{"gene":"CBX1","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1999,"finding":"SUV39H1/Suv39h1 (mammalian SU(VAR)3-9 homologues) physically associate with M31 (CBX1/HP1-beta), forming a mammalian SU(VAR) complex at centromeric heterochromatin during metaphase and at heterochromatic foci during interphase.","method":"Co-immunoprecipitation and immunodetection of endogenous proteins in mammalian cell lines","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-immunoprecipitation and immunolocalization in multiple cell lines, single lab but two orthogonal methods","pmids":["10202156"],"is_preprint":false},{"year":2008,"finding":"DNA damage rapidly mobilizes HP1-beta (CBX1) from chromatin; this mobilization is triggered by CK2-mediated phosphorylation of HP1-beta on Thr51, which disrupts hydrogen bonds folding the chromodomain around H3K9me, releasing HP1-beta. Constitutively chromatin-bound HP1-beta mutant or CK2 inhibition diminishes H2AX phosphorylation, demonstrating HP1-beta mobilization is required to initiate the DNA damage response.","method":"Live-cell imaging (FRAP), site-directed mutagenesis (T51 mutant), CK2 inhibitor treatment, phosphorylation assays, H2AX phosphorylation readout","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (mutagenesis, kinase inhibition, live imaging, biochemical assays) in a single rigorous study establishing mechanism","pmids":["18438399"],"is_preprint":false},{"year":2008,"finding":"HP1-beta (CBX1) is required for normal cerebral neocortex development (neuronal precursor proliferation) and neuromuscular junction formation; Cbx1-null mice die perinatally from respiratory failure with diaphragm neuromuscular junction defects, and Cbx1−/− neurospheres display dramatic genomic instability, demonstrating HP1-beta is not functionally redundant with other HP1 isoforms.","method":"Cbx1 gene knockout mouse, histology, neurosphere culture, in vitro genomic instability assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mouse with specific perinatal lethal phenotype and multiple cellular readouts, demonstrating non-redundant in vivo function","pmids":["19015315"],"is_preprint":false},{"year":2001,"finding":"M31 (CBX1/HP1-beta) colocalizes with macroH2A1.2 at meiotic centromeric heterochromatin, the sex body (XY body), and a focus within the pseudoautosomal region (PAR) containing the Sts gene locus during meiosis in male and female mice.","method":"Immunofluorescence on surface-spread meiocytes from wild-type and sex-chromosomally variant mice","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization by immunofluorescence across multiple mouse genotypes, single lab, no functional assay tied to the colocalization","pmids":["11591824"],"is_preprint":false},{"year":2000,"finding":"M31 (CBX1/HP1-beta) localizes to the chromocenter in round spermatids and is detectable by Western blot in mature spermatozoa despite absence of immunocytological signal in elongated spermatids, indicating a role in higher-order organization of sperm DNA.","method":"Immunocytochemistry, Western blotting across testicular cell types","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization by orthogonal methods (ICC and Western blot) at multiple stages, single lab","pmids":["10623467"],"is_preprint":false},{"year":1999,"finding":"M31 (CBX1/HP1-beta) concentrates in the XY body during male meiosis; a novel nuclear isoform M31(p21) is expressed coincident with XY body formation in neonatal mice, suggesting CBX1 participates in meiotic sex chromosome inactivation via heterochromatin-induced repression.","method":"Immunofluorescence on testicular sections and meiocytes; Western blot characterization of isoforms","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization by immunofluorescence and isoform detection by Western blot, single lab, two orthogonal methods","pmids":["10516442"],"is_preprint":false},{"year":2010,"finding":"CBX1 (HP1-beta) chromodomain specifically recognizes and binds H3K9me3 peptides, replicating the structural and binding features of Drosophila HP1; structural and mutagenic analysis defined the molecular determinants of methyllysine sequence-context binding for CBX1 (and the other HP1 homologs CBX3, CBX5).","method":"X-ray crystallography, biophysical binding assays (ITC, FP), site-directed mutagenesis, peptide permutation arrays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures combined with mutagenesis and multiple biophysical binding assays in a single study","pmids":["21047797"],"is_preprint":false},{"year":2012,"finding":"KAP-1 phosphorylation on Ser-473 by Chk2 promotes mobilization of HP1-beta (CBX1) from heterochromatin and enables DNA double-strand break repair in heterochromatin; a non-phosphorylatable S473A KAP-1 mutant causes defective HP1-beta mobilization and impaired heterochromatin DSB repair that is rescued by HP1-beta depletion.","method":"Expression of phosphomutant S473A KAP-1, shRNA depletion of HP1-beta, DNA damage sensitivity assays, immunofluorescence for DSB repair markers","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis via phosphomutant + rescue by HP1-beta knockdown, multiple orthogonal functional assays, single lab","pmids":["22715096"],"is_preprint":false},{"year":2009,"finding":"The