{"gene":"RBM23","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2005,"finding":"RBM23 (CAPERbeta) functions as a coactivator of steroid hormone receptors (e.g., progesterone receptor) and regulates alternative pre-mRNA splicing. Mutational analysis showed that the transcriptional coactivation and splicing functions reside in distinct, separable domains of the protein.","method":"Luciferase transcription reporter assays, alternative splicing minigene assays, siRNA knockdown, mutational analysis","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays (reporter, splicing, siRNA, mutagenesis) in a single study establishing domain separation, but primarily for CAPERalpha with CAPERbeta as supporting data","pmids":["15694343"],"is_preprint":false},{"year":2019,"finding":"RBM23 is recruited to the CRL4-DCAF15 E3 ubiquitin ligase complex via its RRM2 (RNA recognition motif 2) domain in the presence of aryl sulfonamide drugs (indisulam, E7820, tasisulam), leading to RBM23 ubiquitination and proteasomal degradation. The RRM2 degron motif is shared exclusively between RBM23 and RBM39 among human proteins.","method":"Crystal structure (2.3 Å) and cryo-EM structure of DCAF15-DDB1-DDA1-drug-RBM39(RRM2) complex; domain mapping; random mutagenesis; RBM39/RBM23 degradation assays in HCT116 cells; RBM39 point mutants validated structural model","journal":"Nature chemical biology / Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic resolution crystal structure and cryo-EM structure with mutagenesis validation, independently replicated across three labs in the same year","pmids":["31819272","31686031","31693891"],"is_preprint":false},{"year":2019,"finding":"Degradation of RBM23 by aryl sulfonamides does not account for the widespread splicing changes (intron retention, exon skipping) and gene expression alterations caused by indisulam; these effects are attributable solely to RBM39 degradation.","method":"siRNA knockdown, RNA-seq splicing analysis, selective degradation in HCT116 cells","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean functional dissection of RBM23 vs RBM39 contribution using selective degradation and transcriptome-wide analysis, single lab","pmids":["31693891"],"is_preprint":false},{"year":2021,"finding":"RBM23 knockdown in HCC cells inhibits NF-κB signaling by increasing p65 mRNA levels and enhancing nuclear accumulation of p65, leading to reduced expression of proangiogenic cytokines and impaired tube formation by endothelial cells.","method":"siRNA knockdown in HCC cell lines, tube formation assay, nuclear fractionation, immunoblotting, qRT-PCR","journal":"BioMed research international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown approach with limited mechanistic depth; no direct biochemical interaction established","pmids":["33791378"],"is_preprint":false},{"year":2026,"finding":"RBM23 knockdown in colon cancer cells reduces c-Myc protein stability (assessed by cycloheximide chase), decreases glycolytic enzyme expression and glucose uptake, elevates ROS, and triggers ferroptosis via regulation of GPX4 and KEAP1. RBM23 localizes to the nucleus (confirmed by immunofluorescence and nuclear fractionation).","method":"siRNA knockdown, cycloheximide chase assay, nuclear fractionation, immunofluorescence, CCK-8/colony formation assays, C11-BODIPY and DCFH-DA staining, Western blotting, glucose uptake assay","journal":"Cancer cell international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, multiple cellular assays but no direct biochemical interaction between RBM23 and c-Myc established; mechanism is inferred from downstream phenotypes","pmids":["41857570"],"is_preprint":false}],"current_model":"RBM23 (CAPERbeta) is a dual-function nuclear RNA-binding protein that acts as a steroid hormone receptor transcriptional coactivator and pre-mRNA alternative splicing regulator via distinct separable domains; its RRM2 domain contains a unique degron motif that, in the presence of aryl sulfonamide molecular glues (indisulam, E7820), mediates recruitment to the CRL4-DCAF15 E3 ubiquitin ligase complex, leading to ubiquitination and proteasomal degradation, though RBM23 degradation alone does not drive the major splicing changes caused by these compounds."