{"gene":"CHRAC1","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2004,"finding":"CHRAC1 (CHRAC-15) forms a histone-fold heterodimer with CHRAC-17, and this complex directly interacts with the ACF1 subunit of the ACF chromatin-remodeling complex. This interaction is essential for facilitating ATP-dependent nucleosome sliding by ACF. CHRAC-15 specifically is required for the interaction with ACF and enhancement of nucleosome sliding, while CHRAC-17 can also interact with p12 of DNA polymerase epsilon. Additionally, the CHRAC-15/17 complex facilitates ACF-mediated chromatin assembly by a mechanism distinct from nucleosome sliding enhancement.","method":"In vitro nucleosome sliding assays, chromatin assembly assays, direct protein-protein interaction studies (pulldown/binding), histone-fold protein biochemistry","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of nucleosome sliding and chromatin assembly assays with direct mutagenesis-level dissection of which subunit (CHRAC-15 vs CHRAC-17) is required; multiple orthogonal functional assays in a single rigorous study","pmids":["14759371"],"is_preprint":false},{"year":2000,"finding":"CHRAC1 (YCL1) is a histone-fold protein of the H2A/H2B sub-family. In nucleosome reconstitution assays, YCL1 (and its partner YBL1) can form complexes with core histones in solution and on DNA. Glycerol gradient sedimentation shows that YCL1 is part of relatively large complexes. Unlike NF-YB/NF-YC, YCL1 has no intrinsic CCAAT or TATA-binding capacity.","method":"Nucleosome reconstitution assays, glycerol gradient sedimentation, biochemical characterization","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro reconstitution and sedimentation assays with multiple methods in a single study, but no functional mutagenesis or cellular validation","pmids":["11000277"],"is_preprint":false},{"year":2010,"finding":"CHRAC1 (CHRAC15) is a component of the CHRAC complex (ACF1, SNF2H, CHRAC15, CHRAC17) that becomes physically more associated with KU70/80 after DSB-inducing treatments. The ACF1-containing complex is required for accumulation of KU proteins at DSBs, and cells depleted of ACF1 or SNF2H show failure of both NHEJ and HR, establishing that the CHRAC complex participates in DSB repair pathway choice and execution.","method":"Co-immunoprecipitation, siRNA knockdown with DSB repair assays (NHEJ and HR frequency measurement), live-cell imaging of protein accumulation at DSBs","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and functional knockdown with defined cellular phenotype (DSB repair failure), but the CHRAC15-specific contribution is inferred from complex membership rather than tested directly","pmids":["21172662"],"is_preprint":false},{"year":2006,"finding":"CHRAC1 (YCL1/CHRAC15) heterodimerizes with POLE3 (DPB4/YBL1/CHRAC17) via histone-like domains, and POLE3 also heterodimerizes with its DNA polymerase epsilon partner POLE4 (DPB3). The POLE3/CHRAC15 dimer associates with the ACF1/SNF2H remodeling complex. The Pole3 gene is regulated in a cell-cycle-dependent manner (peak at S phase entry) by E2F1/4 and MYC as shown by chromatin immunoprecipitation.","method":"Protein interaction characterization, chromatin immunoprecipitation (ChIP), promoter mutagenesis, cell-cycle expression analysis","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and mutagenesis used; interaction characterized biochemically; single lab study","pmids":["16403426"],"is_preprint":false},{"year":2023,"finding":"CHRAC1 interacts with POLE3 to promote DNA double-strand break repair by regulating expression of homology-directed repair proteins and KU80 recruitment. A cancer-associated CHRAC1 D121Y mutation (identified in colorectal cancer) attenuates the CHRAC1-POLE3 interaction and leads to defects in DNA repair.","method":"Co-immunoprecipitation, cell-based DNA repair assays, biochemical interaction studies with cancer mutation analysis","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and functional cell-based repair assays with cancer mutation validation; single lab","pmids":["37682991"],"is_preprint":false},{"year":2022,"finding":"CHRAC1 physically binds the transcriptional coactivator YAP, enhances transcription of downstream YAP target oncogenes in the Hippo pathway, and promotes lung cancer cell proliferation, migration in vitro, and tumor growth in a KrasG12D mouse model. CHRAC1 silencing inhibits these phenotypes and suppresses xenograft tumor growth.","method":"Co-immunoprecipitation (CHRAC1-YAP binding), overexpression and siRNA knockdown with proliferation/migration assays, genetically engineered mouse model, xenograft mouse model","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding demonstrated by Co-IP, functional consequence shown in vitro and in vivo with multiple models; single lab","pmids":["34718437"],"is_preprint":false},{"year":2024,"finding":"CHRAC1 interacts with YAP (identified by Bio-ID proximity labeling and confirmed by immunofluorescence co-localization), and CHRAC1 depletion suppresses YAP target gene transcription and inhibits breast and cervical cancer cell proliferation and tumor growth.","method":"Bio-ID proximity labeling, immunofluorescence, CCK8 and colony formation assays, subcutaneous xenograft assay, RNA-seq","journal":"PeerJ","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Bio-ID and immunofluorescence for interaction; functional assays in vitro and in vivo; single lab, corroborates prior lung cancer study","pmids":["38223760"],"is_preprint":false},{"year":2025,"finding":"CHRAC1 transcriptionally activates the NOD-like receptor signaling pathway and promotes IRF9 expression; the CHRAC1-IRF9-GSDMD-CASP-1 axis drives caspase-1-dependent pyroptosis in cardiomyocytes, contributing to doxorubicin-induced cardiotoxicity. CHRAC1 knockdown preserved cardiac function and reduced cell death; IRF9 silencing reversed CHRAC1-driven pathological phenotypes.","method":"RNA-seq and ATAC-seq in murine and cellular models, CHRAC1 knockdown/overexpression, IRF9 silencing epistasis, cell viability and ROS assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — integrated ATAC-seq + RNA-seq + epistasis (IRF9 silencing rescues CHRAC1 overexpression phenotype) with in vivo murine model; single lab, no direct biochemical binding assay","pmids":["41325875"],"is_preprint":false}],"current_model":"CHRAC1 (CHRAC15/YCL1) is a histone-fold protein that heterodimerizes with CHRAC17 via H2A/H2B-type histone-fold domains; this dimer integrates into the CHRAC/ACF chromatin-remodeling complex by directly binding ACF1, thereby facilitating ATP-dependent nucleosome sliding and chromatin assembly; CHRAC1 also interacts with POLE3 to support DNA double-strand break repair and KU80 recruitment, interacts with the transcriptional coactivator YAP to drive oncogenic gene expression in the Hippo pathway, and transcriptionally activates IRF9 to promote pyroptotic signaling in cardiomyocytes."},"narrative":{"mechanistic_narrative":"CHRAC1 is a histone-fold protein of the H2A/H2B sub-family that functions as an accessory subunit of ATP-dependent chromatin-remodeling machinery and, through context-specific partners, in DNA repair and transcriptional control [PMID:14759371, PMID:11000277]. It heterodimerizes through its histone-fold domain with CHRAC17/POLE3 and directly contacts the ACF1 subunit of the ACF/CHRAC remodeling complex; this CHRAC15/17 dimer is specifically required for ACF1 binding, enhances ATP-dependent nucleosome sliding, and facilitates chromatin assembly by a mechanism distinct from sliding [PMID:14759371, PMID:16403426]. Within this complex CHRAC1 contributes to DNA double-strand break repair: the ACF1-containing remodeler associates with KU70/80 after damage and is required for KU accumulation at breaks and for both NHEJ and HR [PMID:21172662], and the CHRAC1–POLE3 interaction supports homology-directed repair protein expression and KU80 recruitment, an activity attenuated by the colorectal-cancer-associated CHRAC1 D121Y mutation [PMID:37682991]. Beyond chromatin remodeling, CHRAC1 binds the Hippo-pathway coactivator YAP and enhances transcription of YAP target oncogenes to drive proliferation and tumor growth in lung, breast, and cervical cancer models [PMID:34718437, PMID:38223760], and it transcriptionally activates IRF9 to engage a NOD-like-receptor/GSDMD/caspase-1 pyroptotic axis underlying doxorubicin-induced cardiomyocyte death [PMID:41325875].","teleology":[{"year":2000,"claim":"Establishing the biochemical identity of CHRAC1 answered whether it is a histone-fold protein capable of nucleosome-associated function rather than a sequence-specific DNA-binding factor.","evidence":"Nucleosome reconstitution and glycerol gradient sedimentation of YCL1 with core histones","pmids":["11000277"],"confidence":"Medium","gaps":["No functional mutagenesis or cellular validation","Did not define the in vivo complex CHRAC1 acts within","Partner specificity for