{"gene":"INO80C","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2018,"finding":"Cryo-EM structure of the evolutionarily conserved INO80 core complex from Chaetomium thermophilum bound to a nucleosome at 4.3 Å (major parts at 3.7 Å) revealed that Arp5 and Ies6 (INO80C) bind superhelical locations -2 and -3 to act as a counter grip for the ATPase motor on the opposite side of the H2A-H2B dimer. The Arp5 insertion domain forms a grappler element that contacts the nucleosome dyad and packs against histone H2A-H2B near the acidic patch, while the ATPase motor pumps entry DNA into the nucleosome against this Arp5-Ies6 grip.","method":"Cryo-EM structure determination; biochemical assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structure with biochemical validation, replicated by parallel human INO80 structure in the same issue","pmids":["29643509"],"is_preprint":false},{"year":2018,"finding":"Cryo-EM structure of the human INO80 complex bound to a nucleosome showed that the ARP5-IES6 (INO80C) module makes contacts on the opposite face of the nucleosome from the motor domains, and that histone H3 tails (rather than H4 tails as in other remodelers) regulate INO80 motor domain activity in a manner dependent on this ARP5-IES6 arrangement.","method":"Cryo-EM structure determination; biochemical regulation assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structure with biochemical validation, independently corroborated by parallel fungal INO80 structure","pmids":["29643506"],"is_preprint":false},{"year":2011,"finding":"The human INO80 complex is organized into three modules assembling on distinct domains of hIno80 ATPase. The third module, comprising the hIno80 Snf2 ATPase domain, Ies2, Ies6 (INO80C), Tip49a, Tip49b, and Arp5, is part of the evolutionarily conserved core required for ATP-dependent nucleosome remodeling activity.","method":"Subcomplex purification; biochemical reconstitution; ATPase and nucleosome remodeling assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution and biochemical characterization of subunit modules with nucleosome remodeling assays, single lab with multiple orthogonal methods","pmids":["21303910"],"is_preprint":false},{"year":2013,"finding":"In the human INO80 complex, Ies6 (INO80C) and Arp5 function together to promote binding of the Ino80 ATPase to nucleosomes, whereas Ies2 functions as a potent activator of the intrinsic ATPase catalytic activity. Ies6 and Arp5 thus regulate substrate recognition rather than intrinsic catalysis.","method":"Biochemical reconstitution; ATPase assays; nucleosome-binding assays with purified subcomplexes","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with ATPase and nucleosome-binding assays distinguishing roles of individual subunits, single lab with multiple orthogonal methods","pmids":["24297934"],"is_preprint":false},{"year":2015,"finding":"The Ies6/Arp5 module is essential for INO80 complex chromatin remodeling activity in vitro, and controls conformational changes that couple nucleosome binding to remodeling. By contrast, the Arp8/Arp4/Act1 module enhances nucleosome-binding affinity but is largely dispensable for remodeling. EM class averages and mass spectrometry positioned these modules within the overall architecture.","method":"Electron microscopy; mass spectrometry; biochemical remodeling assays with defined subunit deletions","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — EM structural data combined with biochemical remodeling assays and mass spectrometry, multiple orthogonal methods in one study","pmids":["25964121"],"is_preprint":false},{"year":2016,"finding":"Arp5 and Ies6 (INO80C) form an abundant and distinct subcomplex in vivo in yeast, stimulate INO80-mediated ATP hydrolysis and nucleosome sliding in vitro, and their genomic occupancy correlates with nucleosome positioning at transcriptional start sites and expression levels of >1,000 INO80-regulated genes enriched in energy metabolism pathways. Loss of ies6 leads to decreased glycolytic gene expression and elevated mitochondrial potential.","method":"Co-immunoprecipitation; in vitro ATPase and nucleosome sliding assays; genomic ChIP-seq; gene expression analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, in vitro biochemical assays, and genome-wide ChIP in the same study","pmids":["26755556"],"is_preprint":false},{"year":2015,"finding":"Assembly of the Arp5-Ies6 module with the INO80 complex requires distinct conserved domains within Arp5, Ies6, and the Ino80 spacer region. Ies2 is required for Arp5-Ies6 association with the catalytic components; loss of IES2 or INO80 abolishes Arp5-Ies6 chromatin association. A mutant Arp5 lacking its insertion domains can stimulate ATPase activity but not nucleosome sliding, indicating the insertion domain couples hydrolysis to translocation.","method":"Domain deletion mutagenesis; Co-immunoprecipitation; chromatin immunoprecipitation; in vitro ATPase and nucleosome sliding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis combined with Co-IP, ChIP, and in vitro biochemical assays in a single study","pmids":["26306040"],"is_preprint":false},{"year":2016,"finding":"Using a recombinant minimal human INO80 core complex, Arp5/Ies6 and Ies2 were shown to regulate nucleosome sliding synergistically and antagonistically. Inositol hexaphosphate (IP6) is a non-competitive inhibitor that blocks the stimulatory effect of nucleosomes on ATPase activity, with its binding site in the C-terminal region of Ino80. An Arp5 bypass mutation restores activity in the absence of Ies2, revealing coupling between Ies2 and Arp5/Ies6 in controlling ATP hydrolysis-to-sliding coupling.","method":"Recombinant protein reconstitution; ATPase assays; nucleosome sliding assays; inhibitor studies; mutagenesis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted recombinant complex with biochemical assays and mutagenesis, multiple orthogonal methods","pmids":["27257055"],"is_preprint":false},{"year":2012,"finding":"Loss of the Ies6 subunit (INO80C) in budding yeast phenocopies loss of the Ino80 catalytic subunit, causing rapid polyploidy, defective chromosome segregation, and altered pericentric chromatin structure due to misincorporation of H2A.Z into pericentric nucleosomes. Ies6 is thus critical for INO80 function in preventing H2A.Z misincorporation at centromeres.","method":"Genetic deletion; flow cytometry (ploidy measurement); chromatin immunoprecipitation; live-cell imaging of chromosome segregation","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO with multiple defined phenotypic readouts and ChIP mechanistic follow-up in a single study","pmids":["23207916"],"is_preprint":false},{"year":2009,"finding":"In