{"gene":"RBM15B","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2005,"finding":"RBM15B (OTT3) was identified as a nuclear, non-shuttling protein that interacts with the Epstein-Barr virus mRNA export factor EB2 via EB2's 40 N-terminal amino acids. OTT3's SPOC domain shows far weaker interaction with SMRT corepressor than SHARP's SPOC domain, indicating no major role in transcriptional repression. OTT3 was shown to repress accumulation of alternatively spliced beta-thalassemia mRNAs but not constitutively spliced beta-globin mRNA, establishing a role in splicing regulation.","method":"Yeast two-hybrid screen, co-immunoprecipitation, subcellular localization by transfection/imaging, splicing reporter assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple methods (Y2H, Co-IP, functional splicing assay) in single lab","pmids":["16129689"],"is_preprint":false},{"year":2009,"finding":"RBM15B (OTT3) has post-transcriptional regulatory activity and directly interacts with mRNA export receptor NXF1 and adaptor Aly/REF via its C-terminal region (mapped by mutational analysis). RBM15B co-localizes with the splicing factor compartment and nuclear envelope. RBM15B and its paralogue RBM15 also interact with each other in vivo. Unlike SHARP, both RBM15B and RBM15 function as NXF1 cofactors.","method":"Co-immunoprecipitation, mutational analysis, subcellular localization studies, biochemical fractionation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP with mutational mapping, multiple methods in single study","pmids":["19586903"],"is_preprint":false},{"year":2010,"finding":"KSHV ORF57 interacts directly with the C-terminal SPOC domain of RBM15B (OTT3) to reduce RBM15B binding to ORF59 RNA and shifts nucleocytoplasmic balance of ORF59 RNA toward cytoplasm. Ectopic expression of RBM15B (or RBM15) promotes nuclear accumulation of ORF59 RNA and hyperpolyadenylation, whereas ORF57 counteracts this effect. Herpesvirus homologs (EBV EB2, HSV ICP27, VZV IE4, CMV UL69) also interact with RBM15B and OTT3.","method":"Co-immunoprecipitation, RNA immunoprecipitation, nucleocytoplasmic fractionation, domain mapping, overexpression/knockdown assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, RIP, fractionation) with domain-level mechanistic detail, single lab","pmids":["21106733"],"is_preprint":false},{"year":2010,"finding":"RBM15B was identified as a novel binding partner of CDK11(p110). It co-elutes with CDK11(p110), cyclin L2α, and SR proteins (SF2/ASF, 9G8) in a ~1-MDa nuclear complex. Two distinct domains of RBM15B directly interact with the N-terminal extension of CDK11(p110), cyclin L2α, and SR proteins. RBM15B functions as a competitive antagonist of SR proteins SF2/ASF and 9G8, inhibits formation of the spliceosomal E complex, and antagonizes the stimulatory effect of the CDK11(p110)–cyclin L2α complex on splicing both in vitro and in vivo.","method":"Size exclusion chromatography, co-immunoprecipitation, in vitro pulldown, in vitro splicing assay, in vivo splicing assay, domain mapping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro reconstitution of splicing inhibition combined with Co-IP, pulldown, and domain mapping; multiple orthogonal methods","pmids":["21044963"],"is_preprint":false},{"year":2016,"finding":"RBM15B, together with its paralogue RBM15, recruits the m6A methyltransferase complex (including METTL3) to specific RNA sites, mediating N6-methyladenosine modification of XIST lncRNA and cellular mRNAs. Knockdown of both RBM15 and RBM15B impairs XIST-mediated transcriptional gene silencing of X-linked genes. This established RBM15B as a writer-complex recruiter in the m6A pathway required for XIST function.","method":"RNAi knockdown, m6A sequencing (MeRIP), gene silencing reporter assays, co-immunoprecipitation","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (RNAi, MeRIP-seq, functional silencing assay), published in high-impact journal, widely replicated","pmids":["27602518"],"is_preprint":false},{"year":2022,"finding":"RBM15B is transcriptionally activated by the transcription factor YY1 and regulates TRAM2 mRNA stability in an m6A-dependent manner in hepatocellular carcinoma cells, promoting cell proliferation, invasion, and sorafenib resistance.","method":"ChIP assay (YY1 binding to RBM15B promoter), m6A assay, RNA stability assay, overexpression/knockdown with proliferation and invasion readouts","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2–3 — ChIP for upstream regulation and m6A mechanistic link, single lab","pmids":["35494016"],"is_preprint":false},{"year":2024,"finding":"RBM15B promotes PCNA mRNA m6A methylation in prostate cancer cells; YTHDF1 recognizes these m6A sites and stabilizes PCNA mRNA, thereby enhancing prostate cancer cell proliferation. PCNA overexpression rescues the proliferation defect caused by RBM15B knockdown.","method":"RNA immunoprecipitation (RIP), m6A quantification, mRNA stability assay (actinomycin D), knockdown/rescue experiments, xenograft model","journal":"Cell biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 2–3 — RIP, m6A assay, in vivo rescue validation, single lab","pmids":["39361104"],"is_preprint":false},{"year":2025,"finding":"MEX3A physically interacts with RBM15B (confirmed by co-immunoprecipitation) and together they promote m6A methylation of super-enhancer RNAs (seRNAs). The RBM15B/IGF2BP3 complex maintains KMT2C mRNA stability, and KMT2C subsequently promotes H3K4me1 deposition, linking RBM15B-dependent m6A to chromatin modification in breast cancer.","method":"Co-immunoprecipitation, methylated RNA immunoprecipitation (MeRIP), FISH, knockdown/overexpression functional assays, in vivo xenograft","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP and MeRIP establish RBM15B interaction and m6A activity; single lab","pmids":["41161249"],"is_preprint":false},{"year":2025,"finding":"RBM15B knockdown in CVB3-infected HL-1 cardiomyocytes reduced viral replication and attenuated apoptosis, establishing an anti-apoptotic and pro-viral role for RBM15B-mediated m6A methylation in viral myocarditis.","method":"siRNA knockdown, viral plaque assay, Calcein AM/PI viability staining, Western blotting, MeRIP-seq/RNA-seq","journal":"Journal of inflammation research","confidence":"Low","confidence_rationale":"Tier 3 — functional knockdown with defined readouts but limited mechanistic pathway placement; single lab, single study","pmids":["40546402"],"is_preprint":false},{"year":2025,"finding":"RBM15B increases m6A modification of FNBP1 mRNA; IGF2BP2 recognizes this m6A mark to stabilize FNBP1 mRNA in glioblastoma cells. FNBP1 then interacts with LASP1 to activate Smad3-mediated glycolysis, promoting GBM progression.","method":"MeRIP, RNA immunoprecipitation, co-immunoprecipitation, knockdown/overexpression, xenograft model","journal":"Drug development research","confidence":"Medium","confidence_rationale":"Tier 2–3 — MeRIP and RIP establish m6A writer role for RBM15B; pathway placement through rescue experiments; single lab","pmids":["41086050"],"is_preprint":false},{"year":2026,"finding":"RBM15B recognizes the H3K79me2 histone mark through its H47 residue, guiding selective m6A deposition preferentially in 5'UTRs and around start codons of mRNAs in MLL-rearranged leukemia. This H3K79me2-RBM15B axis enhances translation efficiency of oncogenic transcripts and promotes leukemic stem cell self-renewal. Blockade of this axis inhibits leukemia cell survival and promotes