assembly into remodeling complexes untested"]},{"year":2004,"claim":"In vitro reconstitution defined CHRAC1's mechanistic role, showing the CHRAC15/17 dimer bridges to ACF1 and is required to enhance ATP-dependent nucleosome sliding and chromatin assembly.","evidence":"In vitro nucleosome sliding and chromatin assembly assays with subunit-resolved dissection","pmids":["14759371"],"confidence":"High","gaps":["Structural basis of the ACF1 contact not resolved","Mechanism distinguishing assembly enhancement from sliding undefined","In vivo consequences of CHRAC1 loss not tested"]},{"year":2006,"claim":"Characterizing the histone-fold heterodimers clarified how CHRAC1 partitions between the remodeling complex and DNA polymerase epsilon machinery via shared POLE3 partnering.","evidence":"Protein interaction characterization, ChIP, and cell-cycle expression analysis","pmids":["16403426"],"confidence":"Medium","gaps":["Functional consequence of POLE3/CHRAC15 association with ACF1/SNF2H not measured","CHRAC1-specific role versus POLE3 not separated","Single-lab interaction study"]},{"year":2010,"claim":"Linking the CHRAC complex to damage signaling answered whether ACF-type remodeling participates in DSB repair, showing it is needed for KU recruitment and repair pathway execution.","evidence":"Co-IP, siRNA knockdown with NHEJ/HR assays, and live-cell imaging of accumulation at DSBs","pmids":["21172662"],"confidence":"Medium","gaps":["CHRAC15-specific contribution inferred from complex membership, not directly tested","Direct CHRAC1–KU interaction not demonstrated","Mechanism of remodeler recruitment to breaks unresolved"]},{"year":2023,"claim":"Disease-mutation analysis tied CHRAC1's repair role to a concrete molecular interface, showing the CHRAC1–POLE3 contact supports HDR protein expression and KU80 recruitment.","evidence":"Co-IP and cell-based DNA repair assays with the cancer-associated D121Y mutation","pmids":["37682991"],"confidence":"Medium","gaps":["How the interaction regulates repair-protein expression mechanistically unclear","Single-lab validation","Structural effect of D121Y not determined"]},{"year":2022,"claim":"Identifying a YAP partnership revealed a chromatin-independent oncogenic role, showing CHRAC1 binds YAP and amplifies Hippo-pathway target oncogene transcription to drive lung tumorigenesis.","evidence":"Co-IP, knockdown/overexpression proliferation and migration assays, KrasG12D and xenograft mouse models","pmids":["34718437"],"confidence":"Medium","gaps":["Direct binding interface with YAP not mapped","Relationship between this role and chromatin remodeling function unclear","Single-lab study"]},{"year":2024,"claim":"Extending the YAP connection to additional cancers tested its generality, confirming CHRAC1 co-localizes with YAP and drives target gene transcription and tumor growth in breast and cervical models.","evidence":"Bio-ID proximity labeling, immunofluorescence, colony/proliferation assays, xenograft, RNA-seq","pmids":["38223760"],"confidence":"Medium","gaps":["Proximity labeling does not establish direct binding","Mechanism of YAP target selection unresolved","Single-lab corroboration"]},{"year":2025,"claim":"Defining a CHRAC1-IRF9 transcriptional axis revealed a pyroptotic function, showing CHRAC1 activates IRF9 to engage GSDMD/caspase-1 cell death in cardiomyocytes during doxorubicin cardiotoxicity.","evidence":"RNA-seq, ATAC-seq, knockdown/overexpression, and IRF9-silencing epistasis in murine and cellular models","pmids":["41325875"],"confidence":"Medium","gaps":["No direct biochemical binding assay for CHRAC1 at the IRF9 locus","How a histone-fold accessory protein achieves gene-specific transcriptional activation unclear","Single-lab study"]},{"year":null,"claim":"It remains unresolved how CHRAC1 mechanistically switches between its core chromatin-remodeling/DSB-repair role and its partner-specific transcriptional functions with YAP and IRF9.