{"gene":"RIOX1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2004,"finding":"NO66 localizes constitutively to the nucleolus (granular component) and to nucleoplasmic entities overlapping with late-replicating heterochromatin clusters; it cofractionates with large preribosomal particles but is absent from cytoplasmic ribosomes, indicating a role in ribosome biogenesis and/or heterochromatin replication/remodeling.","method":"Immunolocalization (monoclonal antibodies), colocalization with Ki-67, HP1α, and PCNA, biochemical fractionation, mass spectrometry of nucleolar proteins from Xenopus laevis oocyte amplified nucleoli","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct fractionation and immunolocalization with multiple markers in single study; no functional mutagenesis to dissect mechanism","pmids":["14742713"],"is_preprint":false},{"year":2009,"finding":"NO66 directly interacts with the osteoblast-specific transcription factor Osterix (Osx) and inhibits Osx-mediated promoter activation; NO66 exhibits JmjC-dependent histone demethylase activity specific for H3K4me and H3K36me both in vitro and in vivo, and this demethylase activity is required for repression of osteoblast-specific promoters.","method":"Proteomics/co-immunoprecipitation to identify Osx-interacting proteins, in vitro histone demethylase assay, in vivo chromatin immunoprecipitation (ChIP), siRNA knockdown of NO66 with readout of osteoblast differentiation/mineralization and target gene expression","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro enzymatic assay combined with in vivo ChIP, knockdown phenotype, and protein interaction; replicated in subsequent studies","pmids":["19927124"],"is_preprint":false},{"year":2012,"finding":"PHF19 (a PRC2 component) associates with NO66, and PHF19 is required to recruit both the PRC2 complex and NO66 to stem cell genes during differentiation; recruitment leads to H3K36me3 demethylation by NO66 and PRC2-mediated H3K27me3, resulting in transcriptional silencing.","method":"Co-immunoprecipitation, ChIP, knockdown of PHF19 with readout of H3K36me3/H3K27me3 levels and gene expression in mouse embryonic stem cells","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP for multiple histone marks, genetic knockdown with defined chromatin and transcriptional phenotype; published in high-impact journal with replication of NO66 demethylase role","pmids":["23160351"],"is_preprint":false},{"year":2013,"finding":"Crystal structure of NO66 reveals it forms a functional tetramer; a hinge domain links the N-terminal JmjC domain and C-terminal winged helix-turn-helix (wHTH) domain, and both are essential for tetrameric assembly. The oligomerization interface of NO66 interacts with a conserved fragment of Osterix, and hinge domain-dependent oligomerization is required for inhibition of Osx-dependent gene activation.","method":"X-ray crystallography, mutagenesis of oligomerization interface, promoter reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure combined with mutagenesis and functional reporter assay in single rigorous study","pmids":["23620590"],"is_preprint":false},{"year":2014,"finding":"In Osx-null cells, NO66 occupancy at osteoblast target gene promoters is increased; NO66 interacts with DNMT1A, HDAC1A, and HP1, forming a repressor complex. HP1 stimulates the demethylase activity of NO66 towards H3K4me3 and H3K36me3 substrates.","method":"ChIP in Osx-null vs wild-type calvarial cells, co-immunoprecipitation to detect NO66-DNMT1A/HDAC1A/HP1 interactions, in vitro demethylase activity assay with HP1","journal":"Journal of bone and mineral research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and in vitro enzymatic assay with HP1 stimulation, ChIP data; single lab but multiple orthogonal methods","pmids":["24115157"],"is_preprint":false},{"year":2015,"finding":"NO66 functions as a ribosomal protein hydroxylase: it catalyzes C-3 histidine hydroxylation of Rpl8 (ribosomal protein L8); oligomerization of NO66 is required for efficient Rpl8 hydroxylation activity. Crystal structures of NO66(176-C) complexed with an Rpl8 peptide identified the consensus recognition motif NHXH for NO66 substrates.","method":"Crystal structure of NO66–Rpl8 peptide complex, in vitro hydroxylase activity assays, oligomeric mutant analysis","journal":"Acta crystallographica. Section D, Biological crystallography","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with substrate peptide plus biochemical hydroxylase assay and mutagenesis of oligomerization in a single study","pmids":["26327385"],"is_preprint":false},{"year":2015,"finding":"Mesenchymal-specific deletion of NO66 in mice (Prx1-Cre) promotes osteogenesis, increases osteoblast numbers, and upregulates Bmp2, Igf1, osteoprotegerin, Osx, type I collagen, and Bsp, establishing that NO66 demethylase activity negatively regulates bone formation in vivo.","method":"Conditional knockout mouse model (Prx1-Cre), histomorphometry, qPCR/protein expression analysis of bone markers","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 / Strong — defined genetic loss-of-function in vivo with specific cellular (osteoblast number) and molecular (target gene expression) phenotypic readouts; consistent with multiple prior mechanistic studies","pmids":["25736226"],"is_preprint":false},{"year":2018,"finding":"RIOX1 (NO66) is an intronless single-exon gene in humans and several other species; immunofluorescence in HeLa cells identified a nucleolar localization signal within the unique N-terminal extension