},"narrative":{"mechanistic_narrative":"RBM23 (CAPERbeta) is a nuclear RNA-binding protein that functions both as a transcriptional coactivator of steroid hormone receptors, including the progesterone receptor, and as a regulator of alternative pre-mRNA splicing, with these two activities residing in distinct, separable domains [PMID:15694343]. Its RRM2 domain harbors a degron motif shared exclusively with RBM39 among human proteins; in the presence of aryl sulfonamide molecular glues (indisulam, E7820, tasisulam), this motif mediates recruitment to the CRL4-DCAF15 E3 ubiquitin ligase complex, driving RBM23 ubiquitination and proteasomal degradation, as resolved by crystal and cryo-EM structures of the DCAF15-DDB1-DDA1-drug-RRM2 assembly [PMID:31819272, PMID:31686031, PMID:31693891]. RBM23 degradation alone does not account for the widespread intron retention, exon skipping, and gene-expression changes produced by these compounds, which are instead attributable to RBM39 degradation [PMID:31693891]. Beyond [PMID:15694343], [PMID:31819272, PMID:31686031, PMID:31693891], and [PMID:31693891], the broader transcriptomic targets and direct splicing substrates of RBM23 have not been characterized in the available corpus.","teleology":[{"year":2005,"claim":"Established that RBM23 is bifunctional, separating its role as a steroid hormone receptor coactivator from its role in alternative splicing into distinct protein domains.","evidence":"Luciferase reporter, splicing minigene, siRNA knockdown, and mutational analysis","pmids":["15694343"],"confidence":"Medium","gaps":["Direct RNA substrates and splicing targets of RBM23 not defined","Most data derived for the CAPERalpha paralog with CAPERbeta as supporting evidence","No structural basis for either function resolved here"]},{"year":2019,"claim":"Defined how aryl sulfonamides convert the RBM23 RRM2 domain into a drug-induced degron, answering how a small molecule glues RBM23 to an E3 ligase for degradation.","evidence":"2.3 Å crystal structure and cryo-EM of the DCAF15-DDB1-DDA1-drug-RRM2 complex with domain mapping, random mutagenesis, and degradation assays in HCT116 cells, replicated across three labs","pmids":["31819272","31686031","31693891"],"confidence":"High","gaps":["Physiological (drug-independent) regulators of RBM23 stability unknown","Functional consequence of RBM23 loss in normal cells not addressed","Whether the RRM2 degron has an endogenous ligand unresolved"]},{"year":2019,"claim":"Determined that RBM23 degradation is not the driver of the splicing and expression changes caused by indisulam, isolating RBM39 as the functionally relevant target.","evidence":"Selective degradation, siRNA knockdown, and RNA-seq splicing analysis in HCT116 cells","pmids":["31693891"],"confidence":"Medium","gaps":["Endogenous splicing program controlled by RBM23 not mapped","Single-lab finding in one cell line","Possible context-dependent RBM23 splicing roles untested"]},{"year":2021,"claim":"Linked RBM23 to NF-κB signaling and tumor angiogenesis, indicating a role in regulating p65 and proangiogenic cytokine output.","evidence":"siRNA knockdown in HCC cell lines with tube formation assay, nuclear fractionation, immunoblotting, and qRT-PCR","pmids":["33791378"],"confidence":"Low","gaps":["No direct biochemical interaction between RBM23 and p65 established","Single lab, single knockdown approach with limited mechanistic depth","Mechanism by which RBM23 controls p65 mRNA levels unknown"]},{"year":2026,"claim":"Implicated RBM23 in metabolic and redox control of colon cancer cells through effects on c-Myc stability, glycolysis, and ferroptosis.","evidence":"siRNA knockdown, cycloheximide chase, nuclear fractionation, immunofluorescence, glucose uptake, and ROS/lipid peroxidation staining","pmids":["41857570"],"confidence":"Low","gaps":["No direct biochemical interaction between RBM23 and c-Myc shown","Mechanism inferred from downstream phenotypes only","Single lab without orthogonal validation"]},{"year":null,"claim":"The endogenous RNA targets, splicing program, and physiological regulation of RBM23 remain undefined, as does the mechanism connecting it to NF-κB and c-Myc.","evidence":"","pmids":[],"confidence":"Low","gaps":["No transcriptome-wide direct target map for RBM23","No structural basis for its coactivator or splicing functions","Cancer phenotypes lack direct biochemical mechanism"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0]}],"complexes":["CRL4-DCAF15 E3 ubiquitin ligase (drug-induced neosubstrate)"],"partners":["DCAF15","RBM39"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86U06","full_name":"Probable RNA-binding protein 23","aliases":["CAPER beta","CAPERbeta","RNA-binding motif protein 23","RNA-binding region-containing protein 4","Splicing factor SF2"],"length_aa":439,"mass_kda":48.7,"function":"RNA-binding protein that acts both as a transcription coactivator and pre-mRNA splicing factor (PubMed:15694343). Regulates steroid hormone receptor-mediated transcription, independently of the pre-mRNA splicing factor activity (PubMed:15694343)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q86U06/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RBM23","classification":"Not Classified","n_dependent_lines":60,"n_total_lines":1208,"dependency_fraction":0.04966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"RAF1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/RBM23","total_profiled":1310},"omim":[{"mim_id":"621023","title":"RNA-BINDING MOTIF PROTEIN 