differentiation.","method":"ChIP-seq, MeRIP-seq, mutagenesis of H47 residue, polysome profiling (translation efficiency), knockdown/CRISPR, leukemic stem cell self-renewal assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 — site-specific mutagenesis identifies key residue, MeRIP-seq maps m6A sites, translation readouts, functional rescue; multiple orthogonal methods","pmids":["41629530"],"is_preprint":false},{"year":2026,"finding":"FOXP2 transcriptionally represses RBM15B expression (shown by ChIP and dual-luciferase assay); reduced RBM15B leads to decreased m6A modification of KDM4C mRNA, lowering KDM4C expression, increasing H3K9me3 at the SLC7A11 promoter, and suppressing SLC7A11 to enhance ferroptosis in HCC cells.","method":"ChIP assay, dual-luciferase reporter assay, MeRIP, Western blotting, ferroptosis markers, xenograft model","journal":"Applied biochemistry and biotechnology","confidence":"Medium","confidence_rationale":"Tier 2–3 — ChIP and reporter assay for upstream regulation; MeRIP for m6A; pathway epistasis by rescue; single lab","pmids":["41661469"],"is_preprint":false},{"year":2026,"finding":"RBM15B promotes m6A modification of ITSN2 (intersectin2) mRNA; the m6A reader IGF2BP1 recognizes this mark and stabilizes ITSN2 mRNA, driving HCC cell proliferation and invasion. ITSN2 knockdown rescues the pro-tumorigenic phenotype of RBM15B overexpression.","method":"MeRIP-seq, RNA-seq, RNA immunoprecipitation (RIP-qPCR), mRNA stability assay, rescue/overexpression assays, xenograft model","journal":"Journal of cancer research and clinical oncology","confidence":"Medium","confidence_rationale":"Tier 2–3 — MeRIP-seq and RIP establish m6A-dependent mRNA stabilization; rescue epistasis; single lab","pmids":["41795047"],"is_preprint":false},{"year":2025,"finding":"RBM15B (together with SPEN and RBM15) was captured on incoming henipavirus RNA within the first hour of infection by VIR-CLASP, identifying it as a direct host factor promoting viral infection. SPEN depletion caused widespread hypomethylation of ~98% of differentially modified m6A sites, predominantly on the viral L mRNA encoding the RNA-dependent RNA polymerase, linking the SPEN-RBM15B axis to m6A-dependent facilitation of henipavirus replication.","method":"VIR-CLASP (viral crosslinking and solid-phase purification), direct RNA sequencing for m6A profiling, siRNA depletion","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2–3 — novel method VIR-CLASP with direct RNA sequencing; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2025.11.21.689838"],"is_preprint":true}],"current_model":"RBM15B is a SPEN-family RNA-binding protein that functions as a component of the m6A methyltransferase writer complex (recruiting METTL3 to target RNAs, guided in part by reading H3K79me2 histone marks via its H47 residue), a cofactor for the mRNA export receptor NXF1, and a splicing regulator that antagonizes SR proteins and CDK11(p110)–cyclin L2α-stimulated splicing; collectively, these activities control mRNA processing, nuclear export, and translation of specific target mRNAs in contexts ranging from X-chromosome inactivation to viral infection and oncogenesis."},"narrative":{"teleology":[{"year":2005,"claim":"The initial characterization of RBM15B (OTT3) established it as a nuclear, non-shuttling SPEN-family protein with a role in alternative splicing regulation and as a host target of the EBV mRNA export factor EB2, distinguishing it functionally from the transcriptional repressor SHARP.","evidence":"Yeast two-hybrid, co-immunoprecipitation, splicing reporter assays in HeLa cells","pmids":["16129689"],"confidence":"Medium","gaps":["Endogenous splicing targets were not identified","Mechanism of splicing repression was not resolved","Biological relevance of EB2 interaction to viral lifecycle was not tested"]},{"year":2009,"claim":"Mapping of the RBM15B C-terminal region as the NXF1- and Aly/REF-interacting domain established RBM15B as a bona fide mRNA export cofactor, expanding its functional repertoire beyond splicing to nucleocytoplasmic mRNA transport.","evidence":"Co-immunoprecipitation, mutational domain mapping, subcellular localization in HeLa cells","pmids":["19586903"],"confidence":"Medium","gaps":["No RNA export cargo was identified for RBM15B-NXF1","Functional redundancy with paralogue RBM15 in export was not resolved"]},{"year":2010,"claim":"Two contemporaneous studies resolved distinct mechanistic arms of RBM15B: KSHV ORF57 was shown to displace RBM15B from viral RNA via its SPOC domain to facilitate cytoplasmic accumulation, while RBM15B was placed in a ~1 MDa nuclear complex with CDK11(p110)/cyclin L2α/SR proteins where it competitively inhibits SR-protein-stimulated splicing and E-complex formation.","evidence":"RNA immunoprecipitation and nucleocytoplasmic fractionation for ORF57 mechanism; in vitro splicing reconstitution, size-exclusion chromatography, and domain mapping for CDK11 complex","pmids":["21106733","21044963"],"confidence":"High","gaps":["Endogenous cellular mRNA targets of the splicing-inhibitory activity were not defined","Whether ORF57-mediated displacement of RBM15B affects m6A or splicing of viral RNAs was unknown","Structural basis of SR-protein antagonism was not determined"]},{"year":2016,"claim":"The discovery that RBM15B and RBM15 recruit METTL3 to XIST lncRNA for m6A methylation fundamentally reframed RBM15B as a writer-complex recruiter in the epitranscriptomic pathway and linked it to X-chromosome inactivation.","evidence":"RNAi knockdown of RBM15/RBM15B, MeRIP-seq, XIST gene-silencing reporter assays","pmids":["27602518"],"confidence":"High","gaps":["How RBM15B selects specific RNA sites for m6A deposition was unresolved","Whether the mRNA export and splicing functions are coupled to m6A writing was unknown"]},{"year":2022,"claim":"Studies in multiple cancer types identified specific mRNA targets whose stability is controlled by RBM15B-directed m6A modification followed by recognition by m6A reader proteins (YTHDF1, IGF2BP1/2/3), establishing a generalizable writer→reader→mRNA stability axis operating on targets including TRAM2, PCNA, FNBP1, KMT2C, KDM4C, and ITSN2.","evidence":"MeRIP, RIP-qPCR, mRNA stability assays, knockdown/rescue experiments, and xenograft models across hepatocellular carcinoma, prostate cancer, glioblastoma, and breast cancer","pmids":["35494016","39361104","41086050","41161249","41795047","41661469"],"confidence":"Medium","gaps":["Most studies are from single laboratories and await independent replication","Target selectivity — how RBM15B chooses these particular mRNAs — was not addressed in these studies","Whether RBM15B functions via the same mechanism in non-cancer physiology is unknown"]},{"year":2026,"claim":"The identification of H3K79me2 as a chromatin mark read by RBM15B residue H47 resolved a longstanding question of how RBM15B achieves target selectivity, revealing a histone-to-epitranscriptome relay that channels m6A to 5′UTRs and promotes translation of oncogenic mRNAs in MLL-rearranged leukemia.","evidence":"ChIP-seq, MeRIP-seq, site-directed mutagenesis of H47, polysome profiling, CRISPR knockout, leukemic stem cell self-renewal assays","pmids":["41629530"],"confidence":"High","gaps":["Whether H3K79me2 reading applies beyond MLL-rearranged leukemia contexts is untested","Structural basis of H47-H3K79me2 recognition is not resolved","Relationship between the chromatin-guided m6A and the NXF1 export function is unknown"]},{"year":null,"claim":"Key open questions include the structural basis of RBM15B's multivalent interactions (RNA, chromatin, NXF1, splicing machinery), whether its splicing-regulatory, export, and m6A-writing activities are coordinated or operate on distinct RNA pools, and the physiological consequences of RBM15B loss in normal development beyond X-inactivation.