domain of human RIOX1, determining that this domain is responsible for nucleolar targeting.","method":"Immunofluorescence localization in HeLa cells, comparative genomics/phylogenomics across 49 metazoan species","journal":"BMC evolutionary biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiment with domain mapping, supported by comparative genomic analysis; no functional consequence tested","pmids":["29914368"],"is_preprint":false},{"year":2021,"finding":"Wild-type NO66, but not an enzymatically inactive mutant, inhibits proliferation and rDNA transcription in KG1a AML cells stably expressing NO66; loss of NO66 expression in KG1/KG1a cells is caused by hypermethylation of its promoter, reversible by DNA methyltransferase inhibitors. NO66 expression induces a transcriptional program favoring myeloid commitment and suppresses stem cell-maintenance genes.","method":"Stable expression of wild-type vs. catalytic-dead NO66 in KG1a cells, proliferation assays, rDNA transcription assay, bisulfite sequencing of NO66 promoter, gene expression profiling","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzymatic mutant rescue experiment establishes catalytic dependence; single lab, multiple readouts","pmids":["33745927"],"is_preprint":false},{"year":2022,"finding":"RIOX1 removes monomethylation at K491 of cGAS; demethylated cGAS is released from interaction with the methyl-lysine reader SGF29, enabling cGAS to interact with poly(ADP-ribosyl)ated PARP1 at DNA break sites and blocking PARP1-mediated recruitment of Timeless, thereby impeding homologous recombination (HR) repair. Loss of RIOX1 enhances HR but not NHEJ repair in irradiated cells.","method":"RIOX1 depletion (KD/KO) in bone marrow and oral mucosal cells, in vitro demethylation assay on cGAS K491, co-immunoprecipitation (cGAS–SGF29, cGAS–PARP1), HR/NHEJ reporter assays, ionizing radiation survival/proliferation assays","journal":"Bone research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro demethylase assay on defined substrate (cGAS K491), reciprocal Co-IPs for two distinct complexes, and loss-of-function DNA repair phenotype with mechanistic pathway placement; multiple orthogonal methods in single study","pmids":["35210392"],"is_preprint":false},{"year":2023,"finding":"MINA53 and NO66 have narrow substrate selectivity for histidine C-3 hydroxylation in Rpl27a and Rpl8 peptides, respectively; histidine analogues with acyclic side chains (Asn, Gln, homoGln) incorporated into Rpl peptides can inhibit NO66 activity, suggesting that non-oxidized competing peptides/proteins may regulate NO66 activity in vivo.","method":"In vitro hydroxylation assays with natural and unnatural histidine analogues incorporated into Rpl peptides; inhibition assays","journal":"RSC chemical biology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous in vitro enzymatic assay with substrate analogues; single study, no in vivo validation of competitive inhibition mechanism","pmids":["36908702"],"is_preprint":false}],"current_model":"RIOX1 (NO66) is a bifunctional JmjC-domain oxygenase that acts as a histone demethylase (removing H3K4me and H3K36me marks to repress transcription), a ribosomal protein histidine hydroxylase (C-3 hydroxylation of Rpl8 via recognition of an NHXH motif), and a protein demethylase that removes monomethylation at cGAS K491 to regulate homologous recombination repair; it forms functional tetramers through a hinge-domain-dependent oligomerization interface that is required both for catalytic efficiency and for interaction with binding partners such as Osterix, and it is recruited to active chromatin loci through association with PHF19/PRC2 to catalyze H3K36me3 removal and enable Polycomb-mediated gene silencing during differentiation."},"narrative":{"mechanistic_narrative":"RIOX1 (NO66) is a nucleolar and nucleoplasmic JmjC-domain 2-oxoglutarate oxygenase that integrates chromatin regulation, ribosome biogenesis, and DNA repair through distinct catalytic activities [PMID:14742713, PMID:19927124]. As a histone demethylase, it removes H3K4me and H3K36me marks to repress transcription, and this catalytic activity is required to silence osteoblast-specific promoters where it binds and antagonizes the transcription factor Osterix [PMID:19927124, PMID:25736226]. Its chromatin function is directed by partner-based recruitment: PHF19 delivers both RIOX1 and the PRC2 complex to stem cell genes during differentiation, coupling RIOX1-catalyzed H3K36me3 demethylation to PRC2-mediated H3K27me3 deposition and transcriptional silencing [PMID:23160351], while a repressor complex with DNMT1, HDAC1, and HP1 — with HP1 stimulating RIOX1 demethylase activity — reinforces gene repression [PMID:24115157]. Structurally, RIOX1 assembles into a functional tetramer via a hinge domain that links its JmjC and winged helix-turn-helix domains, and this oligomerization interface both engages Osterix and is required for catalytic efficiency [PMID:23620590, PMID:26327385]. Beyond histones, RIOX1 acts as a ribosomal protein hydroxylase, catalyzing C-3 histidine hydroxylation of Rpl8 through recognition of an NHXH consensus motif [PMID:26327385], and as a protein demethylase that removes monomethylation at cGAS K491, releasing cGAS from the reader SGF29 so that it impedes PARP1-dependent homologous recombination repair [PMID:35210392]. In vivo, RIOX1 demethylase activity negatively regulates bone formation [PMID:25736226], and its catalytic function suppresses proliferation and rDNA transcription while promoting myeloid commitment