fission yeast, deletion of ies6 causes defects in DNA damage repair, response to replication stress, and nucleotide metabolism, phenocopying deletion of other INO80 complex subunits. The Ino80 complex from fission yeast containing Ies6 mediates ATP-dependent nucleosome remodeling in vitro.","method":"Genetic deletion; DNA damage sensitivity assays; in vitro nucleosome remodeling assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined phenotypes and in vitro biochemical assay, single lab","pmids":["19933844"],"is_preprint":false},{"year":2018,"finding":"In yeast, the Ies6 subunit module displays a divergent genetic interaction signature that links the INO80 complex to metabolic homeostasis. ies6 mutants show disrupted mitochondrial maintenance, and INO80 (including its Ies6 module) is needed for TORC1-mediated signaling to chromatin, as ino80 mutants exhibit defective transcriptional profiles and altered histone acetylation of TORC1-responsive genes.","method":"Genetic interaction screen; gene expression analysis; histone modification assays","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic genetic screen with chromatin and transcriptional follow-up, single lab","pmids":["29462149"],"is_preprint":false},{"year":2022,"finding":"ACTR5 (Arp5) and its interacting partner IES6 (INO80C) show a distinct, HCC-specific functional signature compared to other INO80 complex members in CRISPR tiling scans, suggesting an INO80-independent mechanism of ACTR5/IES6 in supporting hepatocellular carcinoma cell proliferation. Suppression of ACTR5 activated CDKN2A and ablated CDK/E2F-driven cell cycle signaling.","method":"CRISPR interference screen; CRISPR gene tiling scans; gene expression analysis; xenograft tumor assays","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR functional screen with mechanistic follow-up, single lab, multiple orthogonal approaches","pmids":["36563143"],"is_preprint":false},{"year":2017,"finding":"INO80 complex function in homologous recombination includes at least two distinct steps: DNA end resection and presynaptic filament formation. The second function is linked to H2A.Z: in the absence of H2A.Z, presynaptic filament formation and HR are restored in INO80-C-deficient yeast mutants, indicating that INO80-C facilitates HR by removing H2A.Z to promote filament formation.","method":"Genetic epistasis (double mutant analysis); fluorescence microscopy of repair intermediates; HR frequency assays in yeast","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with defined molecular phenotype, single lab","pmids":["28514650"],"is_preprint":false},{"year":2016,"finding":"In budding yeast, the INO80 complex cooperates with Mec1 (ATR) and PAF1C to remove RNAPII from transcribed genes near early-firing replication origins upon replication stress (hydroxyurea). This removal is required for efficient replication fork restart; failure to evict RNAPII in ino80 mutants correlates with inability to restart stalled forks.","method":"Genetic epistasis; ChIP; proteomic analyses; replication fork restart assays","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and proteomic analyses with ChIP and functional replication assays, single lab","pmids":["26798134"],"is_preprint":false},{"year":2020,"finding":"INO80 complex co-localizes with the origin recognition complex (ORC) at yeast replication origins and replication initiation sites in mouse ESCs, preventing pervasive transcription through origin sequences. Genetic studies show that INO80C and Mot1/NC2 function through distinct pathways to limit origin transcription; absence of INO80C leads to formation of new DNA double-strand breaks at origins.","method":"ChIP-seq; nascent transcript sequencing; genetic epistasis; DSB detection assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq, nascent RNA sequencing, and genetic analysis in the same study","pmids":["32905765"],"is_preprint":false},{"year":2021,"finding":"During DNA damage in yeast, INO80C-dependent recruitment of five ubiquitin-conjugating factors (Rad6, Bre1, Pep5, Ufd4, and Rsp5) contributes to core and linker histone depletion at damaged chromatin, reducing chromatin compaction and enhancing DNA locus mobility and strand invasion kinetics during homology-driven repair.","method":"Chromatin-associated proteomics; genetic epistasis; live-cell imaging; strand invasion assays","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics plus genetic and imaging approaches in a single study, single lab","pmids":["33529595"],"is_preprint":false},{"year":2023,"finding":"Abasic sites and UV-irradiation damage abolish the DNA translocation activity of INO80-C by compromising ATP hydrolysis within the Ino80 catalytic subunit, while nucleosome binding remains unaffected. INO80-C also facilitates cleavage of abasic (AP) sites by AP-endonuclease 1 (APE1) independently of its DNA translocation activity.","method":"In vitro DNA translocation assays; ATPase assays with damaged substrates; AP site cleavage assay; nucleosome binding assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro biochemical assays with multiple damage types, but single lab and no mutagenesis to confirm active site","pmids":["37696438"],"is_preprint":false},{"year":2024,"finding":"Loss of cytoplasmic actin filaments (via TORC2 inhibition or Las17 degradation) raises nuclear actin levels, which in complex with Arp4 is an essential subunit of INO80C. Genetic ablation of INO80C activity leads to partial resistance to yeast chromosome shattering (YCS), suggesting that elevated nuclear G-actin stimulates INO80C to increase DNA polymerase processivity and thereby converts single-strand lesions into double-strand breaks.","method":"Phosphoproteomics; auxin-induced protein degradation; genetic ablation; nuclear actin quantification","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic ablation with defined phenotypic readout and phosphoproteomics, single lab","pmids":["39548059"],"is_preprint":false},{"year":2026,"finding":"Deletion of IES6 in yeast reduces genome-wide nucleosome spacing by 3 bp and disrupts regular nucleosome arrays across most genes. IES6 deletion is synthetically lethal with deletion of ISW2 (an ISWI-family remodeler), indicating functional redundancy in nucleosome organization. INO80 binding directly predicts the role of Ies6 in nucleosome organization, whereas gene expression changes do not correlate with altered spacing.","method":"Genome-wide nucleosome mapping (MNase-seq); genetic epistasis (synthetic lethality); ChIP-seq","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide nucleosome mapping and genetic epistasis in the same study, single lab","pmids":["41720950"],"is_preprint":false},{"year":2018,"finding":"In the human INO80 complex, biochemical approaches indicated that INO80-C and the H3K27 acetyltransferase P300 physically interact, suggesting they may jointly coordinate chromatin accessibility at canonical INO80 target sites.","method":"Co-immunoprecipitation; ChIP-seq for INO80 subunits","journal":"G3 (Bethesda, Md.)