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of RBM15B or its complexes exists","Genetic loss-of-function models in whole organisms are lacking","Integration of splicing, export, and m6A functions into a unified mechanistic model has not been achieved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,2,4,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,4,10]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[1,3]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,3,4,10]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,6,9,12]}],"complexes":["m6A methyltransferase writer complex","CDK11(p110)–cyclin L2α–SR protein complex"],"partners":["METTL3","NXF1","RBM15","CDK11B","SRSF1","ALYREF","MEX3A","IGF2BP1"],"other_free_text":[]},"mechanistic_narrative":"RBM15B is a SPEN-family RNA-binding protein that functions as a recruitment adaptor for the m6A methyltransferase complex, directing METTL3-mediated N6-methyladenosine deposition on specific mRNAs and long noncoding RNAs to regulate their stability, nuclear export, and translation. RBM15B and its paralogue RBM15 recruit the m6A writer complex to XIST lncRNA, and their combined depletion impairs XIST-mediated X-chromosome gene silencing [PMID:27602518]; in MLL-rearranged leukemia, RBM15B reads the H3K79me2 histone mark via residue H47 to guide m6A deposition preferentially at 5′UTRs, enhancing translation of oncogenic transcripts and leukemic stem cell self-renewal [PMID:41629530]. Beyond m6A writing, RBM15B acts as a cofactor for the mRNA export receptor NXF1, directly binding NXF1 and Aly/REF through its C-terminal region [PMID:19586903], and functions as a splicing regulator that antagonizes SR proteins and inhibits spliceosomal E-complex formation in a CDK11(p110)–cyclin L2α complex [PMID:21044963]. Multiple herpesvirus-encoded mRNA export factors (KSHV ORF57, EBV EB2) interact with the RBM15B SPOC domain to co-opt its RNA-regulatory activities for viral gene expression [PMID:21106733, PMID:16129689]."},"prefetch_data":{"uniprot":{"accession":"Q8NDT2","full_name":"Putative RNA-binding protein 15B","aliases":["One-twenty two protein 3","HsOTT3","HuOTT3","RNA-binding motif protein 15B"],"length_aa":890,"mass_kda":97.2,"function":"RNA-binding protein that acts as a key regulator of N6-methyladenosine (m6A) methylation of RNAs, thereby regulating different processes, such as alternative splicing of mRNAs and X chromosome inactivation mediated by Xist RNA (PubMed:16129689, PubMed:27602518). Associated component of the WMM complex, a complex that mediates N6-methyladenosine (m6A) methylation of RNAs, a modification that plays a role in the efficiency of mRNA splicing and RNA processing (PubMed:27602518). Plays a key role in m6A methylation, possibly by binding target RNAs and recruiting the WMM complex (PubMed:27602518). Involved in random X inactivation mediated by Xist RNA: acts by binding Xist RNA and recruiting the WMM complex, which mediates m6A methylation, leading to target YTHDC1 reader on Xist RNA and promoting transcription repression activity of Xist (PubMed:27602518). Functions in the regulation of alternative or illicit splicing, possibly by regulating m6A methylation (PubMed:16129689). Inhibits pre-mRNA splicing (PubMed:21044963). Also functions as a mRNA export factor by acting as a cofactor for the nuclear export receptor NXF1 (PubMed:19586903)","subcellular_location":"Nucleus, nucleoplasm; Nucleus speckle; Nucleus envelope","url":"https://www.uniprot.org/uniprotkb/Q8NDT2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RBM15B","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000259956","cell_line_id":"CID001472","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"chromatin","grade":2}],"interactors":[{"gene":"WTAP","stoichiometry":0.2},{"gene":"RBBP5","stoichiometry":0.2},{"gene":"KIAA1429","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001472","total_profiled":1310},"omim":[{"mim_id":"612602","title":"RNA-BINDING MOTIF PROTEIN 15B; RBM15B","url":"https://www.omim.org/entry/612602"},{"mim_id":"612472","title":"METHYLTRANSFERASE 3, N6-ADENOSINE-METHYLTRANSFERASE COMPLEX CATALYTIC SUBUNIT; METTL3","url":"https://www.omim.org/entry/612472"},{"mim_id":"606077","title":"RNA-BINDING MOTIF PROTEIN 15; RBM15","url":"https://www.omim.org/entry/606077"},{"mim_id":"314670","title":"X INACTIVATION-SPECIFIC TRANSCRIPT; XIST","url":"https://www.omim.org/entry/314670"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RBM15B"},"hgnc":{"alias_symbol":["HUMAGCGB","OTT3"],"prev_symbol":[]},"alphafold":{"accession":"Q8NDT2","domains":[{"cath_id":"3.30.70.330","chopping":"139-216","consensus_level":"high","plddt":86.1074,"start":139,"end":216},{"cath_id":"3.30.70.330","chopping":"327-414","consensus_level":"medium","plddt":87.9073,"start":327,"end":414},{"cath_id":"3.30.70.330","chopping":"419-492","consensus_level":"medium","plddt":86.1027,"start":419,"end":492},{"cath_id":"2.40.290.10","chopping":"710-802_813-886","consensus_level":"high","plddt":83.4343,"start":710,"end":886}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NDT2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NDT2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NDT2-F1-predicted_aligned_error_v6.png","plddt_mean":61.34},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RBM15B","jax_strain_url":"https://www.jax.org/strain/search?query=RBM15B"},"sequence":{"accession":"Q8NDT2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NDT2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NDT2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NDT2"}},"corpus_meta":[{"pmid":"16129689","id":"PMC_16129689","title":"Interaction of the Epstein-Barr virus mRNA export factor EB2 with human Spen proteins SHARP, OTT1, and a novel member of the family, OTT3, links Spen proteins with splicing regulation and mRNA export.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16129689","citation_count":81,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19586903","id":"PMC_19586903","title":"The RNA-binding motif protein 15B (RBM15B/OTT3) acts as cofactor of the nuclear export receptor NXF1.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19586903","citation_count":48,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21106733","id":"PMC_21106733","title":"Kaposi's sarcoma-associated herpesvirus ORF57 interacts with cellular RNA export cofactors RBM15 and OTT3 to promote expression of viral ORF59.","date":"2010","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/21106733","citation_count":45,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35494016","id":"PMC_35494016","title":"YY1-Targeted RBM15B Promotes Hepatocellular Carcinoma Cell Proliferation and Sorafenib Resistance by Promoting TRAM2 Expression in an m6A-Dependent Manner.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35494016","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21044963","id":"PMC_21044963","title":"The RNA binding motif protein 15B (RBM15B/OTT3) is a functional competitor of serine-arginine (SR) proteins and antagonizes the positive effect of the CDK11p110-cyclin L2α complex on splicing.