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model unifying histone-fold remodeling and transcriptional coactivation","Direct DNA/chromatin binding at YAP and IRF9 targets not demonstrated","Whether these roles are independent or share the CHRAC15/17 dimer unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5,6,7]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,2]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[2,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6]}],"complexes":["CHRAC","ACF"],"partners":["CHRAC17/POLE3","ACF1","SNF2H","KU70","KU80","YAP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NRG0","full_name":"Chromatin accessibility complex protein 1","aliases":["Chromatin accessibility complex 15 kDa protein","CHRAC-15","HuCHRAC15","DNA polymerase epsilon subunit p15"],"length_aa":131,"mass_kda":14.7,"function":"Forms a complex with DNA polymerase epsilon subunit POLE3 and binds naked DNA, which is then incorporated into chromatin, aided by the nucleosome remodeling activity of ISWI/SNF2H and ACF1. Does not enhance nucleosome sliding activity of the ACF-5 ISWI chromatin remodeling complex (PubMed:14759371)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9NRG0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CHRAC1","classification":"Not Classified","n_dependent_lines":24,"n_total_lines":1208,"dependency_fraction":0.019867549668874173},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"BAZ1A","stoichiometry":10.0},{"gene":"SMARCA1","stoichiometry":10.0},{"gene":"NUCKS1","stoichiometry":4.0},{"gene":"SMARCA5","stoichiometry":4.0},{"gene":"H2AFZ","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HMGA1","stoichiometry":0.2},{"gene":"HMGN5","stoichiometry":0.2},{"gene":"MECP2","stoichiometry":0.2},{"gene":"NUMA1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CHRAC1","total_profiled":1310},"omim":[{"mim_id":"610657","title":"WASH COMPLEX, SUBUNIT 5; WASHC5","url":"https://www.omim.org/entry/610657"},{"mim_id":"607268","title":"CHROMATIN ACCESSIBILITY COMPLEX, SUBUNIT 1; CHRAC1","url":"https://www.omim.org/entry/607268"},{"mim_id":"607267","title":"POLYMERASE, DNA, EPSILON-3; POLE3","url":"https://www.omim.org/entry/607267"},{"mim_id":"605680","title":"BROMODOMAIN ADJACENT TO ZINC FINGER DOMAIN, 1A; BAZ1A","url":"https://www.omim.org/entry/605680"},{"mim_id":"603375","title":"SWI/SNF-RELATED, MATRIX-ASSOCIATED, ACTIN-DEPENDENT REGULATOR OF CHROMATIN, SUBFAMILY A, MEMBER 5; SMARCA5","url":"https://www.omim.org/entry/603375"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CHRAC1"},"hgnc":{"alias_symbol":["CHRAC15","YCL1"],"prev_symbol":[]},"alphafold":{"accession":"Q9NRG0","domains":[{"cath_id":"1.10.20.10","chopping":"22-121","consensus_level":"high","plddt":93.6552,"start":22,"end":121}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NRG0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NRG0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NRG0-F1-predicted_aligned_error_v6.png","plddt_mean":85.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CHRAC1","jax_strain_url":"https://www.jax.org/strain/search?query=CHRAC1"},"sequence":{"accession":"Q9NRG0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NRG0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NRG0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NRG0"}},"corpus_meta":[{"pmid":"21172662","id":"PMC_21172662","title":"The ACF1 complex is required for DNA double-strand break repair in human cells.","date":"2010","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/21172662","citation_count":171,"is_preprint":false},{"pmid":"14759371","id":"PMC_14759371","title":"The histone-fold protein complex CHRAC-15/17 enhances nucleosome sliding and assembly mediated by ACF.","date":"2004","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/14759371","citation_count":63,"is_preprint":false},{"pmid":"24148822","id":"PMC_24148822","title":"A siRNA screen identifies RAD21, EIF3H, CHRAC1 and TANC2 as driver genes within the 8q23, 8q24.3 and 17q23 amplicons in breast cancer with effects on cell growth, survival and transformation.","date":"2013","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/24148822","citation_count":47,"is_preprint":false},{"pmid":"24667089","id":"PMC_24667089","title":"The PEG13-DMR and brain-specific enhancers dictate imprinted expression within the 8q24 intellectual disability risk locus.","date":"2014","source":"Epigenetics & chromatin","url":"https://pubmed.ncbi.nlm.nih.gov/24667089","citation_count":41,"is_preprint":false},{"pmid":"34030482","id":"PMC_34030482","title":"YY1-Induced lncRNA PART1 Enhanced Resistance of Ovarian Cancer Cells to Cisplatin by Regulating miR-512-3p/CHRAC1 Axis.","date":"2021","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/34030482","citation_count":26,"is_preprint":false},{"pmid":"8139579","id":"PMC_8139579","title":"Histone H1 expressed in Saccharomyces cerevisiae binds to chromatin and affects survival, growth, transcription, and plasmid stability but does not change nucleosomal spacing.","date":"1994","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/8139579","citation_count":26,"is_preprint":false},{"pmid":"36430148","id":"PMC_36430148","title":"The Emerging Role of Chromatin Remodeling Complexes in Ovarian Cancer.