23; RBM23","url":"https://www.omim.org/entry/621023"},{"mim_id":"620109","title":"DDB1- AND CUL4-ASSOCIATED FACTOR 15; DCAF15","url":"https://www.omim.org/entry/620109"},{"mim_id":"604739","title":"RNA-BINDING MOTIF PROTEIN 39; RBM39","url":"https://www.omim.org/entry/604739"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Intermediate filaments","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RBM23"},"hgnc":{"alias_symbol":["FLJ10482","CAPERbeta"],"prev_symbol":["RNPC4"]},"alphafold":{"accession":"Q86U06","domains":[{"cath_id":"3.30.70.330","chopping":"159-251","consensus_level":"high","plddt":86.1551,"start":159,"end":251},{"cath_id":"3.30.70.330","chopping":"259-349","consensus_level":"high","plddt":85.3902,"start":259,"end":349}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86U06","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86U06-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86U06-F1-predicted_aligned_error_v6.png","plddt_mean":63.91},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RBM23","jax_strain_url":"https://www.jax.org/strain/search?query=RBM23"},"sequence":{"accession":"Q86U06","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86U06.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86U06/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86U06"}},"corpus_meta":[{"pmid":"31819272","id":"PMC_31819272","title":"Structural basis of indisulam-mediated RBM39 recruitment to DCAF15 E3 ligase complex.","date":"2019","source":"Nature chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/31819272","citation_count":188,"is_preprint":false},{"pmid":"15694343","id":"PMC_15694343","title":"Steroid hormone receptor coactivation and alternative RNA splicing by U2AF65-related proteins CAPERalpha and CAPERbeta.","date":"2005","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/15694343","citation_count":168,"is_preprint":false},{"pmid":"31686031","id":"PMC_31686031","title":"Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15.","date":"2019","source":"Nature chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/31686031","citation_count":166,"is_preprint":false},{"pmid":"31693891","id":"PMC_31693891","title":"Aryl Sulfonamides Degrade RBM39 and RBM23 by Recruitment to CRL4-DCAF15.","date":"2019","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/31693891","citation_count":93,"is_preprint":false},{"pmid":"36602777","id":"PMC_36602777","title":"E3-Specific Degrader Discovery by Dynamic Tracing of Substrate Receptor Abundance.","date":"2023","source":"Journal of the American Chemical Society","url":"https://pubmed.ncbi.nlm.nih.gov/36602777","citation_count":35,"is_preprint":false},{"pmid":"33791378","id":"PMC_33791378","title":"RBM23 Drives Hepatocellular Carcinoma by Activating NF-κB Signaling Pathway.","date":"2021","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/33791378","citation_count":14,"is_preprint":false},{"pmid":"36313857","id":"PMC_36313857","title":"A new cell-free therapeutic strategy for liver regeneration: Human placental mesenchymal stem cell-derived extracellular vesicles.","date":"2022","source":"Journal of tissue engineering","url":"https://pubmed.ncbi.nlm.nih.gov/36313857","citation_count":14,"is_preprint":false},{"pmid":"26010766","id":"PMC_26010766","title":"Glucose regulates heat shock factor 1 transcription activity via mTOR pathway in HCC cell lines.","date":"2015","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/26010766","citation_count":13,"is_preprint":false},{"pmid":"33168788","id":"PMC_33168788","title":"Aryl Sulfonamides Induce Degradation of Aryl Hydrocarbon Receptor Nuclear Translocator through CRL4DCAF15 E3 Ligase.","date":"2020","source":"Molecules and cells","url":"https://pubmed.ncbi.nlm.nih.gov/33168788","citation_count":8,"is_preprint":false},{"pmid":"33343632","id":"PMC_33343632","title":"Improved Detection of Potentially Pleiotropic Genes in Coronary Artery Disease and Chronic Kidney Disease Using GWAS Summary Statistics.","date":"2020","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33343632","citation_count":8,"is_preprint":false},{"pmid":"36896931","id":"PMC_36896931","title":"CircRBM23 regulates the switch between osteogenesis and adipogenesis of mesenchymal stem cells via sponging miR-338-3p.","date":"2023","source":"Clinical science (London, England : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/36896931","citation_count":7,"is_preprint":false},{"pmid":"37075641","id":"PMC_37075641","title":"Circ_RBM23 knockdown suppresses chemoresistance, proliferation, migration and invasion of sorafenib-resistant HCC cells through miR-338-3p/RAB1B axis.","date":"2023","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/37075641","citation_count":6,"is_preprint":false},{"pmid":"41857570","id":"PMC_41857570","title":"Inhibition of RBM23 induces ferroptosis in colon cancer cells via c-Myc