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21044963","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20828777","id":"PMC_20828777","title":"Requirement of UAP56, URH49, RBM15, and OTT3 in the expression of Kaposi sarcoma-associated herpesvirus ORF57.","date":"2010","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/20828777","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39361104","id":"PMC_39361104","title":"RBM15B Promotes Prostate Cancer Cell Proliferation via PCNA m6A Modification.","date":"2024","source":"Cell biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/39361104","citation_count":7,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41161249","id":"PMC_41161249","title":"MEX3A-mediated super-enhancer RNA m6A methylation promotes aggressiveness of breast cancer via regulating RBM15B/IGF2BP3/KMT2C signaling.","date":"2025","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41161249","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40546402","id":"PMC_40546402","title":"Comprehensive Analysis of Differences in N6-Methyladenosine RNA Methylation Groups in CVB3-Induced Viral Myocarditis and Identification of the Anti-Apoptotic Role of RBM15B.","date":"2025","source":"Journal of inflammation research","url":"https://pubmed.ncbi.nlm.nih.gov/40546402","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41661469","id":"PMC_41661469","title":"Mechanism of FOXP2 in the Hepatocellular Carcinoma Progression via Ferroptosis Through RBM15B-Mediated m6A Modification.","date":"2026","source":"Applied biochemistry and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/41661469","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41629530","id":"PMC_41629530","title":"RBM15B recognizes H3K79me2 to guide selective m6A-modification of mRNA and enhance oncoprotein translation in MLL-r leukemia.","date":"2026","source":"The EMBO 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its SPOC domain interacts more weakly with SMRT/NCoR corepressors compared to SHARP. RBM15B represses accumulation of alternatively spliced beta-thalassemia mRNAs without affecting constitutively spliced beta-globin mRNA, establishing a role in splicing regulation.\",\n      \"method\": \"Yeast two-hybrid screen, co-transfection/co-localization, domain mapping, splicing reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, multiple functional assays but no in vitro reconstitution or epistasis\",\n      \"pmids\": [\"16129689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RBM15B (OTT3) functions as a cofactor of the nuclear export receptor NXF1, interacting directly with NXF1 via its C-terminal region (containing the SPOC domain). RBM15B also interacts with the mRNA export factor Aly/REF and co-localizes with the splicing factor compartment and nuclear envelope. RBM15B and RBM15 interact with each other in vivo.\",\n      \"method\": \"Mutational analysis, co-immunoprecipitation, subcellular localization (biochemical fractionation, imaging), genetic knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, mutational domain mapping, localization studies; replicated across paralogs\",\n      \"pmids\": [\"19586903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RBM15B (OTT3) is a functional competitor of SR splicing factors (SF2/ASF, 9G8), inhibits formation of the spliceosomal E complex, and antagonizes the positive effect of the CDK11p110-cyclin L2α complex on splicing. RBM15B directly interacts with CDK11p110 and cyclin L2α via two distinct mapped domains and co-elutes with these factors in a ~1 MDa nuclear complex.\",\n      \"method\": \"Size exclusion chromatography, co-immunoprecipitation, in vitro pulldown assays, in vitro splicing assays, in vivo splicing reporter assays, domain mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro splicing assay plus co-IP and pulldown with domain mapping, multiple orthogonal methods in single study\",\n      \"pmids\": [\"21044963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RBM15B (OTT3) participates in KSHV ORF57-enhanced expression of ORF59 mRNA; ectopic RBM15B promotes nuclear accumulation of ORF59 RNA. KSHV ORF57 interacts directly with the C-terminal SPOC domain of RBM15B to reduce RBM15B binding to ORF59 RNA and shifts RNA localization from nucleus to cytoplasm. Herpesvirus homologs EBV EB2, HSV ICP27, VZV IE4, and CMV UL69 also interact with RBM15B.\",\n      \"method\": \"Co-immunoprecipitation, RNA immunoprecipitation, nucleocytoplasmic fractionation, RNAi knockdown, domain mapping\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP and RNA-IP with domain mapping; single lab\",\n      \"pmids\": [\"21106733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Knockdown of RBM15B by RNAi leads to decreased nuclear export and decreased expression of KSHV ORF57 RNA, indicating RBM15B is required for proper nuclear export of specific viral mRNAs.\",\n      \"method\": \"RNAi knockdown, nucleocytoplasmic fractionation, qRT-PCR\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with specific RNA export phenotype; single lab\",\n      \"pmids\": [\"20828777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RBM15B regulates the stability of TRAM2 mRNA in an m6A-dependent manner in hepatocellular carcinoma cells, and its own transcription is activated by transcription factor YY1, establishing a YY1-RBM15B-TRAM2 regulatory axis.\",\n      \"method\": \"Overexpression/knockdown functional assays, m6A methylation assays, luciferase reporter (implied from transcriptional activation claim), mRNA stability assays\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, mechanistic follow-up limited in detail\",\n      \"pmids\": [\"35494016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RBM15B promotes m6A modification of PCNA mRNA; the m6A reader YTHDF1 binds these m6A sites and stabilizes PCNA mRNA, thereby promoting prostate cancer cell proliferation.\",\n      \"method\": \"RNA immunoprecipitation (RIP), m6A quantification, mRNA stability assay (actinomycin D), in vivo xenograft, knockdown/overexpression rescue\",\n      \"journal\": \"Cell biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP and mRNA stability assays with rescue; single lab\",\n      \"pmids\": [\"39361104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RBM15B selectively modulates m6A modifications in the 5'UTR and around the start codons of mRNAs. This site-selective deposition is guided by H3K79me2 histone methylation; H47 of RBM15B is a key residue for recognizing H3K79me2. The H3K79me2-RBM15B axis enhances translation efficiency of oncogenic transcripts and promotes leukemic stem cell self-renewal.\",\n      \"method\": \"m6A sequencing (MeRIP-seq), mutagenesis (H47 residue), co-immunoprecipitation/chromatin association studies, functional assays (self-renewal, differentiation, leukemia maintenance in vivo)\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — site-specific mutagenesis, transcriptome-wide m6A mapping, in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"41629530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MEX3A interacts with RBM15B and promotes super-enhancer RNA m6A methylation; the RBM15B/IGF2BP3 complex recruits the H3K4 methyltransferase KMT2C to promote H3K4me1 formation and maintain KMT2C mRNA stability, linking RBM15B m6A activity to chromatin regulation in breast cancer.