in leukemic cells [PMID:33745927].","teleology":[{"year":2004,"claim":"Established where NO66 acts in the cell, placing an uncharacterized protein at the interface of ribosome biogenesis and heterochromatin before any enzymatic activity was known.","evidence":"Immunolocalization with Ki-67/HP1α/PCNA, biochemical fractionation, and mass spectrometry of Xenopus nucleoli","pmids":["14742713"],"confidence":"Medium","gaps":["No catalytic activity or substrate identified","Functional role in ribosome biogenesis vs. heterochromatin not dissected"]},{"year":2009,"claim":"Defined NO66 as a JmjC histone demethylase whose H3K4me/H3K36me activity represses transcription, linking it mechanistically to Osterix-controlled osteoblast gene programs.","evidence":"Co-IP of Osx interactors, in vitro demethylase assays, ChIP, and NO66 knockdown with differentiation readouts","pmids":["19927124"],"confidence":"High","gaps":["Recruitment mechanism to target loci unresolved","Structural basis of demethylation not defined"]},{"year":2012,"claim":"Showed how NO66 is targeted to chromatin, revealing PHF19/PRC2-dependent recruitment that couples its H3K36me3 demethylation to Polycomb silencing during differentiation.","evidence":"Co-IP, ChIP for multiple histone marks, and PHF19 knockdown in mouse embryonic stem cells","pmids":["23160351"],"confidence":"High","gaps":["Direct vs. indirect PHF19-NO66 contact not mapped","Generality beyond stem cell genes untested"]},{"year":2013,"claim":"Resolved the architecture of NO66, establishing that hinge-dependent tetramerization is required both for catalysis and for binding Osterix.","evidence":"X-ray crystallography with mutagenesis of the oligomerization interface and promoter reporter assays","pmids":["23620590"],"confidence":"High","gaps":["Oligomeric state in vivo not directly demonstrated","Structure of the JmjC-substrate complex not yet captured"]},{"year":2014,"claim":"Expanded the repressive machinery around NO66, identifying a DNMT1/HDAC1/HP1 corepressor complex in which HP1 stimulates demethylase activity.","evidence":"ChIP in Osx-null cells, Co-IP of NO66 partners, and in vitro demethylase assays with HP1","pmids":["24115157"],"confidence":"Medium","gaps":["Single-lab data without reciprocal validation of all interactions","Mechanism of HP1 stimulation unresolved"]},{"year":2015,"claim":"Identified a second catalytic activity, defining NO66 as an Rpl8 histidine C-3 hydroxylase that recognizes an NHXH motif and requires oligomerization for efficiency.","evidence":"Crystal structure of NO66-Rpl8 peptide complex, in vitro hydroxylase assays, and oligomeric mutant analysis","pmids":["26327385"],"confidence":"High","gaps":["Functional consequence of Rpl8 hydroxylation for ribosome function untested","Full substrate repertoire of the NHXH motif unknown"]},{"year":2015,"claim":"Provided in vivo loss-of-function proof that NO66 demethylase activity restrains osteogenesis, validating the chromatin-repressor model at the organismal level.","evidence":"Mesenchymal-specific conditional knockout mice (Prx1-Cre), histomorphometry, and bone marker expression analysis","pmids":["25736226"],"confidence":"High","gaps":["Did not separate histone demethylase from hydroxylase contributions in vivo","Cell-autonomy of the phenotype not fully resolved"]},{"year":2018,"claim":"Mapped the determinant of nucleolar targeting to a unique N-terminal extension and established the intronless single-exon gene structure across metazoans.","evidence":"Immunofluorescence with domain mapping in HeLa cells and comparative genomics across 49 species","pmids":["29914368"],"confidence":"Medium","gaps":["Functional consequence of nucleolar targeting not tested","No link to catalytic activities"]},{"year":2021,"claim":"Demonstrated catalytic dependence of NO66's tumor-suppressive role in AML, showing it inhibits proliferation and rDNA transcription and drives myeloid commitment, with promoter hypermethylation silencing it in leukemic cells.","evidence":"Wild-type vs. catalytic-dead NO66 stable expression in KG1a cells, rDNA transcription and proliferation assays, bisulfite sequencing, expression profiling","pmids":["33745927"],"confidence":"Medium","gaps":["Direct substrate driving the AML phenotype not identified","Single cell-line system"]},{"year":2022,"claim":"Extended NO66 substrate specificity beyond histones, showing it demethylates cGAS K491 to control homologous recombination by gating cGAS-PARP1 interaction at DNA breaks.","evidence":"RIOX1 depletion, in vitro demethylation on cGAS K491, reciprocal Co-IPs (cGAS-SGF29, cGAS-PARP1), and HR/NHEJ reporter assays under irradiation","pmids":["35210392"],"confidence":"High","gaps":["Whether cGAS demethylation occurs at chromatin loci shared with histone substrates unknown","Relative contribution to repair vs. innate immune cGAS signaling unresolved"]},{"year":2023,"claim":"Characterized the narrow substrate selectivity of NO66 histidine hydroxylation and showed histidine analogues can inhibit activity, raising the possibility of endogenous competitive regulation.","evidence":"In vitro hydroxylation and inhibition assays with natural and unnatural histidine analogues in Rpl peptides","pmids":["36908702"],"confidence":"Medium","gaps":["In vivo competitive inhibition mechanism not validated","Physiological inhibitor not identified"]},{"year":null,"claim":"How the distinct catalytic activities of RIOX1 — histone demethylation, ribosomal protein hydroxylation, and cGAS demethylation — are coordinated within a single