{"gene":"ACTR5","run_date":"2026-06-09T22:02:40","timeline":{"discoveries":[{"year":2022,"finding":"ACTR5, a component of the INO80 chromatin remodeling complex, is essential for hepatocellular carcinoma (HCC) tumor progression; its suppression activates CDKN2A expression and ablates CDK/E2F-driven cell cycle signaling, attenuating HCC tumor growth.","method":"Epigenetics-focused CRISPR interference screen, high-density CRISPR gene tiling scans, loss-of-function (ACTR5 suppression) with cell cycle signaling and tumor growth phenotypic readouts","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR-based loss-of-function with defined molecular phenotype (CDKN2A activation, CDK/E2F signaling ablation), single lab, multiple orthogonal methods","pmids":["36563143"],"is_preprint":false},{"year":2022,"finding":"ACTR5 and its interacting partner IES6 operate via an INO80-independent mechanism to support HCC cell proliferation, as revealed by differential CRISPR tiling profiles compared to other INO80 complex members.","method":"High-density CRISPR gene tiling scans comparing ACTR5/IES6 vs. other INO80 complex members; genetic epistasis by differential dependency profiling","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR-based genetic epistasis approach distinguishing ACTR5/IES6 from other INO80 subunits, single lab, orthogonal tiling scan methodology","pmids":["36563143"],"is_preprint":false},{"year":2025,"finding":"A de novo variant in ACTR5 enhanced type I interferon (IFN-β) signaling, placing ACTR5 as a positive regulator of type I IFN signaling.","method":"IFN-β luciferase reporter assay using patient-derived de novo ACTR5 variant","journal":"Arthritis & rheumatology (Hoboken, N.J.)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single luciferase assay with one patient variant, single lab, no mechanistic follow-up","pmids":["40386946"],"is_preprint":false}],"current_model":"ACTR5 is a component of the INO80 chromatin remodeling complex that, through an INO80-independent mechanism with partner IES6, represses CDKN2A expression to sustain CDK/E2F-driven cell cycle progression in hepatocellular carcinoma, and additionally functions as a positive regulator of type I interferon signaling."},"narrative":{"mechanistic_narrative":"ACTR5 is a component of the INO80 chromatin remodeling complex that functions as a dependency for hepatocellular carcinoma proliferation [PMID:36563143]. Its loss-of-function activates CDKN2A expression and ablates CDK/E2F-driven cell cycle signaling, thereby attenuating tumor growth [PMID:36563143]. ACTR5 acts together with its partner IES6 through a mechanism distinct from the canonical INO80 complex, since high-density CRISPR tiling profiles of ACTR5 and IES6 diverge from those of other INO80 subunits [PMID:36563143]. Beyond this chromatin-associated cell cycle role, no further biochemical mechanism (substrate specificity, recruitment, or structural basis of CDKN2A repression) has been characterized in the available corpus.","teleology":[{"year":2022,"claim":"Established ACTR5 as a functional tumor dependency by linking its loss to a defined molecular phenotype, answering whether this INO80 subunit has a non-redundant role in cancer cell proliferation.","evidence":"Epigenetics-focused CRISPR interference screen and gene tiling scans with cell cycle and tumor growth readouts in HCC","pmids":["36563143"],"confidence":"Medium","gaps":["Direct molecular mechanism by which ACTR5 represses CDKN2A is not defined","Whether the dependency extends beyond HCC is untested","No biochemical demonstration of ACTR5 binding at the CDKN2A locus"]},{"year":2022,"claim":"Distinguished ACTR5/IES6 function from the canonical INO80 complex, addressing whether ACTR5's pro-proliferative role depends on intact INO80.","evidence":"Differential high-density CRISPR tiling dependency profiling comparing ACTR5/IES6 against other INO80 subunits","pmids":["36563143"],"confidence":"Medium","gaps":["Biochemical nature of the INO80-independent ACTR5/IES6 module is not characterized","Whether ACTR5/IES6 form a stable distinct complex is unresolved"]},{"year":2025,"claim":"Implicated ACTR5 as a positive regulator of type I interferon signaling, addressing a possible role outside cell cycle control via a disease-associated variant.","evidence":"IFN-β luciferase reporter assay using a patient-derived de novo ACTR5 variant","pmids":["40386946"],"confidence":"Low","gaps":["Single luciferase assay with one patient variant and no mechanistic follow-up","Connection between ACTR5's chromatin role and IFN signaling is undefined","No demonstration of endogenous ACTR5 acting in the IFN pathway"]},{"year":null,"claim":"How ACTR5 mechanistically represses CDKN2A and whether this connects to its reported interferon-regulatory activity remains unknown.