\",\n      \"method\": \"Co-immunoprecipitation (MEX3A-RBM15B interaction), methylated RNA immunoprecipitation (MeRIP), FISH, functional proliferation/invasion assays, in vivo tumor models\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, co-IP for interaction but mechanistic chain involves multiple inferences\",\n      \"pmids\": [\"41161249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBM15B acts as an m6A methyltransferase component in cardiomyocytes infected with CVB3; RBM15B knockdown reduces CVB3 replication and attenuates apoptosis in infected HL-1 cells, establishing an anti-apoptotic/pro-viral role linked to m6A modification.\",\n      \"method\": \"m6A dot blot, MeRIP-seq, RNA-seq, RNAi knockdown, viral plaque assay, Calcein AM/PI staining, Western blotting\",\n      \"journal\": \"Journal of inflammation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with specific viral replication and apoptosis phenotypes, supported by MeRIP-seq; single lab\",\n      \"pmids\": [\"40546402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FOXP2 transcriptionally represses RBM15B, reducing RBM15B-mediated m6A modification of KDM4C mRNA; reduced KDM4C expression increases H3K9me3 at the SLC7A11 promoter, suppressing SLC7A11 and enhancing ferroptosis in hepatocellular carcinoma cells.\",\n      \"method\": \"ChIP assay, dual-luciferase reporter assay, MeRIP, Western blot, functional ferroptosis/proliferation assays, xenograft models\",\n      \"journal\": \"Applied biochemistry and biotechnology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, mechanistic chain spans multiple steps with limited direct RBM15B enzymatic validation\",\n      \"pmids\": [\"41661469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RBM15B increases m6A modification of FNBP1 mRNA; the m6A reader IGF2BP2 recognizes this mark and stabilizes FNBP1 mRNA, promoting FNBP1-LASP1 interaction and Smad3-mediated glycolysis in glioblastoma.\",\n      \"method\": \"m6A assays, RIP, knockdown/rescue experiments, in vivo xenograft and lung metastasis models\",\n      \"journal\": \"Drug development research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, functional mechanistic chain but limited direct m6A writer validation for RBM15B\",\n      \"pmids\": [\"41086050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RBM15B mediates m6A modification of ITSN2 mRNA; IGF2BP1 recognizes this m6A mark and stabilizes ITSN2 mRNA, promoting hepatocellular carcinoma progression.\",\n      \"method\": \"MeRIP-seq, RNA-seq, RNA immunoprecipitation (RIP-qPCR), rescue assays, in vitro and in vivo tumor models\",\n      \"journal\": \"Journal of cancer research and clinical oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, RIP used for IGF2BP1-ITSN2 interaction; RBM15B m6A writer role inferred from MeRIP-seq without direct enzymatic reconstitution\",\n      \"pmids\": [\"41795047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBM15B was identified as a direct interactor with henipavirus genomic RNA within the first hour of infection (by VIR-CLASP), and, together with SPEN and RBM15, promotes viral infection. SPEN depletion induces widespread m6A hypomethylation (~98% of differentially modified sites) predominantly on the viral L mRNA, implicating the SPEN/RBM15B complex in m6A deposition on viral RNA.\",\n      \"method\": \"Viral Cross-linking and Solid-phase Purification (VIR-CLASP), direct RNA sequencing, m6A sequencing, RNAi knockdown\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — preprint, novel interactome method, but RBM15B-specific m6A writer activity not independently separated from SPEN\",\n      \"pmids\": [\"bio_10.1101_2025.11.21.689838\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"RBM15B (OTT3) is a multifunctional RNA-binding SPEN family protein that acts as: (1) a cofactor of the mRNA nuclear export receptor NXF1 via direct C-terminal/SPOC domain interaction; (2) a splicing regulator that competes with SR proteins and antagonizes CDK11p110-cyclin L2α-stimulated splicing via direct binding to both partners; and (3) a component of the m6A methyltransferase complex (METTL3/14 writer complex) that guides site-selective m6A deposition—particularly in 5'UTRs and around start codons—through recognition of H3K79me2 histone marks via its H47 residue, thereby enhancing translation of oncogenic transcripts and regulating mRNA stability through m6A readers such as YTHDF1 and IGF2BP proteins.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"RBM15B (OTT3) was identified as a nuclear, non-shuttling protein that interacts with the Epstein-Barr virus mRNA export factor EB2 via EB2's 40 N-terminal amino acids. OTT3's SPOC domain shows far weaker interaction with SMRT corepressor than SHARP's SPOC domain, indicating no major role in transcriptional repression. OTT3 was shown to repress accumulation of alternatively spliced beta-thalassemia mRNAs but not constitutively spliced beta-globin mRNA, establishing a role in splicing regulation.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, subcellular localization by transfection/imaging, splicing reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple methods (Y2H, Co-IP, functional splicing assay) in single lab\",\n      \"pmids\": [\"16129689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RBM15B (OTT3) has post-transcriptional regulatory activity and directly interacts with mRNA export receptor NXF1 and adaptor Aly/REF via its C-terminal region (mapped by mutational analysis). RBM15B co-localizes with the splicing factor compartment and nuclear envelope. RBM15B and its paralogue RBM15 also interact with each other in vivo. Unlike SHARP, both RBM15B and RBM15 function as NXF1 cofactors.\",\n      \"method\": \"Co-immunoprecipitation, mutational analysis, subcellular localization studies, biochemical fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with mutational mapping, multiple methods in single study\",\n      \"pmids\": [\"19586903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"KSHV ORF57 interacts directly with the C-terminal SPOC domain of RBM15B (OTT3) to reduce RBM15B binding to ORF59 RNA and shifts nucleocytoplasmic balance of ORF59 RNA toward cytoplasm. Ectopic expression of RBM15B (or RBM15) promotes nuclear accumulation of ORF59 RNA and hyperpolyadenylation, whereas ORF57 counteracts this effect. Herpesvirus homologs (EBV EB2, HSV ICP27, VZV IE4, CMV UL69) also interact with RBM15B and OTT3.\",\n      \"method\": \"Co-immunoprecipitation, RNA immunoprecipitation, nucleocytoplasmic fractionation, domain mapping, overexpression/knockdown assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, RIP, fractionation) with domain-level mechanistic detail, single lab\",\n      \"pmids\": [\"21106733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RBM15B was identified as a novel binding partner of CDK11(p110). It co-elutes with CDK11(p110), cyclin L2α, and SR proteins (SF2/ASF, 9G8) in a ~1-MDa nuclear complex. Two distinct domains of RBM15B directly interact with the N-terminal extension of CDK11(p110), cyclin L2α, and SR proteins. RBM15B functions as a competitive antagonist of SR proteins SF2/ASF and 9G8, inhibits formation of the spliceosomal E complex, and antagonizes the stimulatory effect of the CDK11(p110)–cyclin L2α complex on splicing both in vitro and in vivo.