C-terminal domain of Ring1B adopts a variant ubiquitin-like fold with a conserved surface responsible for interaction with CBX proteins (including CBX1) within PRC1 and for Ring1B homodimerization, as defined by crystal structure and mutational analysis.","method":"X-ray crystallography of Ring1B C-terminal domain, mutational analysis of conserved surface","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure combined with mutagenesis, single lab, two orthogonal methods (structure + mutant binding assays)","pmids":["19791798"],"is_preprint":false},{"year":2009,"finding":"HP1-beta (CBX1) localizes to fibrillarin-positive nucleolar interiors in a manner independent of SUV39h histone methyltransferases and HDAC activity, distinguishing this nucleolar association from its chromocenter localization which does depend on SUV39h/H3K9 trimethylation.","method":"Immunofluorescence in SUV39h-deficient cells and HDAC inhibitor-treated cells, colocalization with fibrillarin and RNA Pol I markers","journal":"Chromosoma","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function (SUV39h KO) plus pharmacological inhibition with subcellular localization readouts, single lab","pmids":["20033197"],"is_preprint":false},{"year":2022,"finding":"CBX1 promotes NPC cell migration, invasion, and proliferation through transcriptional repression of MAP7 via H3K9me3-mediated heterochromatin formation; additionally, CBX1 facilitates immune evasion through IFN-γ-STAT1 signaling-mediated PD-L1 upregulation. The CBX1 mRNA transcript is destabilized by the m6A reader YTHDF3.","method":"CBX1 knockdown/overexpression in NPC cells, ChIP for H3K9me3, luciferase reporter, Western blot for STAT1/PD-L1, YTHDF3 interaction assays","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays (KD/OE, ChIP, reporter) with pathway placement, single lab","pmids":["36310139"],"is_preprint":false},{"year":2018,"finding":"CBX1 interacts with transcription factor HMGA2 to activate Wnt/β-catenin signaling in hepatocellular carcinoma cells; suppression of β-catenin by siRNA or the inhibitor XAV-939 markedly attenuates CBX1-mediated cell growth.","method":"Co-immunoprecipitation of CBX1 with HMGA2, siRNA knockdown of β-catenin, pharmacological inhibition with XAV-939, proliferation and migration assays","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP plus epistasis via inhibitor/siRNA rescue, single lab","pmids":["30031230"],"is_preprint":false},{"year":2022,"finding":"CBX1, together with PurB and Sp3, forms a trimeric complex that binds cardiomyocyte gene loci, positions nucleosomes, and recruits the PRC2 complex to deposit H3K27me3, thereby mediating long-term tissue-specific gene silencing; knockdown of any one member is sufficient to induce cardiomyocyte gene expression in fibroblasts.","method":"Co-immunoprecipitation, high-throughput DNA sequencing (ChIP-seq), gene knockdown (shRNA), in vivo gene editing, cardiomyocyte reprogramming assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ChIP-seq, and KD with functional readout, single lab, multiple orthogonal methods","pmids":["35605661"],"is_preprint":false},{"year":2023,"finding":"Heterozygous de novo variants in the CBX1 chromodomain reduce HP1-beta binding to heterochromatin (confirmed by ChIP) and cause a neurodevelopmental disorder; mutant HP1-beta likely sequesters wild-type HP1-beta through homodimer/heterodimer formation, acting as a dominant-negative. The HP1-beta interactome was largely unchanged between wild-type and mutant.","method":"Clinical genetics, in vitro cellular assays, ChIP, HP1-beta interactome analysis (mass spectrometry), Cbx1 chromodomain mutant mouse lines with neurobehavioral testing","journal":"Genetics in medicine : official journal of the American College of Medical Genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP, interactome MS, mouse behavioral phenotyping, human genetics), convergent evidence across human patients and mouse model","pmids":["37087635"],"is_preprint":false},{"year":2002,"finding":"The chromo shadow domain (CSD) of mouse M31 (CBX1/HP1-beta) was crystallized and diffraction data collected to 2.9 Å, providing initial structural information on this dimerization domain.","method":"Protein crystallization, X-ray diffraction data collection","journal":"Acta crystallographica. Section D, Biological crystallography","confidence":"Low","confidence_rationale":"Tier 1 / Weak — crystallization and preliminary data only, no functional validation reported in the abstract","pmids":["12037314"],"is_preprint":false},{"year":2024,"finding":"CBX1 promotes hepatocellular carcinoma EMT and TKI (sorafenib/lenvatinib) resistance through the IGF-1R/AKT/SNAIL signaling axis; CBX1 oncogenic activities are attenuated by AKT pathway inhibition or IGF-1R silencing.","method":"CBX1 knockdown/overexpression in HCC cells, AKT inhibitor treatment, IGF-1R siRNA, in vitro proliferation/invasion/migration assays, xenograft mouse model","journal":"Hepatology international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via inhibitor/siRNA rescue, KD/OE with pathway placement, in vivo validation, single lab","pmids":["38769286"],"is_preprint":false}],"current_model":"CBX1 (HP1-beta) is a chromodomain-containing heterochromatin protein that specifically reads H3K9me3 via its chromodomain, associates with SUV39H1 and other HP1-interacting partners to maintain pericentromeric heterochromatin organization, and is mobilized from chromatin upon DNA damage through CK2-mediated Thr51 phosphorylation to facilitate H2AX phosphorylation and DNA repair; it also forms complexes with PurB/Sp3 and interacts with PRC2 to enforce tissue-specific gene silencing via H3K27me3 deposition, and its chromodomain-disrupting mutations cause dominant-negative neurodevelopmental pathology."