regulation.","date":"2026","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/41857570","citation_count":0,"is_preprint":false},{"pmid":"40985266","id":"PMC_40985266","title":"Network-driven identification of indisulam neo-substrates for targeted protein degradation.","date":"2025","source":"Molecular omics","url":"https://pubmed.ncbi.nlm.nih.gov/40985266","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8822,"output_tokens":1409,"usd":0.0238,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8089,"output_tokens":2109,"usd":0.046585,"stage2_stop_reason":"end_turn"},"total_usd":0.070385,"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\": 2005,\n      \"finding\": \"RBM23 (CAPERbeta) functions as a coactivator of steroid hormone receptors (e.g., progesterone receptor) and regulates alternative pre-mRNA splicing. Mutational analysis showed that the transcriptional coactivation and splicing functions reside in distinct, separable domains of the protein.\",\n      \"method\": \"Luciferase transcription reporter assays, alternative splicing minigene assays, siRNA knockdown, mutational analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays (reporter, splicing, siRNA, mutagenesis) in a single study establishing domain separation, but primarily for CAPERalpha with CAPERbeta as supporting data\",\n      \"pmids\": [\"15694343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RBM23 is recruited to the CRL4-DCAF15 E3 ubiquitin ligase complex via its RRM2 (RNA recognition motif 2) domain in the presence of aryl sulfonamide drugs (indisulam, E7820, tasisulam), leading to RBM23 ubiquitination and proteasomal degradation. The RRM2 degron motif is shared exclusively between RBM23 and RBM39 among human proteins.\",\n      \"method\": \"Crystal structure (2.3 Å) and cryo-EM structure of DCAF15-DDB1-DDA1-drug-RBM39(RRM2) complex; domain mapping; random mutagenesis; RBM39/RBM23 degradation assays in HCT116 cells; RBM39 point mutants validated structural model\",\n      \"journal\": \"Nature chemical biology / Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic resolution crystal structure and cryo-EM structure with mutagenesis validation, independently replicated across three labs in the same year\",\n      \"pmids\": [\"31819272\", \"31686031\", \"31693891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Degradation of RBM23 by aryl sulfonamides does not account for the widespread splicing changes (intron retention, exon skipping) and gene expression alterations caused by indisulam; these effects are attributable solely to RBM39 degradation.\",\n      \"method\": \"siRNA knockdown, RNA-seq splicing analysis, selective degradation in HCT116 cells\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean functional dissection of RBM23 vs RBM39 contribution using selective degradation and transcriptome-wide analysis, single lab\",\n      \"pmids\": [\"31693891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RBM23 knockdown in HCC cells inhibits NF-κB signaling by increasing p65 mRNA levels and enhancing nuclear accumulation of p65, leading to reduced expression of proangiogenic cytokines and impaired tube formation by endothelial cells.\",\n      \"method\": \"siRNA knockdown in HCC cell lines, tube formation assay, nuclear fractionation, immunoblotting, qRT-PCR\",\n      \"journal\": \"BioMed research international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown approach with limited mechanistic depth; no direct biochemical interaction established\",\n      \"pmids\": [\"33791378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RBM23 knockdown in colon cancer cells reduces c-Myc protein stability (assessed by cycloheximide chase), decreases glycolytic enzyme expression and glucose uptake, elevates ROS, and triggers ferroptosis via regulation of GPX4 and KEAP1. RBM23 localizes to the nucleus (confirmed by immunofluorescence and nuclear fractionation).\",\n      \"method\": \"siRNA knockdown, cycloheximide chase assay, nuclear fractionation, immunofluorescence, CCK-8/colony formation assays, C11-BODIPY and DCFH-DA staining, Western blotting, glucose uptake assay\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, multiple cellular assays but no direct biochemical interaction between RBM23 and c-Myc established; mechanism is inferred from downstream phenotypes\",\n      \"pmids\": [\"41857570\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RBM23 (CAPERbeta) is a dual-function nuclear RNA-binding protein that acts as a steroid hormone receptor transcriptional coactivator and pre-mRNA alternative splicing regulator via distinct separable domains; its RRM2 domain contains a unique degron motif that, in the presence of aryl sulfonamide molecular glues (indisulam, E7820), mediates recruitment to the CRL4-DCAF15 E3 ubiquitin ligase complex, leading to ubiquitination and proteasomal degradation, though RBM23 degradation alone does not drive the major splicing changes caused by these compounds.