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36430148","citation_count":21,"is_preprint":false},{"pmid":"11000277","id":"PMC_11000277","title":"Cloning and characterization of the histone-fold proteins YBL1 and YCL1.","date":"2000","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/11000277","citation_count":16,"is_preprint":false},{"pmid":"27128794","id":"PMC_27128794","title":"Allelic expression imbalance polymorphisms in susceptibility chromosome regions and the risk and survival of breast cancer.","date":"2016","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/27128794","citation_count":15,"is_preprint":false},{"pmid":"16403426","id":"PMC_16403426","title":"The Pole3 bidirectional unit is regulated by MYC and E2Fs.","date":"2006","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/16403426","citation_count":11,"is_preprint":false},{"pmid":"37682991","id":"PMC_37682991","title":"Requirement of WDR70 for POLE3-mediated DNA double-strand breaks repair.","date":"2023","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/37682991","citation_count":10,"is_preprint":false},{"pmid":"34718437","id":"PMC_34718437","title":"CHRAC1 promotes human lung cancer growth through regulating YAP transcriptional activity.","date":"2022","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/34718437","citation_count":7,"is_preprint":false},{"pmid":"37050850","id":"PMC_37050850","title":"Comparative proteomic analysis identifies differentially expressed proteins associated with meiotic arrest in cattle-yak hybrids.","date":"2023","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/37050850","citation_count":6,"is_preprint":false},{"pmid":"36313557","id":"PMC_36313557","title":"Variable allelic expression of imprinted genes at the Peg13, Trappc9, Ago2 cluster in single neural cells.","date":"2022","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/36313557","citation_count":4,"is_preprint":false},{"pmid":"37810050","id":"PMC_37810050","title":"Differential expression of mRNA 3'-end isoforms in cervical and ovarian cancers.","date":"2023","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/37810050","citation_count":3,"is_preprint":false},{"pmid":"38223760","id":"PMC_38223760","title":"Chromatin accessibility complex subunit 1 enhances tumor growth by regulating the oncogenic transcription of YAP in breast and cervical cancer.","date":"2024","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/38223760","citation_count":2,"is_preprint":false},{"pmid":"41325875","id":"PMC_41325875","title":"Chromatin remodeling factor CHRAC1 regulates doxorubicin-induced cardiotoxicity via IRF9/GSDMD/CASP-1.","date":"2025","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/41325875","citation_count":0,"is_preprint":false},{"pmid":"39526719","id":"PMC_39526719","title":"Association of overexpression of PLD6, CHRAC1 and PDCD5 with type 2 diabetes mellitus.","date":"2024","source":"Medicinski glasnik : official publication of the Medical Association of Zenica-Doboj Canton, Bosnia and Herzegovina","url":"https://pubmed.ncbi.nlm.nih.gov/39526719","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10656,"output_tokens":2334,"usd":0.033489,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9493,"output_tokens":3130,"usd":0.062857,"stage2_stop_reason":"end_turn"},"total_usd":0.096346,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"CHRAC1 (CHRAC-15) forms a histone-fold heterodimer with CHRAC-17, and this complex directly interacts with the ACF1 subunit of the ACF chromatin-remodeling complex. This interaction is essential for facilitating ATP-dependent nucleosome sliding by ACF. CHRAC-15 specifically is required for the interaction with ACF and enhancement of nucleosome sliding, while CHRAC-17 can also interact with p12 of DNA polymerase epsilon. Additionally, the CHRAC-15/17 complex facilitates ACF-mediated chromatin assembly by a mechanism distinct from nucleosome sliding enhancement.