\",\n      \"method\": \"Size exclusion chromatography, co-immunoprecipitation, in vitro pulldown, in vitro splicing assay, in vivo splicing assay, domain mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro reconstitution of splicing inhibition combined with Co-IP, pulldown, and domain mapping; multiple orthogonal methods\",\n      \"pmids\": [\"21044963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RBM15B, together with its paralogue RBM15, recruits the m6A methyltransferase complex (including METTL3) to specific RNA sites, mediating N6-methyladenosine modification of XIST lncRNA and cellular mRNAs. Knockdown of both RBM15 and RBM15B impairs XIST-mediated transcriptional gene silencing of X-linked genes. This established RBM15B as a writer-complex recruiter in the m6A pathway required for XIST function.\",\n      \"method\": \"RNAi knockdown, m6A sequencing (MeRIP), gene silencing reporter assays, co-immunoprecipitation\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (RNAi, MeRIP-seq, functional silencing assay), published in high-impact journal, widely replicated\",\n      \"pmids\": [\"27602518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RBM15B is transcriptionally activated by the transcription factor YY1 and regulates TRAM2 mRNA stability in an m6A-dependent manner in hepatocellular carcinoma cells, promoting cell proliferation, invasion, and sorafenib resistance.\",\n      \"method\": \"ChIP assay (YY1 binding to RBM15B promoter), m6A assay, RNA stability assay, overexpression/knockdown with proliferation and invasion readouts\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — ChIP for upstream regulation and m6A mechanistic link, single lab\",\n      \"pmids\": [\"35494016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RBM15B promotes PCNA mRNA m6A methylation in prostate cancer cells; YTHDF1 recognizes these m6A sites and stabilizes PCNA mRNA, thereby enhancing prostate cancer cell proliferation. PCNA overexpression rescues the proliferation defect caused by RBM15B knockdown.\",\n      \"method\": \"RNA immunoprecipitation (RIP), m6A quantification, mRNA stability assay (actinomycin D), knockdown/rescue experiments, xenograft model\",\n      \"journal\": \"Cell biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — RIP, m6A assay, in vivo rescue validation, single lab\",\n      \"pmids\": [\"39361104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MEX3A physically interacts with RBM15B (confirmed by co-immunoprecipitation) and together they promote m6A methylation of super-enhancer RNAs (seRNAs). The RBM15B/IGF2BP3 complex maintains KMT2C mRNA stability, and KMT2C subsequently promotes H3K4me1 deposition, linking RBM15B-dependent m6A to chromatin modification in breast cancer.\",\n      \"method\": \"Co-immunoprecipitation, methylated RNA immunoprecipitation (MeRIP), FISH, knockdown/overexpression functional assays, in vivo xenograft\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP and MeRIP establish RBM15B interaction and m6A activity; single lab\",\n      \"pmids\": [\"41161249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBM15B knockdown in CVB3-infected HL-1 cardiomyocytes reduced viral replication and attenuated apoptosis, establishing an anti-apoptotic and pro-viral role for RBM15B-mediated m6A methylation in viral myocarditis.\",\n      \"method\": \"siRNA knockdown, viral plaque assay, Calcein AM/PI viability staining, Western blotting, MeRIP-seq/RNA-seq\",\n      \"journal\": \"Journal of inflammation research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — functional knockdown with defined readouts but limited mechanistic pathway placement; single lab, single study\",\n      \"pmids\": [\"40546402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBM15B increases m6A modification of FNBP1 mRNA; IGF2BP2 recognizes this m6A mark to stabilize FNBP1 mRNA in glioblastoma cells. FNBP1 then interacts with LASP1 to activate Smad3-mediated glycolysis, promoting GBM progression.\",\n      \"method\": \"MeRIP, RNA immunoprecipitation, co-immunoprecipitation, knockdown/overexpression, xenograft model\",\n      \"journal\": \"Drug development research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — MeRIP and RIP establish m6A writer role for RBM15B; pathway placement through rescue experiments; single lab\",\n      \"pmids\": [\"41086050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RBM15B recognizes the H3K79me2 histone mark through its H47 residue, guiding selective m6A deposition preferentially in 5'UTRs and around start codons of mRNAs in MLL-rearranged leukemia. This H3K79me2-RBM15B axis enhances translation efficiency of oncogenic transcripts and promotes leukemic stem cell self-renewal. Blockade of this axis inhibits leukemia cell survival and promotes differentiation.\",\n      \"method\": \"ChIP-seq, MeRIP-seq, mutagenesis of H47 residue, polysome profiling (translation efficiency), knockdown/CRISPR, leukemic stem cell self-renewal assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — site-specific mutagenesis identifies key residue, MeRIP-seq maps m6A sites, translation readouts, functional rescue; multiple orthogonal methods\",\n      \"pmids\": [\"41629530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FOXP2 transcriptionally represses RBM15B expression (shown by ChIP and dual-luciferase assay); reduced RBM15B leads to decreased m6A modification of KDM4C mRNA, lowering KDM4C expression, increasing H3K9me3 at the SLC7A11 promoter, and suppressing SLC7A11 to enhance ferroptosis in HCC cells.\",\n      \"method\": \"ChIP assay, dual-luciferase reporter assay, MeRIP, Western blotting, ferroptosis markers, xenograft model\",\n      \"journal\": \"Applied biochemistry and biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — ChIP and reporter assay for upstream regulation; MeRIP for m6A; pathway epistasis by rescue; single lab\",\n      \"pmids\": [\"41661469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RBM15B promotes m6A modification of ITSN2 (intersectin2) mRNA; the m6A reader IGF2BP1 recognizes this mark and stabilizes ITSN2 mRNA, driving HCC cell proliferation and invasion. ITSN2 knockdown rescues the pro-tumorigenic phenotype of RBM15B overexpression.\",\n      \"method\": \"MeRIP-seq, RNA-seq, RNA immunoprecipitation (RIP-qPCR), mRNA stability assay, rescue/overexpression assays, xenograft model\",\n      \"journal\": \"Journal of cancer research and clinical oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — MeRIP-seq and RIP establish m6A-dependent mRNA stabilization; rescue epistasis; single lab\",\n      \"pmids\": [\"41795047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBM15B (together with SPEN and RBM15) was captured on incoming henipavirus RNA within the first hour of infection by VIR-CLASP, identifying it as a direct host factor promoting viral infection. SPEN depletion caused widespread hypomethylation of ~98% of differentially modified m6A sites, predominantly on the viral L mRNA encoding the RNA-dependent RNA polymerase, linking the SPEN-RBM15B axis to m6A-dependent facilitation of henipavirus replication.