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural or biochemical model of ACTR5 action","No identified DNA target or recruitment mechanism at CDKN2A","Relationship between cell cycle and interferon roles unestablished"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1]}],"complexes":["INO80 chromatin remodeling complex"],"partners":["IES6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H9F9","full_name":"Actin-related protein 5","aliases":["Sarcoma antigen NY-SAR-16"],"length_aa":607,"mass_kda":68.3,"function":"Proposed core component of the chromatin remodeling INO80 complex which is involved in transcriptional regulation, DNA replication and probably DNA repair. Involved in DNA double-strand break repair and UV-damage excision repair","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9H9F9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ACTR5","classification":"Not Classified","n_dependent_lines":292,"n_total_lines":1208,"dependency_fraction":0.24172185430463577},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000101442","cell_line_id":"CID001830","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"chromatin","grade":2}],"interactors":[{"gene":"INO80C","stoichiometry":10.0},{"gene":"INO80","stoichiometry":4.0},{"gene":"RUVBL1","stoichiometry":0.2},{"gene":"RUVBL2","stoichiometry":0.2},{"gene":"YY1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001830","total_profiled":1310},"omim":[{"mim_id":"619730","title":"ACTIN-RELATED PROTEIN 5; ACTR5","url":"https://www.omim.org/entry/619730"},{"mim_id":"619716","title":"ACTIN-RELATED PROTEIN 8; ACTR8","url":"https://www.omim.org/entry/619716"},{"mim_id":"610169","title":"INO80 COMPLEX, ATPase SUBUNIT; INO80","url":"https://www.omim.org/entry/610169"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ACTR5"},"hgnc":{"alias_symbol":["FLJ12785","Arp5","INO80M"],"prev_symbol":[]},"alphafold":{"accession":"Q9H9F9","domains":[{"cath_id":"3.30.420.570","chopping":"212-280_441-526","consensus_level":"medium","plddt":96.3244,"start":212,"end":526},{"cath_id":"1.20.1270","chopping":"299-380","consensus_level":"high","plddt":86.4633,"start":299,"end":380}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H9F9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H9F9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H9F9-F1-predicted_aligned_error_v6.png","plddt_mean":82.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ACTR5","jax_strain_url":"https://www.jax.org/strain/search?query=ACTR5"},"sequence":{"accession":"Q9H9F9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H9F9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H9F9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H9F9"}},"corpus_meta":[{"pmid":"19557832","id":"PMC_19557832","title":"Using microarray technology to select housekeeping genes in Chinese hamster ovary cells.","date":"2009","source":"Biotechnology and bioengineering","url":"https://pubmed.ncbi.nlm.nih.gov/19557832","citation_count":33,"is_preprint":false},{"pmid":"36563143","id":"PMC_36563143","title":"ACTR5 controls CDKN2A and tumor progression in an INO80-independent manner.","date":"2022","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/36563143","citation_count":14,"is_preprint":false},{"pmid":"40386946","id":"PMC_40386946","title":"Trio Whole Exome Sequencing in Chinese Childhood-Onset Lupus Reveals Novel Candidate Genes.","date":"2025","source":"Arthritis & rheumatology (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/40386946","citation_count":2,"is_preprint":false},{"pmid":"39748273","id":"PMC_39748273","title":"Improved Diagnostic Yield in Recessive Intellectual Disability Utilizing Systematic Whole Exome Sequencing Data Reanalysis.","date":"2025","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39748273","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4198,"output_tokens":772,"usd":0.012087,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7163,"output_tokens":1391,"usd":0.035295,"stage2_stop_reason":"end_turn"},"total_usd":0.047382,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2022,\n      \"finding\": \"ACTR5, a component of the INO80 chromatin remodeling complex, is essential for hepatocellular carcinoma (HCC) tumor progression; its suppression activates CDKN2A expression and ablates CDK/E2F-driven cell cycle signaling, attenuating HCC tumor growth.\",\n      \"method\": \"Epigenetics-focused CRISPR interference screen, high-density CRISPR gene tiling scans, loss-of-function (ACTR5 suppression) with cell cycle signaling and tumor growth phenotypic readouts\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR-based loss-of-function with defined molecular phenotype (CDKN2A activation, CDK/E2F signaling ablation), single lab, multiple orthogonal methods\",\n      \"pmids\": [\"36563143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ACTR5 and its interacting partner IES6 operate via an INO80-independent mechanism to support HCC cell proliferation, as revealed by differential CRISPR tiling profiles compared to other INO80 complex members.