\",\n      \"method\": \"In vitro nucleosome sliding assays, chromatin assembly assays, direct protein-protein interaction studies (pulldown/binding), histone-fold protein biochemistry\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of nucleosome sliding and chromatin assembly assays with direct mutagenesis-level dissection of which subunit (CHRAC-15 vs CHRAC-17) is required; multiple orthogonal functional assays in a single rigorous study\",\n      \"pmids\": [\"14759371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CHRAC1 (YCL1) is a histone-fold protein of the H2A/H2B sub-family. In nucleosome reconstitution assays, YCL1 (and its partner YBL1) can form complexes with core histones in solution and on DNA. Glycerol gradient sedimentation shows that YCL1 is part of relatively large complexes. Unlike NF-YB/NF-YC, YCL1 has no intrinsic CCAAT or TATA-binding capacity.\",\n      \"method\": \"Nucleosome reconstitution assays, glycerol gradient sedimentation, biochemical characterization\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro reconstitution and sedimentation assays with multiple methods in a single study, but no functional mutagenesis or cellular validation\",\n      \"pmids\": [\"11000277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CHRAC1 (CHRAC15) is a component of the CHRAC complex (ACF1, SNF2H, CHRAC15, CHRAC17) that becomes physically more associated with KU70/80 after DSB-inducing treatments. The ACF1-containing complex is required for accumulation of KU proteins at DSBs, and cells depleted of ACF1 or SNF2H show failure of both NHEJ and HR, establishing that the CHRAC complex participates in DSB repair pathway choice and execution.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown with DSB repair assays (NHEJ and HR frequency measurement), live-cell imaging of protein accumulation at DSBs\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and functional knockdown with defined cellular phenotype (DSB repair failure), but the CHRAC15-specific contribution is inferred from complex membership rather than tested directly\",\n      \"pmids\": [\"21172662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CHRAC1 (YCL1/CHRAC15) heterodimerizes with POLE3 (DPB4/YBL1/CHRAC17) via histone-like domains, and POLE3 also heterodimerizes with its DNA polymerase epsilon partner POLE4 (DPB3). The POLE3/CHRAC15 dimer associates with the ACF1/SNF2H remodeling complex. The Pole3 gene is regulated in a cell-cycle-dependent manner (peak at S phase entry) by E2F1/4 and MYC as shown by chromatin immunoprecipitation.\",\n      \"method\": \"Protein interaction characterization, chromatin immunoprecipitation (ChIP), promoter mutagenesis, cell-cycle expression analysis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and mutagenesis used; interaction characterized biochemically; single lab study\",\n      \"pmids\": [\"16403426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CHRAC1 interacts with POLE3 to promote DNA double-strand break repair by regulating expression of homology-directed repair proteins and KU80 recruitment. A cancer-associated CHRAC1 D121Y mutation (identified in colorectal cancer) attenuates the CHRAC1-POLE3 interaction and leads to defects in DNA repair.\",\n      \"method\": \"Co-immunoprecipitation, cell-based DNA repair assays, biochemical interaction studies with cancer mutation analysis\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and functional cell-based repair assays with cancer mutation validation; single lab\",\n      \"pmids\": [\"37682991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CHRAC1 physically binds the transcriptional coactivator YAP, enhances transcription of downstream YAP target oncogenes in the Hippo pathway, and promotes lung cancer cell proliferation, migration in vitro, and tumor growth in a KrasG12D mouse model. CHRAC1 silencing inhibits these phenotypes and suppresses xenograft tumor growth.\",\n      \"method\": \"Co-immunoprecipitation (CHRAC1-YAP binding), overexpression and siRNA knockdown with proliferation/migration assays, genetically engineered mouse model, xenograft mouse model\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding demonstrated by Co-IP, functional consequence shown in vitro and in vivo with multiple models; single lab\",\n      \"pmids\": [\"34718437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CHRAC1 interacts with YAP (identified by Bio-ID proximity labeling and confirmed by immunofluorescence co-localization), and CHRAC1 depletion suppresses YAP target gene transcription and inhibits breast and cervical cancer cell proliferation and tumor growth.