\",\n      \"method\": \"VIR-CLASP (viral crosslinking and solid-phase purification), direct RNA sequencing for m6A profiling, siRNA depletion\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2–3 — novel method VIR-CLASP with direct RNA sequencing; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.11.21.689838\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"RBM15B is a SPEN-family RNA-binding protein that functions as a component of the m6A methyltransferase writer complex (recruiting METTL3 to target RNAs, guided in part by reading H3K79me2 histone marks via its H47 residue), a cofactor for the mRNA export receptor NXF1, and a splicing regulator that antagonizes SR proteins and CDK11(p110)–cyclin L2α-stimulated splicing; collectively, these activities control mRNA processing, nuclear export, and translation of specific target mRNAs in contexts ranging from X-chromosome inactivation to viral infection and oncogenesis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RBM15B is a SPEN-family RNA-binding protein that functions both as a splicing/mRNA export regulator and as a substrate-specifying component of the m6A methyltransferase complex. In its nuclear export role, RBM15B interacts directly with the export receptor NXF1 via its C-terminal SPOC domain and with the adaptor Aly/REF, and it is exploited by herpesvirus factors (KSHV ORF57, EBV EB2) that modulate RBM15B–RNA interactions to redirect viral transcripts to the cytoplasm [PMID:19586903, PMID:21106733]. RBM15B inhibits spliceosome E-complex formation by competing with SR proteins and antagonizing CDK11p110–cyclin L2α-stimulated splicing [PMID:21044963]. As a component of the m6A writer machinery, RBM15B directs site-selective m6A deposition—preferentially in 5′UTRs and around start codons—guided by recognition of H3K79me2 through its H47 residue, thereby enhancing translation of oncogenic transcripts and promoting leukemic stem cell self-renewal [PMID:41629530].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing RBM15B as a nuclear, non-shuttling protein with a role in splicing regulation resolved its basic cell biology and distinguished it from shuttling mRNA export factors.\",\n      \"evidence\": \"Yeast two-hybrid, co-transfection, and splicing reporter assays in mammalian cells\",\n      \"pmids\": [\"16129689\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No in vitro reconstitution of the splicing effect\",\n        \"Mechanism of splice-site selection unresolved\",\n        \"Relationship between SPOC–SMRT interaction and splicing function unclear\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identification of RBM15B as a direct NXF1 cofactor through its SPOC domain established that, beyond splicing, RBM15B participates in the mRNA nuclear export pathway.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, domain mutagenesis, biochemical fractionation, and localization imaging\",\n      \"pmids\": [\"19586903\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"RNA targets whose export depends on RBM15B not identified\",\n        \"Structural basis of SPOC–NXF1 interaction unknown\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstration that RBM15B inhibits spliceosomal E-complex assembly by competing with SR proteins and antagonizing CDK11p110–cyclin L2α provided a concrete mechanistic basis for its splicing-repressive activity.\",\n      \"evidence\": \"In vitro splicing assays, co-IP, in vitro pulldown, size-exclusion chromatography showing ~1 MDa complex\",\n      \"pmids\": [\"21044963\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of endogenous mRNA targets regulated via this mechanism unknown\",\n        \"Whether CDK11 phosphorylates RBM15B not tested\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Multiple herpesvirus factors (KSHV ORF57, EBV EB2, HSV ICP27) were shown to co-opt RBM15B via its SPOC domain, establishing RBM15B as a common viral target that bridges RNA binding and nuclear export.\",\n      \"evidence\": \"Co-IP, RNA-IP, nucleocytoplasmic fractionation, RNAi knockdown of RBM15B\",\n      \"pmids\": [\"21106733\", \"20828777\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether RBM15B delivers viral RNAs to NXF1 directly or through Aly/REF not resolved\",\n        \"Cellular transcripts affected by viral hijacking not mapped\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The first report linking RBM15B to m6A-dependent mRNA stability regulation (TRAM2 in hepatocellular carcinoma) pivoted the field toward RBM15B's role as a component of the m6A writer complex.\",\n      \"evidence\": \"Overexpression/knockdown, m6A methylation assays, mRNA stability assays in HCC cells\",\n      \"pmids\": [\"35494016\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Direct reconstitution of RBM15B within the METTL3/METTL14 writer complex not performed\",\n        \"Specificity of m6A effect versus general RNA-binding not distinguished\",\n        \"Single lab without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"RBM15B-mediated m6A modification was extended to a specific target (PCNA mRNA), with the m6A reader YTHDF1 shown to stabilize the modified transcript, linking RBM15B m6A activity to cell proliferation.\",\n      \"evidence\": \"RNA immunoprecipitation, m6A quantification, actinomycin D stability assay, knockdown/overexpression rescue, xenograft\",\n      \"pmids\": [\"39361104\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct enzymatic reconstitution of RBM15B-guided m6A deposition on PCNA\",\n        \"Whether RBM15B–PCNA interaction is direct or mediated by other writer subunits unknown\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Transcriptome-wide m6A mapping combined with H47 mutagenesis revealed that RBM15B selectively deposits m6A in 5′UTRs/start codons guided by H3K79me2 recognition, establishing a chromatin-to-epitranscriptome signaling axis that enhances translation of oncogenic mRNAs and leukemic stem cell self-renewal.\",\n      \"evidence\": \"MeRIP-seq, site-directed mutagenesis of H47, chromatin association studies, in vivo leukemia models\",\n      \"pmids\": [\"41629530\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of H47–H3K79me2 interaction not determined\",\n        \"Whether RBM15 (paralog) shares the same histone-reading mechanism not addressed\",\n        \"Downstream reader(s) mediating translation enhancement at 5′UTR m6A sites not identified in this study\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of RBM15B as a direct interactor with henipavirus genomic RNA during early infection expanded its m6A-related role to viral RNA biology, connecting the SPEN/RBM15B complex to viral m6A deposition.\",\n      \"evidence\": \"VIR-CLASP, direct RNA sequencing, m6A sequencing, RNAi knockdown (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.11.21.689838\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Preprint; not peer-reviewed\",\n        \"RBM15B-specific contribution to viral m6A deposition not separated from SPEN\",\n        \"Mechanism of initial viral RNA recognition by RBM15B unclear\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of RBM15B's dual functions — chromatin reading via H47 and RNA target selection — and how its splicing-regulatory and m6A writer activities are coordinated or segregated remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No atomic-resolution structure of RBM15B or its SPOC domain in complex with any partner\",\n        \"Genome-wide identification of endogenous splicing targets distinct from m6A targets not performed\",\n        \"Whether post-translational modifications (e.g., CDK11 phosphorylation) switch RBM15B between splicing and m6A functions untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 3, 7, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 2, 4]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"complexes\": [\n      \"m6A methyltransferase writer complex (METTL3/METTL14)\",\n      \"CDK11p110–cyclin L2α splicing complex\"\n    ],\n    \"partners\": [\n      \"NXF1\",\n      \"CDK11p110\",\n      \"CCNL2\",\n      \"RBM15\",\n      \"ALYREF\",\n      \"SPEN\",\n      \"IGF2BP1\",\n      \"YTHDF1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"RBM15B is a SPEN-family RNA-binding protein that functions as a recruitment adaptor for the m6A methyltransferase complex, directing METTL3-mediated N6-methyladenosine deposition on specific mRNAs and long noncoding RNAs to regulate their stability, nuclear export, and translation. RBM15B and its paralogue RBM15 recruit the m6A writer complex to XIST lncRNA, and their combined depletion impairs XIST-mediated X-chromosome gene silencing [PMID:27602518]; in MLL-rearranged leukemia, RBM15B reads the H3K79me2 histone mark via residue H47 to guide m6A deposition preferentially at 5′UTRs, enhancing translation of oncogenic transcripts and leukemic stem cell self-renewal [PMID:41629530]. Beyond m6A writing, RBM15B acts as a cofactor for the mRNA export receptor NXF1, directly binding NXF1 and Aly/REF through its C-terminal region [PMID:19586903], and functions as a splicing regulator that antagonizes SR proteins and inhibits spliceosomal E-complex formation in a CDK11(p110)–cyclin L2α complex [PMID:21044963]. Multiple herpesvirus-encoded mRNA export factors (KSHV ORF57, EBV EB2) interact with the RBM15B SPOC domain to co-opt its RNA-regulatory activities for viral gene expression [PMID:21106733, PMID:16129689].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"The initial characterization of RBM15B (OTT3) established it as a nuclear, non-shuttling SPEN-family protein with a role in alternative splicing regulation and as a host target of the EBV mRNA export factor EB2, distinguishing it functionally from the transcriptional repressor SHARP.\",\n      \"evidence\": \"Yeast two-hybrid, co-immunoprecipitation, splicing reporter assays in HeLa cells\",\n      \"pmids\": [\"16129689\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Endogenous splicing targets were not identified\",\n        \"Mechanism of splicing repression was not resolved\",\n        \"Biological relevance of EB2 interaction to viral lifecycle was not tested\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Mapping of the RBM15B C-terminal region as the NXF1- and Aly/REF-interacting domain established RBM15B as a bona fide mRNA export cofactor, expanding its functional repertoire beyond splicing to nucleocytoplasmic mRNA transport.\",\n      \"evidence\": \"Co-immunoprecipitation, mutational domain mapping, subcellular localization in HeLa cells\",\n      \"pmids\": [\"19586903\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No RNA export cargo was identified for RBM15B-NXF1\",\n        \"Functional redundancy with paralogue RBM15 in export was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Two contemporaneous studies resolved distinct mechanistic arms of RBM15B: KSHV ORF57 was shown to displace RBM15B from viral RNA via its SPOC domain to facilitate cytoplasmic accumulation, while RBM15B was placed in a ~1 MDa nuclear complex with CDK11(p110)/cyclin L2α/SR proteins where it competitively inhibits SR-protein-stimulated splicing and E-complex formation.\",\n      \"evidence\": \"RNA immunoprecipitation and nucleocytoplasmic fractionation for ORF57 mechanism; in vitro splicing reconstitution, size-exclusion chromatography, and domain mapping for CDK11 complex\",\n      \"pmids\": [\"21106733\", \"21044963\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Endogenous cellular mRNA targets of the splicing-inhibitory activity were not defined\",\n        \"Whether ORF57-mediated displacement of RBM15B affects m6A or splicing of viral RNAs was unknown\",\n        \"Structural basis of SR-protein antagonism was not determined\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The discovery that RBM15B and RBM15 recruit METTL3 to XIST lncRNA for m6A methylation fundamentally reframed RBM15B as a writer-complex recruiter in the epitranscriptomic pathway and linked it to X-chromosome inactivation.\",\n      \"evidence\": \"RNAi knockdown of RBM15/RBM15B, MeRIP-seq, XIST gene-silencing reporter assays\",\n      \"pmids\": [\"27602518\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How RBM15B selects specific RNA sites for m6A deposition was unresolved\",\n        \"Whether the mRNA export and splicing functions are coupled to m6A writing was unknown\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Studies in multiple cancer types identified specific mRNA targets whose stability is controlled by RBM15B-directed m6A modification followed by recognition by m6A reader proteins (YTHDF1, IGF2BP1/2/3), establishing a generalizable writer→reader→mRNA stability axis operating on targets including TRAM2, PCNA, FNBP1, KMT2C, KDM4C, and ITSN2.\",\n      \"evidence\": \"MeRIP, RIP-qPCR, mRNA stability assays, knockdown/rescue experiments, and xenograft models across hepatocellular carcinoma, prostate cancer, glioblastoma, and breast cancer\",\n      \"pmids\": [\"35494016\", \"39361104\", \"41086050\", \"41161249\", \"41795047\", \"41661469\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Most studies are from single laboratories and await independent replication\",\n        \"Target selectivity — how RBM15B chooses these particular mRNAs — was not addressed in these studies\",\n        \"Whether RBM15B functions via the same mechanism in non-cancer physiology is unknown\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"The identification of H3K79me2 as a chromatin mark read by RBM15B residue H47 resolved a longstanding question of how RBM15B achieves target selectivity, revealing a histone-to-epitranscriptome relay that channels m6A to 5′UTRs and promotes translation of oncogenic mRNAs in MLL-rearranged leukemia.\",\n      \"evidence\": \"ChIP-seq, MeRIP-seq, site-directed mutagenesis of H47, polysome profiling, CRISPR knockout, leukemic stem cell self-renewal assays\",\n      \"pmids\": [\"41629530\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether H3K79me2 reading applies beyond MLL-rearranged leukemia contexts is untested\",\n        \"Structural basis of H47-H3K79me2 recognition is not resolved\",\n        \"Relationship between the chromatin-guided m6A and the NXF1 export function is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the structural basis of RBM15B's multivalent interactions (RNA, chromatin, NXF1, splicing machinery), whether its splicing-regulatory, export, and m6A-writing activities are coordinated or operate on distinct RNA pools, and the physiological consequences of RBM15B loss in normal development beyond X-inactivation.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structure of RBM15B or its complexes exists\",\n        \"Genetic loss-of-function models in whole organisms are lacking\",\n        \"Integration of splicing, export, and m6A functions into a unified mechanistic model has not been achieved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 2, 4, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 4, 10]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 3, 4, 10]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 6, 9, 12]}\n    ],\n    \"complexes\": [\n      \"m6A methyltransferase writer complex\",\n      \"CDK11(p110)–cyclin L2α–SR protein complex\"\n    ],\n    \"partners\": [\n      \"METTL3\",\n      \"NXF1\",\n      \"RBM15\",\n      \"CDK11B\",\n      \"SRSF1\",\n      \"ALYREF\",\n      \"MEX3A\",\n      \"IGF2BP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}