},"narrative":{"mechanistic_narrative":"CBX1 (HP1-beta) is a chromodomain-containing heterochromatin protein whose chromodomain specifically reads H3K9me3, establishing it as a reader that translates this histone mark into higher-order chromatin organization [PMID:21047797]. At pericentromeric and centromeric heterochromatin it associates with the H3K9 methyltransferase SUV39H1 [PMID:10202156], and its chromocenter localization depends on SUV39h/H3K9 trimethylation, whereas a distinct nucleolar pool localizes independently of SUV39h and HDAC activity [PMID:20033197]. CBX1 has non-redundant developmental functions: its loss in mice causes perinatal lethality with neocortical and neuromuscular junction defects and genomic instability [PMID:19015315]. Beyond constitutive heterochromatin, CBX1 nucleates tissue-specific silencing by forming a trimeric complex with PurB and Sp3 that positions nucleosomes and recruits PRC2 to deposit H3K27me3 at cardiomyocyte loci [PMID:35605661]. CBX1 also acts dynamically in the DNA damage response: CK2-mediated phosphorylation of Thr51 disrupts chromodomain folding around H3K9me, mobilizing HP1-beta from chromatin, an event required to initiate H2AX phosphorylation [PMID:18438399]; KAP-1 Ser473 phosphorylation by Chk2 likewise drives HP1-beta mobilization to enable double-strand break repair within heterochromatin [PMID:22715096]. Heterozygous de novo chromodomain variants that reduce heterochromatin binding cause a dominant-negative neurodevelopmental disorder, with mutant HP1-beta sequestering wild-type protein [PMID:37087635]. In cancer contexts CBX1 promotes proliferation, invasion, EMT, and immune evasion through H3K9me3-mediated repression and signaling axes including Wnt/β-catenin and IGF-1R/AKT/SNAIL [PMID:36310139, PMID:30031230, PMID:38769286].","teleology":[{"year":1999,"claim":"Establishing how CBX1 connects to the histone-modifying machinery of heterochromatin, this work showed it physically partners with the SU(VAR)3-9 methyltransferase at centromeric heterochromatin.","evidence":"Co-immunoprecipitation and immunolocalization of endogenous SUV39H1 and M31/CBX1 in mammalian cell lines","pmids":["10202156"],"confidence":"Medium","gaps":["Did not define whether the interaction is direct or mediated by chromatin","Functional consequence of the complex for silencing not tested"]},{"year":2010,"claim":"To define the molecular basis of CBX1 chromatin reading, structural and biophysical work showed its chromodomain specifically binds H3K9me3 and resolved the determinants of methyllysine recognition.","evidence":"X-ray crystallography with ITC/FP binding assays, mutagenesis, and peptide arrays","pmids":["21047797"],"confidence":"High","gaps":["Binding affinities measured on peptides, not native chromatin","Does not address how reading is converted into silencing in vivo"]},{"year":2008,"claim":"Genetic ablation answered whether CBX1 has a unique organismal role, demonstrating non-redundant requirements in neurodevelopment and genome stability.","evidence":"Cbx1-null mouse with histology, neurosphere culture, and genomic instability assays","pmids":["19015315"],"confidence":"High","gaps":["Molecular cause of genomic instability not pinpointed","Cell-type-specific contributions not dissected"]},{"year":2008,"claim":"Resolving how a stable heterochromatin reader participates in dynamic repair, this study showed CK2 phosphorylation of Thr51 releases HP1-beta from chromatin to initiate the DNA damage response.","evidence":"FRAP live imaging, T51 phosphomutant, CK2 inhibition, and H2AX phosphorylation readouts","pmids":["18438399"],"confidence":"High","gaps":["Direct link between HP1-beta release and the H2AX kinase not fully mechanistic","Genomic loci affected not mapped"]},{"year":2012,"claim":"Extending the mobilization model, this work placed a second signaling input on HP1-beta release required specifically for repair within heterochromatin.","evidence":"KAP-1 S473A phosphomutant, HP1-beta shRNA rescue, and DSB repair marker assays","pmids":["22715096"],"confidence":"High","gaps":["How KAP-1 phosphorylation mechanistically displaces HP1-beta unresolved","Interplay with the CK2/Thr51 pathway not reconciled"]},{"year":2009,"claim":"Structural characterization of Ring1B defined a surface mediating CBX-protein interaction, situating CBX1 within PRC1-type assemblies.","evidence":"Crystal structure of Ring1B C-terminal ubiquitin-like domain with mutational interaction analysis","pmids":["19791798"],"confidence":"High","gaps":["Did not test CBX1 binding directly versus other CBX paralogs","Functional role of CBX1 in this complex not assayed"]},{"year":2022,"claim":"Defining a route to tissue-specific silencing, CBX1 