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RBM23 (CAPERbeta) is a nuclear RNA-binding protein that functions both as a transcriptional coactivator of steroid hormone receptors, including the progesterone receptor, and as a regulator of alternative pre-mRNA splicing, with these two activities residing in distinct, separable domains [#0]. Its RRM2 domain harbors a degron motif shared exclusively with RBM39 among human proteins; in the presence of aryl sulfonamide molecular glues (indisulam, E7820, tasisulam), this motif mediates recruitment to the CRL4-DCAF15 E3 ubiquitin ligase complex, driving RBM23 ubiquitination and proteasomal degradation, as resolved by crystal and cryo-EM structures of the DCAF15-DDB1-DDA1-drug-RRM2 assembly [#1]. RBM23 degradation alone does not account for the widespread intron retention, exon skipping, and gene-expression changes produced by these compounds, which are instead attributable to RBM39 degradation [#2]. Beyond [#0], [#1], and [#2], the broader transcriptomic targets and direct splicing substrates of RBM23 have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that RBM23 is bifunctional, separating its role as a steroid hormone receptor coactivator from its role in alternative splicing into distinct protein domains.\",\n      \"evidence\": \"Luciferase reporter, splicing minigene, siRNA knockdown, and mutational analysis\",\n      \"pmids\": [\"15694343\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RNA substrates and splicing targets of RBM23 not defined\", \"Most data derived for the CAPERalpha paralog with CAPERbeta as supporting evidence\", \"No structural basis for either function resolved here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined how aryl sulfonamides convert the RBM23 RRM2 domain into a drug-induced degron, answering how a small molecule glues RBM23 to an E3 ligase for degradation.\",\n      \"evidence\": \"2.3 Å crystal structure and cryo-EM of the DCAF15-DDB1-DDA1-drug-RRM2 complex with domain mapping, random mutagenesis, and degradation assays in HCT116 cells, replicated across three labs\",\n      \"pmids\": [\"31819272\", \"31686031\", \"31693891\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological (drug-independent) regulators of RBM23 stability unknown\", \"Functional consequence of RBM23 loss in normal cells not addressed\", \"Whether the RRM2 degron has an endogenous ligand unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Determined that RBM23 degradation is not the driver of the splicing and expression changes caused by indisulam, isolating RBM39 as the functionally relevant target.\",\n      \"evidence\": \"Selective degradation, siRNA knockdown, and RNA-seq splicing analysis in HCT116 cells\",\n      \"pmids\": [\"31693891\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous splicing program controlled by RBM23 not mapped\", \"Single-lab finding in one cell line\", \"Possible context-dependent RBM23 splicing roles untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked RBM23 to NF-κB signaling and tumor angiogenesis, indicating a role in regulating p65 and proangiogenic cytokine output.\",\n      \"evidence\": \"siRNA knockdown in HCC cell lines with tube formation assay, nuclear fractionation, immunoblotting, and qRT-PCR\",\n      \"pmids\": [\"33791378\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct biochemical interaction between RBM23 and p65 established\", \"Single lab, single knockdown approach with limited mechanistic depth\", \"Mechanism by which RBM23 controls p65 mRNA levels unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Implicated RBM23 in metabolic and redox control of colon cancer cells through effects on c-Myc stability, glycolysis, and ferroptosis.\",\n      \"evidence\": \"siRNA knockdown, cycloheximide chase, nuclear fractionation, immunofluorescence, glucose uptake, and ROS/lipid peroxidation staining\",\n      \"pmids\": [\"41857570\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct biochemical interaction between RBM23 and c-Myc shown\", \"Mechanism inferred from downstream phenotypes only\", \"Single lab without orthogonal validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The endogenous RNA targets, splicing program, and physiological regulation of RBM23 remain undefined, as does the mechanism connecting it to NF-κB and c-Myc.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No transcriptome-wide direct target map for RBM23\", \"No structural basis for its coactivator or splicing functions\", \"Cancer phenotypes lack direct biochemical mechanism\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"CRL4-DCAF15 E3 ubiquitin ligase (drug-induced neosubstrate)\"],\n    \"partners\": [\"DCAF15\", \"RBM39\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}