protein and partitioned between nucleolar and chromatin compartments remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model integrating the three activities","Compartment-specific substrate engagement not mapped","Regulation switching between functions unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2,9]},{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[5,10]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,8]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[0,7]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[0]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,7]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,2,4]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,2,8]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[9]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6]}],"complexes":["PRC2 (via PHF19)","DNMT1/HDAC1/HP1 corepressor complex"],"partners":["SP7","PHF19","DNMT1","HDAC1","CBX5","RPL8","CGAS"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H6W3","full_name":"Ribosomal oxygenase 1","aliases":["60S ribosomal protein L8 histidine hydroxylase","Bifunctional lysine-specific demethylase and histidyl-hydroxylase NO66","Myc-associated protein with JmjC domain","Nucleolar protein 66","hsNO66","Ribosomal oxygenase NO66","ROX"],"length_aa":641,"mass_kda":71.1,"function":"Oxygenase that can act as both a histone lysine demethylase and a ribosomal histidine hydroxylase (PubMed:23103944). Specifically demethylates 'Lys-4' (H3K4me) and 'Lys-36' (H3K36me) of histone H3, thereby playing a central role in histone code (By similarity). Preferentially demethylates trimethylated H3 'Lys-4' (H3K4me3) and monomethylated H3 'Lys-4' (H3K4me1) residues, while it has weaker activity for dimethylated H3 'Lys-36' (H3K36me2) (By similarity). Acts as a regulator of osteoblast differentiation via its interaction with SP7/OSX by demethylating H3K4me and H3K36me, thereby inhibiting SP7/OSX-mediated promoter activation (By similarity). Also catalyzes demethylation of non-histone proteins, such as CGAS: demethylation of monomethylated CGAS promotes interaction between CGAS and PARP1, followed by PARP1 inactivation (By similarity). Also catalyzes the hydroxylation of 60S ribosomal protein L8 on 'His-216', thereby playing a role in ribosome biogenesis (PubMed:23103944). Participates in MYC-induced transcriptional activation (PubMed:17308053)","subcellular_location":"Nucleus, nucleolus; Nucleus, nucleoplasm","url":"https://www.uniprot.org/uniprotkb/Q9H6W3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RIOX1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":70,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RIOX1","total_profiled":1310},"omim":[{"mim_id":"611919","title":"RIBOSOMAL OXYGENASE 1; RIOX1","url":"https://www.omim.org/entry/611919"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoli rim","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RIOX1"},"hgnc":{"alias_symbol":["FLJ21802","NO66","MAPJD","JMJD9"],"prev_symbol":["C14orf169"]},"alphafold":{"accession":"Q9H6W3","domains":[{"cath_id":"2.60.120.650","chopping":"185-427","consensus_level":"high","plddt":98.3417,"start":185,"end":427},{"cath_id":"1.10.10.1500","chopping":"430-494","consensus_level":"high","plddt":97.8845,"start":430,"end":494},{"cath_id":"3.90.930.40","chopping":"510-635","consensus_level":"high","plddt":96.9333,"start":510,"end":635}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H6W3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H6W3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H6W3-F1-predicted_aligned_error_v6.png","plddt_mean":79.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RIOX1","jax_strain_url":"https://www.jax.org/strain/search?query=RIOX1"},"sequence":{"accession":"Q9H6W3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H6W3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H6W3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H6W3"}},"corpus_meta":[{"pmid":"23160351","id":"PMC_23160351","title":"Polycomb PHF19 binds H3K36me3 and recruits PRC2 and demethylase NO66 to embryonic stem cell genes during differentiation.","date":"2012","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/23160351","citation_count":205,"is_preprint":false},{"pmid":"19927124","id":"PMC_19927124","title":"Regulation of the osteoblast-specific transcription factor Osterix by NO66, a Jumonji family histone demethylase.","date":"2009","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/19927124","citation_count":123,"is_preprint":false},{"pmid":"14742713","id":"PMC_14742713","title":"NO66, a highly conserved dual location protein in the nucleolus and in a special type of synchronously replicating chromatin.","date":"2004","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/14742713","citation_count":44,"is_preprint":false},{"pmid":"15819408","id":"PMC_15819408","title":"Protein NO52--a constitutive nucleolar component sharing high sequence homologies to protein NO66.","date":"2005","source":"European journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/15819408","citation_count":41,"is_preprint":false},{"pmid":"24115157","id":"PMC_24115157","title":"Osterix and NO66 histone demethylase control the chromatin of Osterix target genes during osteoblast differentiation.","date":"2014","source":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","url":"https://pubmed.ncbi.nlm.nih.gov/24115157","citation_count":39,"is_preprint":false},{"pmid":"25736226","id":"PMC_25736226","title":"Mesenchymal Deletion