was shown to form a PurB/Sp3 complex that recruits PRC2 and deposits H3K27me3 at lineage genes.","evidence":"Reciprocal Co-IP, ChIP-seq, shRNA knockdown, and cardiomyocyte reprogramming assay","pmids":["35605661"],"confidence":"Medium","gaps":["Direct versus indirect PRC2 recruitment not separated","Generality beyond cardiomyocyte loci untested"]},{"year":2023,"claim":"Establishing a disease mechanism, de novo chromodomain variants were shown to impair heterochromatin binding and cause a neurodevelopmental disorder by a dominant-negative sequestration model.","evidence":"Human genetics, ChIP, interactome mass spectrometry, and chromodomain-mutant mouse behavioral phenotyping","pmids":["37087635"],"confidence":"High","gaps":["Direct demonstration of wild-type sequestration inferred rather than shown","Downstream dysregulated genes not defined"]},{"year":2024,"claim":"Multiple cancer studies positioned CBX1 as an oncogenic driver acting through H3K9me3 repression and signaling axes, linking its chromatin function to tumor phenotypes.","evidence":"Knockdown/overexpression with ChIP, reporter, inhibitor/siRNA epistasis, and xenografts across NPC and HCC models","pmids":["36310139","30031230","38769286"],"confidence":"Medium","gaps":["Direct chromatin targets versus indirect signaling effects not cleanly separated","Single-lab models per cancer type"]},{"year":null,"claim":"How CBX1's reader activity, signaling-dependent mobilization, and PRC1/PRC2 partnerships are coordinated into a unified mechanism remains unresolved.","evidence":"No integrating study in the available corpus","pmids":[],"confidence":"Medium","gaps":["No genome-wide map reconciling H3K9me3 reading with H3K27me3 deposition","Mechanistic basis of paralog non-redundancy unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[6]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[10,12]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[12]}],"localization":[{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,3]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[9]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[6,12]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[1,7]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[10,12]}],"complexes":["PRC1","CBX1-PurB-Sp3 complex","SUV39H1-HP1 complex"],"partners":["SUV39H1","KAP1","RING1B","PURB","SP3","HMGA2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P83916","full_name":"Chromobox protein homolog 1","aliases":["HP1Hsbeta","Heterochromatin protein 1 homolog beta","HP1 beta","Heterochromatin protein p25","M31","Modifier 1 protein","p25beta"],"length_aa":185,"mass_kda":21.4,"function":"Component of heterochromatin, which recognizes and binds histone H3 tails methylated at 'Lys-9', leading to epigenetic repression (By similarity). Also recognizes and binds histone H1.4 methylated at 'Lys-26' (H1.4K26me) (PubMed:16127177). Excluded from chromatin when histone H1.4 is Simultaneously methylated at Lys-26 (H1.4K26me) and phosphorylated at Ser-27 (H1.4S27Ph) (PubMed:16127177). Interaction with lamin B receptor (LBR) can contribute to the association of the heterochromatin with the inner nuclear membrane (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P83916/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CBX1","classification":"Not Classified","n_dependent_lines":277,"n_total_lines":1208,"dependency_fraction":0.2293046357615894},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000108468","cell_line_id":"CID001101","localizations":[{"compartment":"nuclear_punctae","grade":3},{"compartment":"chromatin","grade":1},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"TRIM28","stoichiometry":10.0},{"gene":"CBX3","stoichiometry":10.0},{"gene":"NUCKS1","stoichiometry":10.0},{"gene":"ADNP","stoichiometry":4.0},{"gene":"PSIP1","stoichiometry":0.2},{"gene":"GLRX3","stoichiometry":0.2},{"gene":"ACTL6A","stoichiometry":0.2},{"gene":"SS18","stoichiometry":0.2},{"gene":"TRIM24","stoichiometry":0.2},{"gene":"KPNA3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001101","total_profiled":1310},"omim":[{"mim_id":"617884","title":"HEPATOMA-DERIVED GROWTH FACTOR-LIKE PROTEIN 2; HDGFL2","url":"https://www.omim.org/entry/617884"},{"mim_id":"613644","title":"ACTIVATING TRANSCRIPTION FACTOR 7-INTERACTING PROTEIN; ATF7IP","url":"https://www.omim.org/entry/613644"},{"mim_id":"613198","title":"LYSINE METHYLTRANSFERASE 5C; KMT5C","url":"https://www.omim.org/entry/613198"},{"mim_id":"612000","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 66; TRIM66","url":"https://www.omim.org/entry/612000"},{"mim_id":"606503","title":"SUV39H2 HISTONE LYSINE METHYLTRANSFERASE; SUV39H2","url":"https://www.omim.org/entry/606503"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CBX1"},"hgnc":{"alias_symbol":["HP1Hs-beta","M31","MOD1","CBX","HP1-BETA","Hp1beta"],"prev_symbol":[]},"alphafold":{"accession":"P83916","domains":[{"cath_id":"2.40.50.40","chopping":"22-74","consensus_level":"high","plddt":85.0179,"start":22,"end":74},{"cath_id":"2.40.50.40","chopping":"113-165","consensus_level":"high","plddt":93.9345,"start":113,"end":165}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P83916","model_url":"https://alphafold.ebi.ac.uk/files/AF-P83916-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P83916-F1-predicted_aligned_error_v6.png","plddt_mean":76.