\",\n      \"method\": \"High-density CRISPR gene tiling scans comparing ACTR5/IES6 vs. other INO80 complex members; genetic epistasis by differential dependency profiling\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR-based genetic epistasis approach distinguishing ACTR5/IES6 from other INO80 subunits, single lab, orthogonal tiling scan methodology\",\n      \"pmids\": [\"36563143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A de novo variant in ACTR5 enhanced type I interferon (IFN-β) signaling, placing ACTR5 as a positive regulator of type I IFN signaling.\",\n      \"method\": \"IFN-β luciferase reporter assay using patient-derived de novo ACTR5 variant\",\n      \"journal\": \"Arthritis & rheumatology (Hoboken, N.J.)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single luciferase assay with one patient variant, single lab, no mechanistic follow-up\",\n      \"pmids\": [\"40386946\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ACTR5 is a component of the INO80 chromatin remodeling complex that, through an INO80-independent mechanism with partner IES6, represses CDKN2A expression to sustain CDK/E2F-driven cell cycle progression in hepatocellular carcinoma, and additionally functions as a positive regulator of type I interferon signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ACTR5 is a component of the INO80 chromatin remodeling complex that functions as a dependency for hepatocellular carcinoma proliferation [#0]. Its loss-of-function activates CDKN2A expression and ablates CDK/E2F-driven cell cycle signaling, thereby attenuating tumor growth [#0]. ACTR5 acts together with its partner IES6 through a mechanism distinct from the canonical INO80 complex, since high-density CRISPR tiling profiles of ACTR5 and IES6 diverge from those of other INO80 subunits [#1]. Beyond this chromatin-associated cell cycle role, no further biochemical mechanism (substrate specificity, recruitment, or structural basis of CDKN2A repression) has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2022,\n      \"claim\": \"Established ACTR5 as a functional tumor dependency by linking its loss to a defined molecular phenotype, answering whether this INO80 subunit has a non-redundant role in cancer cell proliferation.\",\n      \"evidence\": \"Epigenetics-focused CRISPR interference screen and gene tiling scans with cell cycle and tumor growth readouts in HCC\",\n      \"pmids\": [\"36563143\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct molecular mechanism by which ACTR5 represses CDKN2A is not defined\",\n        \"Whether the dependency extends beyond HCC is untested\",\n        \"No biochemical demonstration of ACTR5 binding at the CDKN2A locus\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Distinguished ACTR5/IES6 function from the canonical INO80 complex, addressing whether ACTR5's pro-proliferative role depends on intact INO80.\",\n      \"evidence\": \"Differential high-density CRISPR tiling dependency profiling comparing ACTR5/IES6 against other INO80 subunits\",\n      \"pmids\": [\"36563143\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Biochemical nature of the INO80-independent ACTR5/IES6 module is not characterized\",\n        \"Whether ACTR5/IES6 form a stable distinct complex is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated ACTR5 as a positive regulator of type I interferon signaling, addressing a possible role outside cell cycle control via a disease-associated variant.\",\n      \"evidence\": \"IFN-β luciferase reporter assay using a patient-derived de novo ACTR5 variant\",\n      \"pmids\": [\"40386946\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single luciferase assay with one patient variant and no mechanistic follow-up\",\n        \"Connection between ACTR5's chromatin role and IFN signaling is undefined\",\n        \"No demonstration of endogenous ACTR5 acting in the IFN pathway\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ACTR5 mechanistically represses CDKN2A and whether this connects to its reported interferon-regulatory activity remains unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural or biochemical model of ACTR5 action\",\n        \"No identified DNA target or recruitment mechanism at CDKN2A\",\n        \"Relationship between cell cycle and interferon roles unestablished\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"INO80 chromatin remodeling complex\"],\n    \"partners\": [\"IES6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}