of Histone Demethylase NO66 in Mice Promotes Bone Formation.","date":"2015","source":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","url":"https://pubmed.ncbi.nlm.nih.gov/25736226","citation_count":20,"is_preprint":false},{"pmid":"27473587","id":"PMC_27473587","title":"Clinical Significance of Histone Demethylase NO66 in Invasive Colorectal Cancer.","date":"2016","source":"Annals of surgical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/27473587","citation_count":17,"is_preprint":false},{"pmid":"30858546","id":"PMC_30858546","title":"Oncogenic and osteolytic functions of histone demethylase NO66 in castration-resistant prostate cancer.","date":"2019","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/30858546","citation_count":16,"is_preprint":false},{"pmid":"23620590","id":"PMC_23620590","title":"Structural insights into histone demethylase NO66 in interaction with osteoblast-specific transcription factor osterix and gene repression.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23620590","citation_count":13,"is_preprint":false},{"pmid":"35210392","id":"PMC_35210392","title":"RIOX1-demethylated cGAS regulates ionizing radiation-elicited DNA repair.","date":"2022","source":"Bone research","url":"https://pubmed.ncbi.nlm.nih.gov/35210392","citation_count":11,"is_preprint":false},{"pmid":"26327385","id":"PMC_26327385","title":"Structure of the JmjC domain-containing protein NO66 complexed with ribosomal protein Rpl8.","date":"2015","source":"Acta crystallographica. Section D, Biological crystallography","url":"https://pubmed.ncbi.nlm.nih.gov/26327385","citation_count":9,"is_preprint":false},{"pmid":"29914368","id":"PMC_29914368","title":"Phylogenetic and genomic analyses of the ribosomal oxygenases Riox1 (No66) and Riox2 (Mina53) provide new insights into their evolution.","date":"2018","source":"BMC evolutionary biology","url":"https://pubmed.ncbi.nlm.nih.gov/29914368","citation_count":8,"is_preprint":false},{"pmid":"31704826","id":"PMC_31704826","title":"The Histone Demethylase NO66 Induces Glioma Cell Proliferation.","date":"2019","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/31704826","citation_count":6,"is_preprint":false},{"pmid":"36908702","id":"PMC_36908702","title":"Substrate selectivity and inhibition of histidine JmjC hydroxylases MINA53 and NO66.","date":"2023","source":"RSC chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/36908702","citation_count":5,"is_preprint":false},{"pmid":"33085743","id":"PMC_33085743","title":"NO66 overexpression rescues ethanol-induced cell apoptosis in human AC16 cardiomyocytes by suppressing PTEN and activating the PI3K/Akt signaling.","date":"2020","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/33085743","citation_count":3,"is_preprint":false},{"pmid":"22750859","id":"PMC_22750859","title":"Purification, crystallization and preliminary crystallographic analysis of histone lysine demethylase NO66 from Homo sapiens.","date":"2012","source":"Acta crystallographica. Section F, Structural biology and crystallization communications","url":"https://pubmed.ncbi.nlm.nih.gov/22750859","citation_count":3,"is_preprint":false},{"pmid":"33745927","id":"PMC_33745927","title":"The JmjC-domain protein NO66/RIOX-1 affects the balance between proliferation and maturation in acute myeloid leukemia.","date":"2021","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/33745927","citation_count":2,"is_preprint":false},{"pmid":"36660551","id":"PMC_36660551","title":"Osteoblast-Specific Overexpression of Nucleolar Protein NO66/RIOX1 in Mouse Embryos Leads to Osteoporosis in Adult Mice.","date":"2023","source":"Journal of osteoporosis","url":"https://pubmed.ncbi.nlm.nih.gov/36660551","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10920,"output_tokens":3114,"usd":0.039735,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10504,"output_tokens":3825,"usd":0.074072,"stage2_stop_reason":"end_turn"},"total_usd":0.113807,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"NO66 localizes constitutively to the nucleolus (granular component) and to nucleoplasmic entities overlapping with late-replicating heterochromatin clusters; it cofractionates with large preribosomal particles but is absent from cytoplasmic ribosomes, indicating a role in ribosome biogenesis and/or heterochromatin replication/remodeling.\",\n      \"method\": \"Immunolocalization (monoclonal antibodies), colocalization with Ki-67, HP1α, and PCNA, biochemical fractionation, mass spectrometry of nucleolar proteins from Xenopus laevis oocyte amplified nucleoli\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct fractionation and immunolocalization with multiple markers in single study; no functional mutagenesis to dissect mechanism\",\n      \"pmids\": [\"14742713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"NO66 directly interacts with the osteoblast-specific transcription factor Osterix (Osx) and inhibits Osx-mediated promoter activation; NO66 exhibits JmjC-dependent histone demethylase activity specific for H3K4me and H3K36me both in vitro and in vivo, and this demethylase activity is required for repression of osteoblast-specific promoters.