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CBX1","jax_strain_url":"https://www.jax.org/strain/search?query=CBX1"},"sequence":{"accession":"P83916","fasta_url":"https://rest.uniprot.org/uniprotkb/P83916.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P83916/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P83916"}},"corpus_meta":[{"pmid":"22325352","id":"PMC_22325352","title":"PCGF homologs, CBX proteins, and RYBP define functionally distinct PRC1 family complexes.","date":"2012","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/22325352","citation_count":702,"is_preprint":false},{"pmid":"10202156","id":"PMC_10202156","title":"Functional mammalian homologues of the Drosophila PEV-modifier Su(var)3-9 encode centromere-associated proteins which complex with the heterochromatin component M31.","date":"1999","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/10202156","citation_count":380,"is_preprint":false},{"pmid":"18438399","id":"PMC_18438399","title":"HP1-beta mobilization promotes chromatin changes that initiate the DNA damage response.","date":"2008","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/18438399","citation_count":341,"is_preprint":false},{"pmid":"22226355","id":"PMC_22226355","title":"Nonoverlapping functions of the Polycomb group Cbx family of proteins in embryonic stem cells.","date":"2012","source":"Cell 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Nai8 with high capacity of degrading novel pyrimidynyloxybenzoic herbicide ZJ0273 and naphthalene.","date":"2015","source":"Environmental science and pollution research international","url":"https://pubmed.ncbi.nlm.nih.gov/26490930","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":31315,"output_tokens":3917,"usd":0.07635,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11711,"output_tokens":3272,"usd":0.070178,"stage2_stop_reason":"end_turn"},"total_usd":0.146528,"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\": 1999,\n      \"finding\": \"SUV39H1/Suv39h1 (mammalian SU(VAR)3-9 homologues) physically associate with M31 (CBX1/HP1-beta), forming a mammalian SU(VAR) complex at centromeric heterochromatin during metaphase and at heterochromatic foci during interphase.\",\n      \"method\": \"Co-immunoprecipitation and immunodetection of endogenous proteins in mammalian cell lines\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-immunoprecipitation and immunolocalization in multiple cell lines, single lab but two orthogonal methods\",\n      \"pmids\": [\"10202156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"DNA damage rapidly mobilizes HP1-beta (CBX1) from chromatin; this mobilization is triggered by CK2-mediated phosphorylation of HP1-beta on Thr51, which disrupts hydrogen bonds folding the chromodomain around H3K9me, releasing HP1-beta. Constitutively chromatin-bound HP1-beta mutant or CK2 inhibition diminishes H2AX phosphorylation, demonstrating HP1-beta mobilization is required to initiate the DNA damage response.\",\n      \"method\": \"Live-cell imaging (FRAP), site-directed mutagenesis (T51 mutant), CK2 inhibitor treatment, phosphorylation assays, H2AX phosphorylation readout\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (mutagenesis, kinase inhibition, live imaging, biochemical assays) in a single rigorous study establishing mechanism\",\n      \"pmids\": [\"18438399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HP1-beta (CBX1) is required for normal cerebral neocortex development (neuronal precursor proliferation) and neuromuscular junction formation; Cbx1-null mice die perinatally from respiratory failure with diaphragm neuromuscular junction defects, and Cbx1−/− neurospheres display dramatic genomic instability, demonstrating HP1-beta is not functionally redundant with other HP1 isoforms.\",\n      \"method\": \"Cbx1 gene knockout mouse, histology, neurosphere culture, in vitro genomic instability assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mouse with specific perinatal lethal phenotype and multiple cellular readouts, demonstrating non-redundant in vivo function\",\n      \"pmids\": [\"19015315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"M31 (CBX1/HP1-beta) colocalizes with macroH2A1.2 at meiotic centromeric heterochromatin, the sex body (XY body), and a focus within the pseudoautosomal region (PAR) containing the Sts gene locus during meiosis in male and female mice.\",\n      \"method\": \"Immunofluorescence on surface-spread meiocytes from wild-type and sex-chromosomally variant mice\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization by immunofluorescence across multiple mouse genotypes, single lab, no functional assay tied to the colocalization\",\n      \"pmids\": [\"11591824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"M31 (CBX1/HP1-beta) localizes to the chromocenter in round spermatids and is detectable by Western blot in mature spermatozoa despite absence of immunocytological signal in elongated spermatids, indicating a role in higher-order organization of sperm DNA.