\",\n      \"method\": \"Bio-ID proximity labeling, immunofluorescence, CCK8 and colony formation assays, subcutaneous xenograft assay, RNA-seq\",\n      \"journal\": \"PeerJ\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Bio-ID and immunofluorescence for interaction; functional assays in vitro and in vivo; single lab, corroborates prior lung cancer study\",\n      \"pmids\": [\"38223760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CHRAC1 transcriptionally activates the NOD-like receptor signaling pathway and promotes IRF9 expression; the CHRAC1-IRF9-GSDMD-CASP-1 axis drives caspase-1-dependent pyroptosis in cardiomyocytes, contributing to doxorubicin-induced cardiotoxicity. CHRAC1 knockdown preserved cardiac function and reduced cell death; IRF9 silencing reversed CHRAC1-driven pathological phenotypes.\",\n      \"method\": \"RNA-seq and ATAC-seq in murine and cellular models, CHRAC1 knockdown/overexpression, IRF9 silencing epistasis, cell viability and ROS assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — integrated ATAC-seq + RNA-seq + epistasis (IRF9 silencing rescues CHRAC1 overexpression phenotype) with in vivo murine model; single lab, no direct biochemical binding assay\",\n      \"pmids\": [\"41325875\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CHRAC1 (CHRAC15/YCL1) is a histone-fold protein that heterodimerizes with CHRAC17 via H2A/H2B-type histone-fold domains; this dimer integrates into the CHRAC/ACF chromatin-remodeling complex by directly binding ACF1, thereby facilitating ATP-dependent nucleosome sliding and chromatin assembly; CHRAC1 also interacts with POLE3 to support DNA double-strand break repair and KU80 recruitment, interacts with the transcriptional coactivator YAP to drive oncogenic gene expression in the Hippo pathway, and transcriptionally activates IRF9 to promote pyroptotic signaling in cardiomyocytes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CHRAC1 is a histone-fold protein of the H2A/H2B sub-family that functions as an accessory subunit of ATP-dependent chromatin-remodeling machinery and, through context-specific partners, in DNA repair and transcriptional control [#0, #1]. It heterodimerizes through its histone-fold domain with CHRAC17/POLE3 and directly contacts the ACF1 subunit of the ACF/CHRAC remodeling complex; this CHRAC15/17 dimer is specifically required for ACF1 binding, enhances ATP-dependent nucleosome sliding, and facilitates chromatin assembly by a mechanism distinct from sliding [#0, #3]. Within this complex CHRAC1 contributes to DNA double-strand break repair: the ACF1-containing remodeler associates with KU70/80 after damage and is required for KU accumulation at breaks and for both NHEJ and HR [#2], and the CHRAC1–POLE3 interaction supports homology-directed repair protein expression and KU80 recruitment, an activity attenuated by the colorectal-cancer-associated CHRAC1 D121Y mutation [#4]. Beyond chromatin remodeling, CHRAC1 binds the Hippo-pathway coactivator YAP and enhances transcription of YAP target oncogenes to drive proliferation and tumor growth in lung, breast, and cervical cancer models [#5, #6], and it transcriptionally activates IRF9 to engage a NOD-like-receptor/GSDMD/caspase-1 pyroptotic axis underlying doxorubicin-induced cardiomyocyte death [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing the biochemical identity of CHRAC1 answered whether it is a histone-fold protein capable of nucleosome-associated function rather than a sequence-specific DNA-binding factor.\",\n      \"evidence\": \"Nucleosome reconstitution and glycerol gradient sedimentation of YCL1 with core histones\",\n      \"pmids\": [\"11000277\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No functional mutagenesis or cellular validation\",\n        \"Did not define the in vivo complex CHRAC1 acts within\",\n        \"Partner specificity for assembly into remodeling complexes untested\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"In vitro reconstitution defined CHRAC1's mechanistic role, showing the CHRAC15/17 dimer bridges to ACF1 and is required to enhance ATP-dependent nucleosome sliding and chromatin assembly.\",\n      \"evidence\": \"In vitro nucleosome sliding and chromatin assembly assays with subunit-resolved dissection\",\n      \"pmids\": [\"14759371\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of the ACF1 contact not resolved\",\n        \"Mechanism distinguishing assembly enhancement from sliding undefined\",\n        \"In vivo consequences of CHRAC1 loss not tested\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Characterizing the histone-fold heterodimers clarified how CHRAC1 partitions between the remodeling complex and DNA polymerase epsilon machinery via shared POLE3 partnering.