\",\n      \"method\": \"Proteomics/co-immunoprecipitation to identify Osx-interacting proteins, in vitro histone demethylase assay, in vivo chromatin immunoprecipitation (ChIP), siRNA knockdown of NO66 with readout of osteoblast differentiation/mineralization and target gene expression\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro enzymatic assay combined with in vivo ChIP, knockdown phenotype, and protein interaction; replicated in subsequent studies\",\n      \"pmids\": [\"19927124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PHF19 (a PRC2 component) associates with NO66, and PHF19 is required to recruit both the PRC2 complex and NO66 to stem cell genes during differentiation; recruitment leads to H3K36me3 demethylation by NO66 and PRC2-mediated H3K27me3, resulting in transcriptional silencing.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, knockdown of PHF19 with readout of H3K36me3/H3K27me3 levels and gene expression in mouse embryonic stem cells\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP for multiple histone marks, genetic knockdown with defined chromatin and transcriptional phenotype; published in high-impact journal with replication of NO66 demethylase role\",\n      \"pmids\": [\"23160351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structure of NO66 reveals it forms a functional tetramer; a hinge domain links the N-terminal JmjC domain and C-terminal winged helix-turn-helix (wHTH) domain, and both are essential for tetrameric assembly. The oligomerization interface of NO66 interacts with a conserved fragment of Osterix, and hinge domain-dependent oligomerization is required for inhibition of Osx-dependent gene activation.\",\n      \"method\": \"X-ray crystallography, mutagenesis of oligomerization interface, promoter reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure combined with mutagenesis and functional reporter assay in single rigorous study\",\n      \"pmids\": [\"23620590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In Osx-null cells, NO66 occupancy at osteoblast target gene promoters is increased; NO66 interacts with DNMT1A, HDAC1A, and HP1, forming a repressor complex. HP1 stimulates the demethylase activity of NO66 towards H3K4me3 and H3K36me3 substrates.\",\n      \"method\": \"ChIP in Osx-null vs wild-type calvarial cells, co-immunoprecipitation to detect NO66-DNMT1A/HDAC1A/HP1 interactions, in vitro demethylase activity assay with HP1\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and in vitro enzymatic assay with HP1 stimulation, ChIP data; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"24115157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NO66 functions as a ribosomal protein hydroxylase: it catalyzes C-3 histidine hydroxylation of Rpl8 (ribosomal protein L8); oligomerization of NO66 is required for efficient Rpl8 hydroxylation activity. Crystal structures of NO66(176-C) complexed with an Rpl8 peptide identified the consensus recognition motif NHXH for NO66 substrates.\",\n      \"method\": \"Crystal structure of NO66–Rpl8 peptide complex, in vitro hydroxylase activity assays, oligomeric mutant analysis\",\n      \"journal\": \"Acta crystallographica. Section D, Biological crystallography\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with substrate peptide plus biochemical hydroxylase assay and mutagenesis of oligomerization in a single study\",\n      \"pmids\": [\"26327385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Mesenchymal-specific deletion of NO66 in mice (Prx1-Cre) promotes osteogenesis, increases osteoblast numbers, and upregulates Bmp2, Igf1, osteoprotegerin, Osx, type I collagen, and Bsp, establishing that NO66 demethylase activity negatively regulates bone formation in vivo.\",\n      \"method\": \"Conditional knockout mouse model (Prx1-Cre), histomorphometry, qPCR/protein expression analysis of bone markers\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — defined genetic loss-of-function in vivo with specific cellular (osteoblast number) and molecular (target gene expression) phenotypic readouts; consistent with multiple prior mechanistic studies\",\n      \"pmids\": [\"25736226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RIOX1 (NO66) is an intronless single-exon gene in humans and several other species; immunofluorescence in HeLa cells identified a nucleolar localization signal within the unique N-terminal extension domain of human RIOX1, determining that this domain is responsible for nucleolar targeting.\",\n      \"method\": \"Immunofluorescence localization in HeLa cells, comparative genomics/phylogenomics across 49 metazoan species\",\n      \"journal\": \"BMC evolutionary biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiment with domain mapping, supported by comparative genomic analysis; no functional consequence tested\",\n      \"pmids\": [\"29914368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Wild-type NO66, but not an enzymatically inactive mutant, inhibits proliferation and rDNA transcription in KG1a AML cells stably expressing NO66; loss of NO66 expression in KG1/KG1a cells is caused by hypermethylation of its promoter, reversible by DNA methyltransferase inhibitors. NO66 expression induces a transcriptional program favoring myeloid commitment and suppresses stem cell-maintenance genes.\",\n      \"method\": \"Stable expression of wild-type vs. catalytic-dead NO66 in KG1a cells, proliferation assays, rDNA transcription assay, bisulfite sequencing of NO66 promoter, gene expression profiling\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzymatic mutant rescue experiment establishes catalytic dependence; single lab, multiple readouts\",\n      \"pmids\": [\"33745927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RIOX1 removes monomethylation at K491 of cGAS; demethylated cGAS is released from interaction with the methyl-lysine reader SGF29, enabling cGAS to interact with poly(ADP-ribosyl)ated PARP1 at DNA break sites and blocking PARP1-mediated recruitment of Timeless, thereby impeding homologous recombination (HR) repair. Loss of RIOX1 enhances HR but not NHEJ repair in irradiated cells.