\",\n      \"method\": \"Immunocytochemistry, Western blotting across testicular cell types\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization by orthogonal methods (ICC and Western blot) at multiple stages, single lab\",\n      \"pmids\": [\"10623467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"M31 (CBX1/HP1-beta) concentrates in the XY body during male meiosis; a novel nuclear isoform M31(p21) is expressed coincident with XY body formation in neonatal mice, suggesting CBX1 participates in meiotic sex chromosome inactivation via heterochromatin-induced repression.\",\n      \"method\": \"Immunofluorescence on testicular sections and meiocytes; Western blot characterization of isoforms\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization by immunofluorescence and isoform detection by Western blot, single lab, two orthogonal methods\",\n      \"pmids\": [\"10516442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CBX1 (HP1-beta) chromodomain specifically recognizes and binds H3K9me3 peptides, replicating the structural and binding features of Drosophila HP1; structural and mutagenic analysis defined the molecular determinants of methyllysine sequence-context binding for CBX1 (and the other HP1 homologs CBX3, CBX5).\",\n      \"method\": \"X-ray crystallography, biophysical binding assays (ITC, FP), site-directed mutagenesis, peptide permutation arrays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures combined with mutagenesis and multiple biophysical binding assays in a single study\",\n      \"pmids\": [\"21047797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KAP-1 phosphorylation on Ser-473 by Chk2 promotes mobilization of HP1-beta (CBX1) from heterochromatin and enables DNA double-strand break repair in heterochromatin; a non-phosphorylatable S473A KAP-1 mutant causes defective HP1-beta mobilization and impaired heterochromatin DSB repair that is rescued by HP1-beta depletion.\",\n      \"method\": \"Expression of phosphomutant S473A KAP-1, shRNA depletion of HP1-beta, DNA damage sensitivity assays, immunofluorescence for DSB repair markers\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis via phosphomutant + rescue by HP1-beta knockdown, multiple orthogonal functional assays, single lab\",\n      \"pmids\": [\"22715096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The C-terminal domain of Ring1B adopts a variant ubiquitin-like fold with a conserved surface responsible for interaction with CBX proteins (including CBX1) within PRC1 and for Ring1B homodimerization, as defined by crystal structure and mutational analysis.\",\n      \"method\": \"X-ray crystallography of Ring1B C-terminal domain, mutational analysis of conserved surface\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure combined with mutagenesis, single lab, two orthogonal methods (structure + mutant binding assays)\",\n      \"pmids\": [\"19791798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"HP1-beta (CBX1) localizes to fibrillarin-positive nucleolar interiors in a manner independent of SUV39h histone methyltransferases and HDAC activity, distinguishing this nucleolar association from its chromocenter localization which does depend on SUV39h/H3K9 trimethylation.\",\n      \"method\": \"Immunofluorescence in SUV39h-deficient cells and HDAC inhibitor-treated cells, colocalization with fibrillarin and RNA Pol I markers\",\n      \"journal\": \"Chromosoma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function (SUV39h KO) plus pharmacological inhibition with subcellular localization readouts, single lab\",\n      \"pmids\": [\"20033197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CBX1 promotes NPC cell migration, invasion, and proliferation through transcriptional repression of MAP7 via H3K9me3-mediated heterochromatin formation; additionally, CBX1 facilitates immune evasion through IFN-γ-STAT1 signaling-mediated PD-L1 upregulation. The CBX1 mRNA transcript is destabilized by the m6A reader YTHDF3.\",\n      \"method\": \"CBX1 knockdown/overexpression in NPC cells, ChIP for H3K9me3, luciferase reporter, Western blot for STAT1/PD-L1, YTHDF3 interaction assays\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays (KD/OE, ChIP, reporter) with pathway placement, single lab\",\n      \"pmids\": [\"36310139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CBX1 interacts with transcription factor HMGA2 to activate Wnt/β-catenin signaling in hepatocellular carcinoma cells; suppression of β-catenin by siRNA or the inhibitor XAV-939 markedly attenuates CBX1-mediated cell growth.\",\n      \"method\": \"Co-immunoprecipitation of CBX1 with HMGA2, siRNA knockdown of β-catenin, pharmacological inhibition with XAV-939, proliferation and migration assays\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP plus epistasis via inhibitor/siRNA rescue, single lab\",\n      \"pmids\": [\"30031230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CBX1, together with PurB and Sp3, forms a trimeric complex that binds cardiomyocyte gene loci, positions nucleosomes, and recruits the PRC2 complex to deposit H3K27me3, thereby mediating long-term tissue-specific gene silencing; knockdown of any one member is sufficient to induce cardiomyocyte gene expression in fibroblasts.