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP result, single lab, no functional validation","pmids":["29432129"],"is_preprint":false}],"current_model":"INO80C (IES6/hIes6) is a conserved subunit of the INO80 ATP-dependent chromatin remodeling complex that, together with Arp5, forms a distinct Arp5-Ies6 module that binds the nucleosome on the opposite face from the ATPase motor (at superhelical locations -2/-3), acts as a counter grip to couple ATP hydrolysis to productive nucleosome sliding and H2A.Z exchange, is required for genome-wide nucleosome spacing and organization, and supports INO80 complex functions in DNA repair, replication origin protection, prevention of H2A.Z misincorporation at centromeres, and metabolic gene regulation."},"narrative":{"mechanistic_narrative":"INO80C (Ies6/hIes6) is a conserved core subunit of the INO80 ATP-dependent chromatin-remodeling complex that, together with Arp5, forms a structural module governing how the complex engages and remodels nucleosomes [PMID:29643509, PMID:21303910]. Cryo-EM of fungal and human INO80 bound to a nucleosome places the Arp5-Ies6 module at superhelical locations -2/-3 on the face opposite the Snf2 ATPase motor, where it acts as a counter grip against which the motor pumps entry DNA into the nucleosome [PMID:29643509, PMID:29643506]. Functionally, Arp5/Ies6 promotes binding of the Ino80 ATPase to nucleosomes and couples ATP hydrolysis to productive translocation, while the partner subunit Ies2 activates intrinsic catalysis; an Arp5 insertion domain is specifically required to convert hydrolysis into nucleosome sliding [PMID:24297934, PMID:26306040, PMID:27257055]. Through these activities INO80C is essential for genome-wide nucleosome spacing and regular array organization, acting redundantly with the ISWI remodeler Isw2 [PMID:41720950]. The module supports the complex's broader genome-maintenance roles: it removes/prevents H2A.Z misincorporation at pericentric chromatin to ensure proper chromosome segregation [PMID:23207916], promotes homologous recombination by H2A.Z-dependent presynaptic filament formation and by recruiting ubiquitin-conjugating factors that deplete histones at damage [PMID:28514650, PMID:33529595], protects replication origins by limiting pervasive transcription and enabling fork restart under replication stress [PMID:26798134, PMID:32905765], and regulates metabolic gene expression and mitochondrial homeostasis [PMID:26755556, PMID:29462149]. ACTR5/IES6 additionally support hepatocellular carcinoma proliferation through CDK/E2F-driven cell-cycle signaling [PMID:36563143].","teleology":[{"year":2009,"claim":"Establishing that Ies6 is a functional INO80 subunit required showing its loss phenocopies other complex members; deletion in fission yeast produced DNA repair, replication-stress, and nucleotide-metabolism defects and the Ies6-containing complex remodeled nucleosomes in vitro.","evidence":"Genetic deletion with damage-sensitivity assays and in vitro remodeling in S. pombe","pmids":["19933844"],"confidence":"Medium","gaps":["Did not resolve Ies6's specific molecular contribution within the complex","No structural placement of the subunit"]},{"year":2011,"claim":"Module organization of human INO80 was defined, assigning Ies6 to the conserved catalytic core module built on the Snf2 ATPase domain alongside Arp5, Tip49a/b, and Ies2.","evidence":"Subcomplex purification and reconstitution with ATPase and remodeling assays","pmids":["21303910"],"confidence":"High","gaps":["Did not separate Ies6's role from Arp5 within the module","No structural detail of nucleosome contacts"]},{"year":2012,"claim":"Loss-of-function showed Ies6 is critical for preventing H2A.Z misincorporation at centromeres, linking the subunit to faithful chromosome segregation.","evidence":"Genetic deletion, flow-cytometry ploidy, ChIP, and live-cell segregation imaging in budding yeast","pmids":["23207916"],"confidence":"High","gaps":["Mechanism of H2A.Z eviction specificity not resolved","Did not address pericentric remodeling biochemistry"]},{"year":2013,"claim":"Dissecting subunit roles revealed Ies6 and Arp5 govern substrate recognition (nucleosome binding by the ATPase) while Ies2 drives intrinsic catalysis, separating substrate engagement from hydrolysis.","evidence":"Biochemical reconstitution with ATPase and nucleosome-binding assays using purified subcomplexes","pmids":["24297934"],"confidence":"High","gaps":["How binding is coupled to remodeling output not yet shown","No structural basis for the binding contribution"]},{"year":2015,"claim":"Two studies established that the Ies6/Arp5 module is essential for remodeling and that the Arp5 insertion domain couples ATP hydrolysis to translocation, defining where coupling is encoded.","evidence":"EM/MS architecture plus domain-deletion mutagenesis with Co-IP, ChIP, and ATPase/sliding assays","pmids":["25964121","26306040"],"confidence":"High","gaps":["Atomic-resolution view of the coupling mechanism still lacking","Assembly determinants in Ino80 spacer only partially mapped"]},{"year":2016,"claim":"In vivo and recombinant work showed Arp5-Ies6 forms a distinct subcomplex that stimulates ATP hydrolysis and sliding, with Ies2 acting synergistically/antagonistically and IP6 inhibiting hydrolysis, while genomic occupancy linked the module to TSS nucleosome positioning and metabolic gene expression.","evidence":"Co-IP, recombinant minimal complex biochemistry, inhibitor and mutagenesis studies, ChIP-seq, and expression analysis","pmids":["26755556","27257055"],"confidence":"High","gaps":["Direct causal link between spacing and the metabolic transcriptional program not established","Physiological role of IP6 regulation unclear"]},{"year":2017,"claim":"Genetic epistasis assigned INO80-C a discrete HR step: it facilitates presynaptic filament formation by removing H2A.Z, since H2A.Z loss rescues HR in INO80-C-deficient mutants.","evidence":"Double-mutant analysis, microscopy of repair intermediates, and HR frequency assays in yeast","pmids":["28514650"],"confidence":"Medium","gaps":["Ies6-specific contribution within INO80-C not isolated","Biochemical reconstitution of the filament-promoting step absent"]},{"year":2018,"claim":"Parallel cryo-EM structures of fungal and human INO80-nucleosome complexes provided the