\",\n      \"method\": \"RIOX1 depletion (KD/KO) in bone marrow and oral mucosal cells, in vitro demethylation assay on cGAS K491, co-immunoprecipitation (cGAS–SGF29, cGAS–PARP1), HR/NHEJ reporter assays, ionizing radiation survival/proliferation assays\",\n      \"journal\": \"Bone research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro demethylase assay on defined substrate (cGAS K491), reciprocal Co-IPs for two distinct complexes, and loss-of-function DNA repair phenotype with mechanistic pathway placement; multiple orthogonal methods in single study\",\n      \"pmids\": [\"35210392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MINA53 and NO66 have narrow substrate selectivity for histidine C-3 hydroxylation in Rpl27a and Rpl8 peptides, respectively; histidine analogues with acyclic side chains (Asn, Gln, homoGln) incorporated into Rpl peptides can inhibit NO66 activity, suggesting that non-oxidized competing peptides/proteins may regulate NO66 activity in vivo.\",\n      \"method\": \"In vitro hydroxylation assays with natural and unnatural histidine analogues incorporated into Rpl peptides; inhibition assays\",\n      \"journal\": \"RSC chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous in vitro enzymatic assay with substrate analogues; single study, no in vivo validation of competitive inhibition mechanism\",\n      \"pmids\": [\"36908702\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RIOX1 (NO66) is a bifunctional JmjC-domain oxygenase that acts as a histone demethylase (removing H3K4me and H3K36me marks to repress transcription), a ribosomal protein histidine hydroxylase (C-3 hydroxylation of Rpl8 via recognition of an NHXH motif), and a protein demethylase that removes monomethylation at cGAS K491 to regulate homologous recombination repair; it forms functional tetramers through a hinge-domain-dependent oligomerization interface that is required both for catalytic efficiency and for interaction with binding partners such as Osterix, and it is recruited to active chromatin loci through association with PHF19/PRC2 to catalyze H3K36me3 removal and enable Polycomb-mediated gene silencing during differentiation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RIOX1 (NO66) is a nucleolar and nucleoplasmic JmjC-domain 2-oxoglutarate oxygenase that integrates chromatin regulation, ribosome biogenesis, and DNA repair through distinct catalytic activities [#0, #1]. As a histone demethylase, it removes H3K4me and H3K36me marks to repress transcription, and this catalytic activity is required to silence osteoblast-specific promoters where it binds and antagonizes the transcription factor Osterix [#1, #6]. Its chromatin function is directed by partner-based recruitment: PHF19 delivers both RIOX1 and the PRC2 complex to stem cell genes during differentiation, coupling RIOX1-catalyzed H3K36me3 demethylation to PRC2-mediated H3K27me3 deposition and transcriptional silencing [#2], while a repressor complex with DNMT1, HDAC1, and HP1 — with HP1 stimulating RIOX1 demethylase activity — reinforces gene repression [#4]. Structurally, RIOX1 assembles into a functional tetramer via a hinge domain that links its JmjC and winged helix-turn-helix domains, and this oligomerization interface both engages Osterix and is required for catalytic efficiency [#3, #5]. Beyond histones, RIOX1 acts as a ribosomal protein hydroxylase, catalyzing C-3 histidine hydroxylation of Rpl8 through recognition of an NHXH consensus motif [#5], and as a protein demethylase that removes monomethylation at cGAS K491, releasing cGAS from the reader SGF29 so that it impedes PARP1-dependent homologous recombination repair [#9]. In vivo, RIOX1 demethylase activity negatively regulates bone formation [#6], and its catalytic function suppresses proliferation and rDNA transcription while promoting myeloid commitment in leukemic cells [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established where NO66 acts in the cell, placing an uncharacterized protein at the interface of ribosome biogenesis and heterochromatin before any enzymatic activity was known.\",\n      \"evidence\": \"Immunolocalization with Ki-67/HP1\\u03b1/PCNA, biochemical fractionation, and mass spectrometry of Xenopus nucleoli\",\n      \"pmids\": [\"14742713\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No catalytic activity or substrate identified\", \"Functional role in ribosome biogenesis vs. heterochromatin not dissected\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined NO66 as a JmjC histone demethylase whose H3K4me/H3K36me activity represses transcription, linking it mechanistically to Osterix-controlled osteoblast gene programs.\",\n      \"evidence\": \"Co-IP of Osx interactors, in vitro demethylase assays, ChIP, and NO66 knockdown with differentiation readouts\",\n      \"pmids\": [\"19927124\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Recruitment mechanism to target loci unresolved\", \"Structural basis of demethylation not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed how NO66 is targeted to chromatin, revealing PHF19/PRC2-dependent recruitment that couples its H3K36me3 demethylation to Polycomb silencing during differentiation.