\",\n      \"method\": \"Co-immunoprecipitation, high-throughput DNA sequencing (ChIP-seq), gene knockdown (shRNA), in vivo gene editing, cardiomyocyte reprogramming assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ChIP-seq, and KD with functional readout, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"35605661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Heterozygous de novo variants in the CBX1 chromodomain reduce HP1-beta binding to heterochromatin (confirmed by ChIP) and cause a neurodevelopmental disorder; mutant HP1-beta likely sequesters wild-type HP1-beta through homodimer/heterodimer formation, acting as a dominant-negative. The HP1-beta interactome was largely unchanged between wild-type and mutant.\",\n      \"method\": \"Clinical genetics, in vitro cellular assays, ChIP, HP1-beta interactome analysis (mass spectrometry), Cbx1 chromodomain mutant mouse lines with neurobehavioral testing\",\n      \"journal\": \"Genetics in medicine : official journal of the American College of Medical Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP, interactome MS, mouse behavioral phenotyping, human genetics), convergent evidence across human patients and mouse model\",\n      \"pmids\": [\"37087635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The chromo shadow domain (CSD) of mouse M31 (CBX1/HP1-beta) was crystallized and diffraction data collected to 2.9 Å, providing initial structural information on this dimerization domain.\",\n      \"method\": \"Protein crystallization, X-ray diffraction data collection\",\n      \"journal\": \"Acta crystallographica. Section D, Biological crystallography\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystallization and preliminary data only, no functional validation reported in the abstract\",\n      \"pmids\": [\"12037314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CBX1 promotes hepatocellular carcinoma EMT and TKI (sorafenib/lenvatinib) resistance through the IGF-1R/AKT/SNAIL signaling axis; CBX1 oncogenic activities are attenuated by AKT pathway inhibition or IGF-1R silencing.\",\n      \"method\": \"CBX1 knockdown/overexpression in HCC cells, AKT inhibitor treatment, IGF-1R siRNA, in vitro proliferation/invasion/migration assays, xenograft mouse model\",\n      \"journal\": \"Hepatology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via inhibitor/siRNA rescue, KD/OE with pathway placement, in vivo validation, single lab\",\n      \"pmids\": [\"38769286\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CBX1 (HP1-beta) is a chromodomain-containing heterochromatin protein that specifically reads H3K9me3 via its chromodomain, associates with SUV39H1 and other HP1-interacting partners to maintain pericentromeric heterochromatin organization, and is mobilized from chromatin upon DNA damage through CK2-mediated Thr51 phosphorylation to facilitate H2AX phosphorylation and DNA repair; it also forms complexes with PurB/Sp3 and interacts with PRC2 to enforce tissue-specific gene silencing via H3K27me3 deposition, and its chromodomain-disrupting mutations cause dominant-negative neurodevelopmental pathology.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CBX1 (HP1-beta) is a chromodomain-containing heterochromatin protein whose chromodomain specifically reads H3K9me3, establishing it as a reader that translates this histone mark into higher-order chromatin organization [#6]. At pericentromeric and centromeric heterochromatin it associates with the H3K9 methyltransferase SUV39H1 [#0], and its chromocenter localization depends on SUV39h/H3K9 trimethylation, whereas a distinct nucleolar pool localizes independently of SUV39h and HDAC activity [#9]. CBX1 has non-redundant developmental functions: its loss in mice causes perinatal lethality with neocortical and neuromuscular junction defects and genomic instability [#2]. Beyond constitutive heterochromatin, CBX1 nucleates tissue-specific silencing by forming a trimeric complex with PurB and Sp3 that positions nucleosomes and recruits PRC2 to deposit H3K27me3 at cardiomyocyte loci [#12]. CBX1 also acts dynamically in the DNA damage response: CK2-mediated phosphorylation of Thr51 disrupts chromodomain folding around H3K9me, mobilizing HP1-beta from chromatin, an event required to initiate H2AX phosphorylation [#1]; KAP-1 Ser473 phosphorylation by Chk2 likewise drives HP1-beta mobilization to enable double-strand break repair within heterochromatin [#7]. Heterozygous de novo chromodomain variants that reduce heterochromatin binding cause a dominant-negative neurodevelopmental disorder, with mutant HP1-beta sequestering wild-type protein [#13]. In cancer contexts CBX1 promotes proliferation, invasion, EMT, and immune evasion through H3K9me3-mediated repression and signaling axes including Wnt/\\u03b2-catenin and IGF-1R/AKT/SNAIL [#10, #11, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing how CBX1 connects to the histone-modifying machinery of heterochromatin, this work showed it physically partners with the SU(VAR)3-9 methyltransferase at centromeric heterochromatin.