atomic framework, placing Arp5-Ies6 as a counter grip at SHL -2/-3 opposite the motor and revealing H3-tail-dependent regulation of the motor through this arrangement.","evidence":"High-resolution cryo-EM with biochemical regulation assays of C. thermophilum and human INO80","pmids":["29643509","29643506"],"confidence":"High","gaps":["Dynamic conformational cycle during translocation not fully captured","Ies6 fold and contacts resolved only at module resolution"]},{"year":2018,"claim":"Genetic-interaction and signaling studies tied the Ies6 module to metabolic homeostasis, mitochondrial maintenance, and TORC1-to-chromatin signaling, broadening INO80C's physiological role beyond remodeling biochemistry.","evidence":"Genetic interaction screen with expression and histone-modification analyses in yeast","pmids":["29462149"],"confidence":"Medium","gaps":["Direct chromatin target of TORC1-INO80 signaling not pinpointed","Mechanism connecting mitochondrial state to Ies6 unresolved"]},{"year":2018,"claim":"A candidate physical link between human INO80-C and the acetyltransferase P300 raised the possibility of coordinated chromatin-accessibility control at INO80 targets.","evidence":"Co-IP and INO80-subunit ChIP-seq","pmids":["29432129"],"confidence":"Low","gaps":["Single Co-IP without reciprocal validation or functional follow-up","Direct Ies6 involvement in the interaction not demonstrated"]},{"year":2021,"claim":"INO80C was shown to drive histone depletion at damaged chromatin by recruiting ubiquitin-conjugating factors, mechanistically connecting remodeling to chromatin decompaction and enhanced repair-locus mobility.","evidence":"Chromatin-associated proteomics, genetic epistasis, live-cell imaging, and strand-invasion assays","pmids":["33529595"],"confidence":"Medium","gaps":["How INO80C recruits the ubiquitin factors not defined","Ies6-specific requirement not separated from whole-complex activity"]},{"year":2022,"claim":"CRISPR tiling revealed an ACTR5/IES6 functional signature distinct from other INO80 members in hepatocellular carcinoma, suggesting a partly INO80-independent role in supporting CDK/E2F-driven proliferation.","evidence":"CRISPR interference and tiling screens with expression analysis and xenograft assays","pmids":["36563143"],"confidence":"Medium","gaps":["Molecular basis of the proposed INO80-independent activity unknown","Direct IES6 effector for CDKN2A/E2F control not identified"]},{"year":2023,"claim":"Damaged-DNA biochemistry showed INO80-C translocation is abolished by abasic and UV lesions via impaired Ino80 ATP hydrolysis, while INO80-C separately stimulates APE1 cleavage of AP sites independently of translocation.","evidence":"In vitro DNA translocation, ATPase on damaged substrates, AP-site cleavage, and nucleosome-binding assays","pmids":["37696438"],"confidence":"Medium","gaps":["No mutagenesis confirming the active-site basis of lesion sensing","Ies6-specific contribution within the complex not tested"]},{"year":2024,"claim":"Nuclear actin levels, set by cytoplasmic actin dynamics, were shown to stimulate INO80C activity, with INO80C ablation conferring partial resistance to chromosome shattering by limiting conversion of single-strand lesions to DSBs.","evidence":"Phosphoproteomics, auxin-induced degradation, genetic ablation, and nuclear actin quantification in yeast","pmids":["39548059"],"confidence":"Medium","gaps":["Direct biochemical link between G-actin levels and Ies6 module activity not reconstituted","How remodeling increases polymerase processivity unclear"]},{"year":2026,"claim":"Genome-wide mapping established that Ies6 is required for proper nucleosome spacing and array regularity, acting redundantly with the ISWI remodeler Isw2, and that this organizing role is predicted by INO80 binding rather than by transcriptional output.","evidence":"MNase-seq nucleosome mapping, synthetic-lethality genetics, and ChIP-seq in yeast","pmids":["41720950"],"confidence":"Medium","gaps":["Mechanism of redundancy with Isw2 not defined","Decoupling of spacing from expression not mechanistically explained"]},{"year":null,"claim":"Whether the candidate INO80C-independent and human-specific roles (e.g., P300 interaction, ACTR5/IES6 in cancer proliferation) reflect distinct molecular activities of Ies6 separate from its structural counter-grip function within INO80 remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No reconstituted INO80-independent activity demonstrated","Human-specific effector pathways for IES6 not mapped","Ies6 isolated contribution distinct from Arp5 not established in vivo"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[3,7,16]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,6,7]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,5]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,14,17]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[8,18]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,2,5,18]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[9,12,15,16]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[13,14]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[8,11]}],"complexes":["INO80 chromatin remodeling complex","Arp5-Ies6 module"],"partners":["ACTR5","INO80","IES2","RUVBL1","RUVBL2","ARP4","EP300"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6PI98","full_name":"INO80 complex subunit C","aliases":["IES6 homolog","hIes6"],"length_aa":192,"mass_kda":20.6,"function":"Proposed core component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and probably DNA repair","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q6PI98/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/INO80C","classification":"Not Classified","n_dependent_lines":52,"n_total_lines":1208,"dependency_fraction":0.04304635761589404},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ACTR5","stoichiometry":10.0},{"gene":"YY1","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/search/INO80C","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli fibrillar center","reliability":"Additional"},{"location":"Vesicles","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/INO80C"},"hgnc":{"alias_symbol":["FLJ38183","hIes6","IES6"],"prev_symbol":["C18orf37"]},"alphafold":{"accession":"Q6PI98","domains":[{"cath_id":"-","chopping":"140-192","consensus_level":"medium","plddt":92.1292,"start":140,"end":192}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6PI98","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6PI98-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6PI98-F1-predicted_aligned_error_v6.png","plddt_mean":69.