W	1.000
15:40987905:C:G	G1214R	1.000
15:40987905:C:T	G1214R	1.000
15:40987910:C:G	R1212P	1.000
15:40987911:G:T	R1212S	1.000
15:40987914:G:C	H1211D	1.000
15:40987916:G:T	A1210D	1.000
15:40987917:C:G	A1210P	1.000
15:40987918:C:A	R1209S	1.000
15:40987918:C:G	R1209S	1.000
15:40987919:C:A	R1209M	1.000
15:40987919:C:G	R1209T	1.000
15:40987922:T:A	D1208V	1.000
15:40987923:C:G	D1208H	1.000
15:40987928:G:T	A1206D	1.000
15:40987929:C:G	A1206P	1.000
15:40987938:C:G	D1203H	1.000
15:40987948:G:C	N1199K	1.000
15:40987948:G:T	N1199K	1.000
15:40987951:C:A	W1198C	1.000

dbSNP variants (sampled 300 via entrez): RS1000029929 (15:41094891 A>G), RS1000068856 (15:41025647 G>A), RS1000087108 (15:41047266 A>G), RS1000133827 (15:41116260 G>A,C,T), RS1000133892 (15:41070754 C>A,T), RS1000155989 (15:41091602 A>G), RS1000179286 (15:40978663 A>G), RS1000184366 (15:41100909 A>G), RS1000224240 (15:41019150 C>T), RS1000230709 (15:41112807 A>C), RS1000254530 (15:41107945 C>G,T), RS1000263018 (15:40988439 A>C,T), RS1000266997 (15:41070619 A>G), RS1000288393 (15:41065002 A>G), RS1000291155 (15:41031275 T>C)

Disease associations

OMIM: gene MIM:610169 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
inborn error of immunity	Moderate	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
immunodeficiency, common variable, 1	Disputed	AR

Mondo (2): intellectual disability (MONDO:0001071), inborn error of immunity (MONDO:0003778)

Orphanet (1): NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

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

GWAS associations

22 associations (top):

Study	Trait	p-value
GCST003372_52	Glomerular filtration rate (creatinine)	9.000000e-09
GCST003401_19	Glomerular filtration rate in non diabetics (creatinine)	3.000000e-08
GCST004133_26	Ulcerative colitis	3.000000e-07
GCST004292_55	Glomerular filtration rate (creatinine)	2.000000e-06
GCST005312_7	Menopause (age at onset)	1.000000e-10
GCST006976_139	Macular thickness	5.000000e-08
GCST007094_141	Diastolic blood pressure	2.000000e-08
GCST007096_199	Pulse pressure	8.000000e-06
GCST007099_21	Systolic blood pressure	2.000000e-10
GCST007563_20	Allergic disease (asthma, hay fever or eczema)	4.000000e-08
GCST008058_175	Estimated glomerular filtration rate	3.000000e-34
GCST008059_132	Estimated glomerular filtration rate	3.000000e-31
GCST008363_98	Offspring birth weight	3.000000e-09
GCST008745_6	Estimated glomerular filtration rate in non-diabetics	6.000000e-15
GCST008747_167	Estimated glomerular filtration rate	1.000000e-17
GCST008747_78	Estimated glomerular filtration rate	7.000000e-15
GCST010725_23	Malaria	2.000000e-06
GCST010725_38	Malaria	3.000000e-06
GCST010725_80	Malaria	7.000000e-06
GCST90000025_207	Appendicular lean mass	2.000000e-11
GCST90002403_477	Red blood cell count	6.000000e-13
GCST90020053_12	Frailty index	2.000000e-08

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0004704	age at menopause
EFO:0006336	diastolic blood pressure
EFO:0005763	pulse pressure measurement
EFO:0006335	systolic blood pressure
EFO:0004344	birth weight
EFO:0005939	parental genotype effect measurement
EFO:0004980	appendicular lean mass
EFO:0004305	erythrocyte count
EFO:0009885	frailty measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D007153	Immunologic Deficiency Syndromes	C20.673
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724657 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.82	Kd	15	nM	MOLIBRESIB
7.70	IC50	20	nM	MOLIBRESIB

PubChem BioAssay actives

2 with measured affinity, of 7 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2179225: Binding affinity against INO80 (unknown origin) assessed as apparent dissociation constant incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	kd	0.0150	uM