\",\n      \"evidence\": \"Co-immunoprecipitation and immunolocalization of endogenous SUV39H1 and M31/CBX1 in mammalian cell lines\",\n      \"pmids\": [\"10202156\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define whether the interaction is direct or mediated by chromatin\", \"Functional consequence of the complex for silencing not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"To define the molecular basis of CBX1 chromatin reading, structural and biophysical work showed its chromodomain specifically binds H3K9me3 and resolved the determinants of methyllysine recognition.\",\n      \"evidence\": \"X-ray crystallography with ITC/FP binding assays, mutagenesis, and peptide arrays\",\n      \"pmids\": [\"21047797\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding affinities measured on peptides, not native chromatin\", \"Does not address how reading is converted into silencing in vivo\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Genetic ablation answered whether CBX1 has a unique organismal role, demonstrating non-redundant requirements in neurodevelopment and genome stability.\",\n      \"evidence\": \"Cbx1-null mouse with histology, neurosphere culture, and genomic instability assays\",\n      \"pmids\": [\"19015315\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular cause of genomic instability not pinpointed\", \"Cell-type-specific contributions not dissected\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolving how a stable heterochromatin reader participates in dynamic repair, this study showed CK2 phosphorylation of Thr51 releases HP1-beta from chromatin to initiate the DNA damage response.\",\n      \"evidence\": \"FRAP live imaging, T51 phosphomutant, CK2 inhibition, and H2AX phosphorylation readouts\",\n      \"pmids\": [\"18438399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct link between HP1-beta release and the H2AX kinase not fully mechanistic\", \"Genomic loci affected not mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extending the mobilization model, this work placed a second signaling input on HP1-beta release required specifically for repair within heterochromatin.\",\n      \"evidence\": \"KAP-1 S473A phosphomutant, HP1-beta shRNA rescue, and DSB repair marker assays\",\n      \"pmids\": [\"22715096\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How KAP-1 phosphorylation mechanistically displaces HP1-beta unresolved\", \"Interplay with the CK2/Thr51 pathway not reconciled\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Structural characterization of Ring1B defined a surface mediating CBX-protein interaction, situating CBX1 within PRC1-type assemblies.\",\n      \"evidence\": \"Crystal structure of Ring1B C-terminal ubiquitin-like domain with mutational interaction analysis\",\n      \"pmids\": [\"19791798\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not test CBX1 binding directly versus other CBX paralogs\", \"Functional role of CBX1 in this complex not assayed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defining a route to tissue-specific silencing, CBX1 was shown to form a PurB/Sp3 complex that recruits PRC2 and deposits H3K27me3 at lineage genes.\",\n      \"evidence\": \"Reciprocal Co-IP, ChIP-seq, shRNA knockdown, and cardiomyocyte reprogramming assay\",\n      \"pmids\": [\"35605661\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect PRC2 recruitment not separated\", \"Generality beyond cardiomyocyte loci untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Establishing a disease mechanism, de novo chromodomain variants were shown to impair heterochromatin binding and cause a neurodevelopmental disorder by a dominant-negative sequestration model.\",\n      \"evidence\": \"Human genetics, ChIP, interactome mass spectrometry, and chromodomain-mutant mouse behavioral phenotyping\",\n      \"pmids\": [\"37087635\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration of wild-type sequestration inferred rather than shown\", \"Downstream dysregulated genes not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Multiple cancer studies positioned CBX1 as an oncogenic driver acting through H3K9me3 repression and signaling axes, linking its chromatin function to tumor phenotypes.\",\n      \"evidence\": \"Knockdown/overexpression with ChIP, reporter, inhibitor/siRNA epistasis, and xenografts across NPC and HCC models\",\n      \"pmids\": [\"36310139\", \"30031230\", \"38769286\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct chromatin targets versus indirect signaling effects not cleanly separated\", \"Single-lab models per cancer type\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CBX1's reader activity, signaling-dependent mobilization, and PRC1/PRC2 partnerships are coordinated into a unified mechanism remains unresolved.\",\n      \"evidence\": \"No integrating study in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No genome-wide map reconciling H3K9me3 reading with H3K27me3 deposition\", \"Mechanistic basis of paralog non-redundancy unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [10, 12]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [6, 12]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [1, 7]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [10, 12]}\n    ],\n    \"complexes\": [\"PRC1\", \"CBX1-PurB-Sp3 complex\", \"SUV39H1-HP1 complex\"],\n    \"partners\": [\"SUV39H1\", \"KAP1\", \"RING1B\", \"PURB\", \"SP3\", \"HMGA2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}