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=INO80C","jax_strain_url":"https://www.jax.org/strain/search?query=INO80C"},"sequence":{"accession":"Q6PI98","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6PI98.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6PI98/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6PI98"}},"corpus_meta":[{"pmid":"29643509","id":"PMC_29643509","title":"Structural 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The Arp5 insertion domain forms a grappler element that contacts the nucleosome dyad and packs against histone H2A-H2B near the acidic patch, while the ATPase motor pumps entry DNA into the nucleosome against this Arp5-Ies6 grip.\",\n      \"method\": \"Cryo-EM structure determination; biochemical assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structure with biochemical validation, replicated by parallel human INO80 structure in the same issue\",\n      \"pmids\": [\"29643509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cryo-EM structure of the human INO80 complex bound to a nucleosome showed that the ARP5-IES6 (INO80C) module makes contacts on the opposite face of the nucleosome from the motor domains, and that histone H3 tails (rather than H4 tails as in other remodelers) regulate INO80 motor domain activity in a manner dependent on this ARP5-IES6 arrangement.\",\n      \"method\": \"Cryo-EM structure determination; biochemical regulation assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structure with biochemical validation, independently corroborated by parallel fungal INO80 structure\",\n      \"pmids\": [\"29643506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The human INO80 complex is organized into three modules assembling on distinct domains of hIno80 ATPase. The third module, comprising the hIno80 Snf2 ATPase domain, Ies2, Ies6 (INO80C), Tip49a, Tip49b, and Arp5, is part of the evolutionarily conserved core required for ATP-dependent nucleosome remodeling activity.\",\n      \"method\": \"Subcomplex purification; biochemical reconstitution; ATPase and nucleosome remodeling assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution and biochemical characterization of subunit modules with nucleosome remodeling assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"21303910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In the human INO80 complex, Ies6 (INO80C) and Arp5 function together to promote binding of the Ino80 ATPase to nucleosomes, whereas Ies2 functions as a potent activator of the intrinsic ATPase catalytic activity. Ies6 and Arp5 thus regulate substrate recognition rather than intrinsic catalysis.\",\n      \"method\": \"Biochemical reconstitution; ATPase assays; nucleosome-binding assays with purified subcomplexes\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with ATPase and nucleosome-binding assays distinguishing roles of individual subunits, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24297934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The Ies6/Arp5 module is essential for INO80 complex chromatin remodeling activity in vitro, and controls conformational changes that couple nucleosome binding to remodeling. By contrast, the Arp8/Arp4/Act1 module enhances nucleosome-binding affinity but is largely dispensable for remodeling. EM class averages and mass spectrometry positioned these modules within the overall architecture.\",\n      \"method\": \"Electron microscopy; mass spectrometry; biochemical remodeling assays with defined subunit deletions\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — EM structural data combined with biochemical remodeling assays and mass spectrometry, multiple orthogonal methods in one study\",\n      \"pmids\": [\"25964121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Arp5 and Ies6 (INO80C) form an abundant and distinct subcomplex in vivo in yeast, stimulate INO80-mediated ATP hydrolysis and nucleosome sliding in vitro, and their genomic occupancy correlates with nucleosome positioning at transcriptional start sites and expression levels of >1,000 INO80-regulated genes enriched in energy metabolism pathways. Loss of ies6 leads to decreased glycolytic gene expression and elevated mitochondrial potential.\",\n      \"method\": \"Co-immunoprecipitation; in vitro ATPase and nucleosome sliding assays; genomic ChIP-seq; gene expression analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, in vitro biochemical assays, and genome-wide ChIP in the same study\",\n      \"pmids\": [\"26755556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Assembly of the Arp5-Ies6 module with the INO80 complex requires distinct conserved domains within Arp5, Ies6, and the Ino80 spacer region. Ies2 is required for Arp5-Ies6 association with the catalytic components; loss of IES2 or INO80 abolishes Arp5-Ies6 chromatin association. A mutant Arp5 lacking its insertion domains can stimulate ATPase activity but not nucleosome sliding, indicating the insertion domain couples hydrolysis to translocation.\",\n      \"method\": \"Domain deletion mutagenesis; Co-immunoprecipitation; chromatin immunoprecipitation; in vitro ATPase and nucleosome sliding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis combined with Co-IP, ChIP, and in vitro biochemical assays in a single study\",\n      \"pmids\": [\"26306040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Using a recombinant minimal human INO80 core complex, Arp5/Ies6 and Ies2 were shown to regulate nucleosome sliding synergistically and antagonistically. Inositol hexaphosphate (IP6) is a non-competitive inhibitor that blocks the stimulatory effect of nucleosomes on ATPase activity, with its binding site in the C-terminal region of Ino80. An Arp5 bypass mutation restores activity in the absence of Ies2, revealing coupling between Ies2 and Arp5/Ies6 in controlling ATP hydrolysis-to-sliding coupling.\",\n      \"method\": \"Recombinant protein reconstitution; ATPase assays; nucleosome sliding assays; inhibitor studies; mutagenesis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted recombinant complex with biochemical assays and mutagenesis, multiple orthogonal methods\",\n      \"pmids\": [\"27257055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Loss of the Ies6 subunit (INO80C) in budding yeast phenocopies loss of the Ino80 catalytic subunit, causing rapid polyploidy, defective chromosome segregation, and altered pericentric chromatin structure due to misincorporation of H2A.Z into pericentric nucleosomes. Ies6 is thus critical for INO80 function in preventing H2A.Z misincorporation at centromeres.