\",\n      \"evidence\": \"Protein interaction characterization, ChIP, and cell-cycle expression analysis\",\n      \"pmids\": [\"16403426\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of POLE3/CHRAC15 association with ACF1/SNF2H not measured\",\n        \"CHRAC1-specific role versus POLE3 not separated\",\n        \"Single-lab interaction study\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linking the CHRAC complex to damage signaling answered whether ACF-type remodeling participates in DSB repair, showing it is needed for KU recruitment and repair pathway execution.\",\n      \"evidence\": \"Co-IP, siRNA knockdown with NHEJ/HR assays, and live-cell imaging of accumulation at DSBs\",\n      \"pmids\": [\"21172662\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"CHRAC15-specific contribution inferred from complex membership, not directly tested\",\n        \"Direct CHRAC1–KU interaction not demonstrated\",\n        \"Mechanism of remodeler recruitment to breaks unresolved\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Disease-mutation analysis tied CHRAC1's repair role to a concrete molecular interface, showing the CHRAC1–POLE3 contact supports HDR protein expression and KU80 recruitment.\",\n      \"evidence\": \"Co-IP and cell-based DNA repair assays with the cancer-associated D121Y mutation\",\n      \"pmids\": [\"37682991\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How the interaction regulates repair-protein expression mechanistically unclear\",\n        \"Single-lab validation\",\n        \"Structural effect of D121Y not determined\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying a YAP partnership revealed a chromatin-independent oncogenic role, showing CHRAC1 binds YAP and amplifies Hippo-pathway target oncogene transcription to drive lung tumorigenesis.\",\n      \"evidence\": \"Co-IP, knockdown/overexpression proliferation and migration assays, KrasG12D and xenograft mouse models\",\n      \"pmids\": [\"34718437\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct binding interface with YAP not mapped\",\n        \"Relationship between this role and chromatin remodeling function unclear\",\n        \"Single-lab study\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extending the YAP connection to additional cancers tested its generality, confirming CHRAC1 co-localizes with YAP and drives target gene transcription and tumor growth in breast and cervical models.\",\n      \"evidence\": \"Bio-ID proximity labeling, immunofluorescence, colony/proliferation assays, xenograft, RNA-seq\",\n      \"pmids\": [\"38223760\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Proximity labeling does not establish direct binding\",\n        \"Mechanism of YAP target selection unresolved\",\n        \"Single-lab corroboration\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defining a CHRAC1-IRF9 transcriptional axis revealed a pyroptotic function, showing CHRAC1 activates IRF9 to engage GSDMD/caspase-1 cell death in cardiomyocytes during doxorubicin cardiotoxicity.\",\n      \"evidence\": \"RNA-seq, ATAC-seq, knockdown/overexpression, and IRF9-silencing epistasis in murine and cellular models\",\n      \"pmids\": [\"41325875\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct biochemical binding assay for CHRAC1 at the IRF9 locus\",\n        \"How a histone-fold accessory protein achieves gene-specific transcriptional activation unclear\",\n        \"Single-lab study\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how CHRAC1 mechanistically switches between its core chromatin-remodeling/DSB-repair role and its partner-specific transcriptional functions with YAP and IRF9.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model unifying histone-fold remodeling and transcriptional coactivation\",\n        \"Direct DNA/chromatin binding at YAP and IRF9 targets not demonstrated\",\n        \"Whether these roles are independent or share the CHRAC15/17 dimer unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5, 6, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"complexes\": [\"CHRAC\", \"ACF\"],\n    \"partners\": [\"CHRAC17/POLE3\", \"ACF1\", \"SNF2H\", \"KU70\", \"KU80\", \"YAP\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}