\",\n      \"evidence\": \"Co-IP, ChIP for multiple histone marks, and PHF19 knockdown in mouse embryonic stem cells\",\n      \"pmids\": [\"23160351\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs. indirect PHF19-NO66 contact not mapped\", \"Generality beyond stem cell genes untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved the architecture of NO66, establishing that hinge-dependent tetramerization is required both for catalysis and for binding Osterix.\",\n      \"evidence\": \"X-ray crystallography with mutagenesis of the oligomerization interface and promoter reporter assays\",\n      \"pmids\": [\"23620590\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Oligomeric state in vivo not directly demonstrated\", \"Structure of the JmjC-substrate complex not yet captured\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Expanded the repressive machinery around NO66, identifying a DNMT1/HDAC1/HP1 corepressor complex in which HP1 stimulates demethylase activity.\",\n      \"evidence\": \"ChIP in Osx-null cells, Co-IP of NO66 partners, and in vitro demethylase assays with HP1\",\n      \"pmids\": [\"24115157\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab data without reciprocal validation of all interactions\", \"Mechanism of HP1 stimulation unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified a second catalytic activity, defining NO66 as an Rpl8 histidine C-3 hydroxylase that recognizes an NHXH motif and requires oligomerization for efficiency.\",\n      \"evidence\": \"Crystal structure of NO66-Rpl8 peptide complex, in vitro hydroxylase assays, and oligomeric mutant analysis\",\n      \"pmids\": [\"26327385\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of Rpl8 hydroxylation for ribosome function untested\", \"Full substrate repertoire of the NHXH motif unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Provided in vivo loss-of-function proof that NO66 demethylase activity restrains osteogenesis, validating the chromatin-repressor model at the organismal level.\",\n      \"evidence\": \"Mesenchymal-specific conditional knockout mice (Prx1-Cre), histomorphometry, and bone marker expression analysis\",\n      \"pmids\": [\"25736226\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate histone demethylase from hydroxylase contributions in vivo\", \"Cell-autonomy of the phenotype not fully resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mapped the determinant of nucleolar targeting to a unique N-terminal extension and established the intronless single-exon gene structure across metazoans.\",\n      \"evidence\": \"Immunofluorescence with domain mapping in HeLa cells and comparative genomics across 49 species\",\n      \"pmids\": [\"29914368\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of nucleolar targeting not tested\", \"No link to catalytic activities\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated catalytic dependence of NO66's tumor-suppressive role in AML, showing it inhibits proliferation and rDNA transcription and drives myeloid commitment, with promoter hypermethylation silencing it in leukemic cells.\",\n      \"evidence\": \"Wild-type vs. catalytic-dead NO66 stable expression in KG1a cells, rDNA transcription and proliferation assays, bisulfite sequencing, expression profiling\",\n      \"pmids\": [\"33745927\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrate driving the AML phenotype not identified\", \"Single cell-line system\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended NO66 substrate specificity beyond histones, showing it demethylates cGAS K491 to control homologous recombination by gating cGAS-PARP1 interaction at DNA breaks.\",\n      \"evidence\": \"RIOX1 depletion, in vitro demethylation on cGAS K491, reciprocal Co-IPs (cGAS-SGF29, cGAS-PARP1), and HR/NHEJ reporter assays under irradiation\",\n      \"pmids\": [\"35210392\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether cGAS demethylation occurs at chromatin loci shared with histone substrates unknown\", \"Relative contribution to repair vs. innate immune cGAS signaling unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Characterized the narrow substrate selectivity of NO66 histidine hydroxylation and showed histidine analogues can inhibit activity, raising the possibility of endogenous competitive regulation.\",\n      \"evidence\": \"In vitro hydroxylation and inhibition assays with natural and unnatural histidine analogues in Rpl peptides\",\n      \"pmids\": [\"36908702\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo competitive inhibition mechanism not validated\", \"Physiological inhibitor not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the distinct catalytic activities of RIOX1 — histone demethylation, ribosomal protein hydroxylation, and cGAS demethylation — are coordinated within a single protein and partitioned between nucleolar and chromatin compartments remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model integrating the three activities\", \"Compartment-specific substrate engagement not mapped\", \"Regulation switching between functions unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 9]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [5, 10]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 2, 4]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 2, 8]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [\"PRC2 (via PHF19)\", \"DNMT1/HDAC1/HP1 corepressor complex\"],\n    \"partners\": [\"SP7\", \"PHF19\", \"DNMT1\", \"HDAC1\", \"CBX5\", \"RPL8\", \"CGAS\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}