\",\n      \"method\": \"Genetic deletion; flow cytometry (ploidy measurement); chromatin immunoprecipitation; live-cell imaging of chromosome segregation\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with multiple defined phenotypic readouts and ChIP mechanistic follow-up in a single study\",\n      \"pmids\": [\"23207916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In fission yeast, deletion of ies6 causes defects in DNA damage repair, response to replication stress, and nucleotide metabolism, phenocopying deletion of other INO80 complex subunits. The Ino80 complex from fission yeast containing Ies6 mediates ATP-dependent nucleosome remodeling in vitro.\",\n      \"method\": \"Genetic deletion; DNA damage sensitivity assays; in vitro nucleosome remodeling assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined phenotypes and in vitro biochemical assay, single lab\",\n      \"pmids\": [\"19933844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In yeast, the Ies6 subunit module displays a divergent genetic interaction signature that links the INO80 complex to metabolic homeostasis. ies6 mutants show disrupted mitochondrial maintenance, and INO80 (including its Ies6 module) is needed for TORC1-mediated signaling to chromatin, as ino80 mutants exhibit defective transcriptional profiles and altered histone acetylation of TORC1-responsive genes.\",\n      \"method\": \"Genetic interaction screen; gene expression analysis; histone modification assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic genetic screen with chromatin and transcriptional follow-up, single lab\",\n      \"pmids\": [\"29462149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ACTR5 (Arp5) and its interacting partner IES6 (INO80C) show a distinct, HCC-specific functional signature compared to other INO80 complex members in CRISPR tiling scans, suggesting an INO80-independent mechanism of ACTR5/IES6 in supporting hepatocellular carcinoma cell proliferation. Suppression of ACTR5 activated CDKN2A and ablated CDK/E2F-driven cell cycle signaling.\",\n      \"method\": \"CRISPR interference screen; CRISPR gene tiling scans; gene expression analysis; xenograft tumor assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR functional screen with mechanistic follow-up, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"36563143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"INO80 complex function in homologous recombination includes at least two distinct steps: DNA end resection and presynaptic filament formation. The second function is linked to H2A.Z: in the absence of H2A.Z, presynaptic filament formation and HR are restored in INO80-C-deficient yeast mutants, indicating that INO80-C facilitates HR by removing H2A.Z to promote filament formation.\",\n      \"method\": \"Genetic epistasis (double mutant analysis); fluorescence microscopy of repair intermediates; HR frequency assays in yeast\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with defined molecular phenotype, single lab\",\n      \"pmids\": [\"28514650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In budding yeast, the INO80 complex cooperates with Mec1 (ATR) and PAF1C to remove RNAPII from transcribed genes near early-firing replication origins upon replication stress (hydroxyurea). This removal is required for efficient replication fork restart; failure to evict RNAPII in ino80 mutants correlates with inability to restart stalled forks.\",\n      \"method\": \"Genetic epistasis; ChIP; proteomic analyses; replication fork restart assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and proteomic analyses with ChIP and functional replication assays, single lab\",\n      \"pmids\": [\"26798134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"INO80 complex co-localizes with the origin recognition complex (ORC) at yeast replication origins and replication initiation sites in mouse ESCs, preventing pervasive transcription through origin sequences. Genetic studies show that INO80C and Mot1/NC2 function through distinct pathways to limit origin transcription; absence of INO80C leads to formation of new DNA double-strand breaks at origins.\",\n      \"method\": \"ChIP-seq; nascent transcript sequencing; genetic epistasis; DSB detection assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq, nascent RNA sequencing, and genetic analysis in the same study\",\n      \"pmids\": [\"32905765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"During DNA damage in yeast, INO80C-dependent recruitment of five ubiquitin-conjugating factors (Rad6, Bre1, Pep5, Ufd4, and Rsp5) contributes to core and linker histone depletion at damaged chromatin, reducing chromatin compaction and enhancing DNA locus mobility and strand invasion kinetics during homology-driven repair.\",\n      \"method\": \"Chromatin-associated proteomics; genetic epistasis; live-cell imaging; strand invasion assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics plus genetic and imaging approaches in a single study, single lab\",\n      \"pmids\": [\"33529595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Abasic sites and UV-irradiation damage abolish the DNA translocation activity of INO80-C by compromising ATP hydrolysis within the Ino80 catalytic subunit, while nucleosome binding remains unaffected. INO80-C also facilitates cleavage of abasic (AP) sites by AP-endonuclease 1 (APE1) independently of its DNA translocation activity.\",\n      \"method\": \"In vitro DNA translocation assays; ATPase assays with damaged substrates; AP site cleavage assay; nucleosome binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro biochemical assays with multiple damage types, but single lab and no mutagenesis to confirm active site\",\n      \"pmids\": [\"37696438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of cytoplasmic actin filaments (via TORC2 inhibition or Las17 degradation) raises nuclear actin levels, which in complex with Arp4 is an essential subunit of INO80C. Genetic ablation of INO80C activity leads to partial resistance to yeast chromosome shattering (YCS), suggesting that elevated nuclear G-actin stimulates INO80C to increase DNA polymerase processivity and thereby converts single-strand lesions into double-strand breaks.\",\n      \"method\": \"Phosphoproteomics; auxin-induced protein degradation; genetic ablation; nuclear actin quantification\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic ablation with defined phenotypic readout and phosphoproteomics, single lab\",\n      \"pmids\": [\"39548059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Deletion of IES6 in yeast reduces genome-wide nucleosome spacing by 3 bp and disrupts regular nucleosome arrays across most genes. IES6 deletion is synthetically lethal with deletion of ISW2 (an ISWI-family remodeler), indicating functional redundancy in nucleosome organization. INO80 binding directly predicts the role of Ies6 in nucleosome organization, whereas gene expression changes do not correlate with altered spacing.