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
FR900359	increases phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	affects expression	1
arsenite	affects binding, decreases reaction	1
cypermethrin	decreases expression	1
coumarin	decreases phosphorylation	1
methacrylaldehyde	decreases expression, affects cotreatment	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
pinostrobin	increases phosphorylation	1
abrine	increases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	increases expression	1
Acrolein	affects cotreatment, decreases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Caffeine	decreases phosphorylation	1
Dexamethasone	affects cotreatment, decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Lead	decreases expression	1
Ozone	affects cotreatment, decreases expression	1
Quercetin	increases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Thiram	increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
Cyclosporine	increases expression	1
Copper Sulfate	increases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697612	Binding	Inhibition of INO80 (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03677557	PHASE4	UNKNOWN	Safety, Tolerability, Patient Satisfaction and Cost of 16.5% Subcutaneous Immunoglobulin (Cutaquig®) Treatment
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00001646	PHASE3	COMPLETED	Voriconazole vs. Amphotericin B in the Treatment of Invasive Aspergillosis
NCT00220766	PHASE3	COMPLETED	Rapid Infusion of Immune Globulin Intravenous (Human) In Primary Immunodeficiency Patients
NCT00468273	PHASE3	COMPLETED	A Clinical Study of Intravenous Immunoglobulin
NCT00811174	PHASE3	TERMINATED	Efficacy, Safety and Kinetics Study of Octagam 10% in Primary Immunodeficiency Diseases
NCT01012323	PHASE3	COMPLETED	A Study of NewGam, Human Immunoglobulin 10%, in Patients With Primary Immunodeficiency Diseases
NCT01313507	PHASE3	COMPLETED	High Infusion Rate Study of Immunoglobulin Intravenous (Human) 10% (NewGam)
NCT01406470	PHASE3	COMPLETED	Phase 3 Study of Immune Globulin Intravenous (Human)IVIG-SN™ in Subjects With Primary Immunodeficiency
NCT02783482	PHASE3	COMPLETED	Study of Immune Globulin Intravenous (Human) GC5107 in Subjects With Primary Humoral Immunodeficiency
NCT02810444	PHASE3	COMPLETED	Study to Investigate Efficacy, Safety and Pharmacokinetics of BT595 in Subjects With PID
NCT03961009	PHASE3	COMPLETED	Clinical Assessment of Pharmacokinetics, Efficacy, and Safety of 10% IVIg in PID Patients
NCT04842643	PHASE3	COMPLETED	An Extension Study of TAK-664 for Japanese People With Primary Immunodeficiency Disease
NCT04944979	PHASE3	ACTIVE_NOT_RECRUITING	Clinical Assessment of Pharmacokinetics, Efficacy, and Safety of 10% IVIg in Pediatric PID Patients (KIDCARES10)
NCT06089122	PHASE3	UNKNOWN	Efficacy, Safety, and Pharmacokinetics of Shu Yang IVIG
NCT06150833	PHASE3	UNKNOWN	Efficacy and Safety and Pharmacokinetics of Boya IVIG
NCT07346859	PHASE3	RECRUITING	Study of BP-SCIG 20% in Patients With Primary Immunodeficiency (PID)
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00001438	PHASE2	COMPLETED	A Pilot Study of the Combination of Retinoic Acid and Interferon-Alpha2a for the Treatment of Lymphoproliferative Disorders in Children With Immunodeficiency Syndromes
NCT00176865	PHASE2	COMPLETED	Stem Cell Transplant for Immunologic or Histiocytic Disorders
NCT00389324	PHASE2	COMPLETED	A Trial of the Pharmacokinetics, Safety, and Tolerability of Subcutaneous Gamunex® in Primary Immunodeficiency
NCT00598481	PHASE2	COMPLETED	ADA Gene Transfer Into Hematopoietic Stem/Progenitor Cells for the Treatment of ADA-SCID
NCT01856582	PHASE2	TERMINATED	CD34+ Stem Cell Infusion to Augment Graft Function
NCT06199427	PHASE2	RECRUITING	PTCy and and Ruxolitinib for GVHD Prophylaxis After HSCT With Thymoglobulin in Conditioning Regimen in Patients With Inborn Errors of Immunity
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT00001158	Not specified	COMPLETED	Studies of the Immune Response in Normal Subjects and Patients With Disorders of the Immune System
NCT00001336	Not specified	COMPLETED	In Vitro Studies of Immunological and Stem Cell Function in Peripheral Blood Mononuclear Cells in Patients
NCT00001788	Not specified	TERMINATED	Genetic Basis of Primary Immunodeficiencies
NCT00006054	Not specified	TERMINATED	Allogeneic Bone Marrow Transplantation in Patients With Primary Immunodeficiencies