\",\n      \"method\": \"Genome-wide nucleosome mapping (MNase-seq); genetic epistasis (synthetic lethality); ChIP-seq\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide nucleosome mapping and genetic epistasis in the same study, single lab\",\n      \"pmids\": [\"41720950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In the human INO80 complex, biochemical approaches indicated that INO80-C and the H3K27 acetyltransferase P300 physically interact, suggesting they may jointly coordinate chromatin accessibility at canonical INO80 target sites.\",\n      \"method\": \"Co-immunoprecipitation; ChIP-seq for INO80 subunits\",\n      \"journal\": \"G3 (Bethesda, Md.)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP result, single lab, no functional validation\",\n      \"pmids\": [\"29432129\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"INO80C (IES6/hIes6) is a conserved subunit of the INO80 ATP-dependent chromatin remodeling complex that, together with Arp5, forms a distinct Arp5-Ies6 module that binds the nucleosome on the opposite face from the ATPase motor (at superhelical locations -2/-3), acts as a counter grip to couple ATP hydrolysis to productive nucleosome sliding and H2A.Z exchange, is required for genome-wide nucleosome spacing and organization, and supports INO80 complex functions in DNA repair, replication origin protection, prevention of H2A.Z misincorporation at centromeres, and metabolic gene regulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"INO80C (Ies6/hIes6) is a conserved core subunit of the INO80 ATP-dependent chromatin-remodeling complex that, together with Arp5, forms a structural module governing how the complex engages and remodels nucleosomes [#0, #2]. Cryo-EM of fungal and human INO80 bound to a nucleosome places the Arp5-Ies6 module at superhelical locations -2/-3 on the face opposite the Snf2 ATPase motor, where it acts as a counter grip against which the motor pumps entry DNA into the nucleosome [#0, #1]. Functionally, Arp5/Ies6 promotes binding of the Ino80 ATPase to nucleosomes and couples ATP hydrolysis to productive translocation, while the partner subunit Ies2 activates intrinsic catalysis; an Arp5 insertion domain is specifically required to convert hydrolysis into nucleosome sliding [#3, #6, #7]. Through these activities INO80C is essential for genome-wide nucleosome spacing and regular array organization, acting redundantly with the ISWI remodeler Isw2 [#18]. The module supports the complex's broader genome-maintenance roles: it removes/prevents H2A.Z misincorporation at pericentric chromatin to ensure proper chromosome segregation [#8], promotes homologous recombination by H2A.Z-dependent presynaptic filament formation and by recruiting ubiquitin-conjugating factors that deplete histones at damage [#12, #15], protects replication origins by limiting pervasive transcription and enabling fork restart under replication stress [#13, #14], and regulates metabolic gene expression and mitochondrial homeostasis [#5, #10]. ACTR5/IES6 additionally support hepatocellular carcinoma proliferation through CDK/E2F-driven cell-cycle signaling [#11].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Establishing that Ies6 is a functional INO80 subunit required showing its loss phenocopies other complex members; deletion in fission yeast produced DNA repair, replication-stress, and nucleotide-metabolism defects and the Ies6-containing complex remodeled nucleosomes in vitro.\",\n      \"evidence\": \"Genetic deletion with damage-sensitivity assays and in vitro remodeling in S. pombe\",\n      \"pmids\": [\"19933844\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not resolve Ies6's specific molecular contribution within the complex\", \"No structural placement of the subunit\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Module organization of human INO80 was defined, assigning Ies6 to the conserved catalytic core module built on the Snf2 ATPase domain alongside Arp5, Tip49a/b, and Ies2.\",\n      \"evidence\": \"Subcomplex purification and reconstitution with ATPase and remodeling assays\",\n      \"pmids\": [\"21303910\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate Ies6's role from Arp5 within the module\", \"No structural detail of nucleosome contacts\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Loss-of-function showed Ies6 is critical for preventing H2A.Z misincorporation at centromeres, linking the subunit to faithful chromosome segregation.\",\n      \"evidence\": \"Genetic deletion, flow-cytometry ploidy, ChIP, and live-cell segregation imaging in budding yeast\",\n      \"pmids\": [\"23207916\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of H2A.Z eviction specificity not resolved\", \"Did not address pericentric remodeling biochemistry\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Dissecting subunit roles revealed Ies6 and Arp5 govern substrate recognition (nucleosome binding by the ATPase) while Ies2 drives intrinsic catalysis, separating substrate engagement from hydrolysis.\",\n      \"evidence\": \"Biochemical reconstitution with ATPase and nucleosome-binding assays using purified subcomplexes\",\n      \"pmids\": [\"24297934\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How binding is coupled to remodeling output not yet shown\", \"No structural basis for the binding contribution\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Two studies established that the Ies6/Arp5 module is essential for remodeling and that the Arp5 insertion domain couples ATP hydrolysis to translocation, defining where coupling is encoded.\",\n      \"evidence\": \"EM/MS architecture plus domain-deletion mutagenesis with Co-IP, ChIP, and ATPase/sliding assays\",\n      \"pmids\": [\"25964121\", \"26306040\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution view of the coupling mechanism still lacking\", \"Assembly determinants in Ino80 spacer only partially mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"In vivo and recombinant work showed Arp5-Ies6 forms a distinct subcomplex that stimulates ATP hydrolysis and sliding, with Ies2 acting synergistically/antagonistically and IP6 inhibiting hydrolysis, while genomic occupancy linked the module to TSS nucleosome positioning and metabolic gene expression.\",\n      \"evidence\": \"Co-IP, recombinant minimal complex biochemistry, inhibitor and mutagenesis studies, ChIP-seq, and expression analysis\",\n      \"pmids\": [\"26755556\", \"27257055\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct causal link between spacing and the metabolic transcriptional program not established\", \"Physiological role of IP6 regulation unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Genetic epistasis assigned INO80-C a discrete HR step: it facilitates presynaptic filament formation by removing H2A.Z, since H2A.Z loss rescues HR in INO80-C-deficient mutants.\",\n      \"evidence\": \"Double-mutant analysis, microscopy of repair intermediates, and HR frequency assays in yeast\",\n      \"pmids\": [\"28514650\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ies6-specific contribution within INO80-C not isolated\", \"Biochemical reconstitution of the filament-promoting step absent\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Parallel cryo-EM structures of fungal and human INO80-nucleosome complexes provided the atomic framework, placing Arp5-Ies6 as a counter grip at SHL -2/-3 opposite the motor and revealing H3-tail-dependent regulation of the motor through this arrangement.\",\n      \"evidence\": \"High-resolution cryo-EM with biochemical regulation assays of C. thermophilum and human INO80\",\n      \"pmids\": [\"29643509\", \"29643506\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamic conformational cycle during translocation not fully captured\", \"Ies6 fold and contacts resolved only at module resolution\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Genetic-interaction and signaling studies tied the Ies6 module to metabolic homeostasis, mitochondrial maintenance, and TORC1-to-chromatin signaling, broadening INO80C's physiological role beyond remodeling biochemistry.\",\n      \"evidence\": \"Genetic interaction screen with expression and histone-modification analyses in yeast\",\n      \"pmids\": [\"29462149\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct chromatin target of TORC1-INO80 signaling not pinpointed\", \"Mechanism connecting mitochondrial state to Ies6 unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"A candidate physical link between human INO80-C and the acetyltransferase P300 raised the possibility of coordinated chromatin-accessibility control at INO80 targets.\",\n      \"evidence\": \"Co-IP and INO80-subunit ChIP-seq\",\n      \"pmids\": [\"29432129\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation or functional follow-up\", \"Direct Ies6 involvement in the interaction not demonstrated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"INO80C was shown to drive histone depletion at damaged chromatin by recruiting ubiquitin-conjugating factors, mechanistically connecting remodeling to chromatin decompaction and enhanced repair-locus mobility.\",\n      \"evidence\": \"Chromatin-associated proteomics, genetic epistasis, live-cell imaging, and strand-invasion assays\",\n      \"pmids\": [\"33529595\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How INO80C recruits the ubiquitin factors not defined\", \"Ies6-specific requirement not separated from whole-complex activity\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"CRISPR tiling revealed an ACTR5/IES6 functional signature distinct from other INO80 members in hepatocellular carcinoma, suggesting a partly INO80-independent role in supporting CDK/E2F-driven proliferation.\",\n      \"evidence\": \"CRISPR interference and tiling screens with expression analysis and xenograft assays\",\n      \"pmids\": [\"36563143\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of the proposed INO80-independent activity unknown\", \"Direct IES6 effector for CDKN2A/E2F control not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Damaged-DNA biochemistry showed INO80-C translocation is abolished by abasic and UV lesions via impaired Ino80 ATP hydrolysis, while INO80-C separately stimulates APE1 cleavage of AP sites independently of translocation.\",\n      \"evidence\": \"In vitro DNA translocation, ATPase on damaged substrates, AP-site cleavage, and nucleosome-binding assays\",\n      \"pmids\": [\"37696438\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mutagenesis confirming the active-site basis of lesion sensing\", \"Ies6-specific contribution within the complex not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Nuclear actin levels, set by cytoplasmic actin dynamics, were shown to stimulate INO80C activity, with INO80C ablation conferring partial resistance to chromosome shattering by limiting conversion of single-strand lesions to DSBs.\",\n      \"evidence\": \"Phosphoproteomics, auxin-induced degradation, genetic ablation, and nuclear actin quantification in yeast\",\n      \"pmids\": [\"39548059\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical link between G-actin levels and Ies6 module activity not reconstituted\", \"How remodeling increases polymerase processivity unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Genome-wide mapping established that Ies6 is required for proper nucleosome spacing and array regularity, acting redundantly with the ISWI remodeler Isw2, and that this organizing role is predicted by INO80 binding rather than by transcriptional output.\",\n      \"evidence\": \"MNase-seq nucleosome mapping, synthetic-lethality genetics, and ChIP-seq in yeast\",\n      \"pmids\": [\"41720950\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of redundancy with Isw2 not defined\", \"Decoupling of spacing from expression not mechanistically explained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether the candidate INO80C-independent and human-specific roles (e.g., P300 interaction, ACTR5/IES6 in cancer proliferation) reflect distinct molecular activities of Ies6 separate from its structural counter-grip function within INO80 remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No reconstituted INO80-independent activity demonstrated\", \"Human-specific effector pathways for IES6 not mapped\", \"Ies6 isolated contribution distinct from Arp5 not established in vivo\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [3, 7, 16]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 6, 7]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 14, 17]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [8, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 2, 5, 18]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [9, 12, 15, 16]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [13, 14]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [8, 11]}\n    ],\n    \"complexes\": [\"INO80 chromatin remodeling complex\", \"Arp5-Ies6 module\"],\n    \"partners\": [\"ACTR5\", \"INO80\", \"IES2\", \"RUVBL1\", \"RUVBL2\", \"ARP4\", \"EP300\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}