{"gene":"RBM15B","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2005,"finding":"OTT3 (RBM15B) was identified as a new member of the SPEN family with N-terminal RNA recognition motifs and a C-terminal SPOC domain. It is a non-shuttling nuclear protein. Its SPOC domain interacts with EBV EB2 (mapped to the 40 N-terminal amino acids of EB2), but the OTT3 SPOC domain shows far weaker interaction with SMRT corepressors compared to SHARP. OTT3 represses accumulation of alternatively spliced beta-thalassemia mRNAs but has no effect on constitutively spliced beta-globin mRNA, establishing a role in splicing regulation.","method":"Yeast two-hybrid screen, transfection/co-localization, domain mapping, splicing assays with beta-globin/beta-thalassemia reporters","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (yeast two-hybrid, co-localization, domain mapping, functional splicing assay) in a single lab; foundational characterization paper","pmids":["16129689"],"is_preprint":false},{"year":2009,"finding":"RBM15B/OTT3 has post-transcriptional regulatory activity and directly interacts with mRNA export receptor NXF1 and export factor Aly/REF via its C-terminal region. Mutational analysis mapped the NXF1-binding activity to the C-terminal portion of OTT3. RBM15B and OTT3 also interact with each other in vivo. OTT3 associates with the splicing factor compartment and the nuclear envelope.","method":"Co-immunoprecipitation, mutational analysis, subcellular localization (fluorescence microscopy), biochemical fractionation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, mutational mapping, subcellular localization, functional comparison across paralogs in a single rigorous study","pmids":["19586903"],"is_preprint":false},{"year":2010,"finding":"RBM15B/OTT3 acts as a functional competitor of SR proteins (SF2/ASF, 9G8) and antagonizes the positive effect of the CDK11p110-cyclin L2α complex on splicing. RBM15B co-elutes with CDK11p110, cyclin L2α, and SR proteins in a ~1-MDa nuclear complex. Two distinct domains of RBM15B mediate direct interactions with the N-terminal extension of CDK11p110, cyclin L2α, and SR proteins. RBM15B inhibits formation of the functional spliceosomal E complex in vitro and in vivo.","method":"Size exclusion chromatography, co-immunoprecipitation, in vitro pulldown assays, domain mapping, in vitro and in vivo splicing assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro reconstitution of splicing inhibition combined with co-IP, pulldown, domain mapping, and both in vitro and in vivo functional assays in a single study","pmids":["21044963"],"is_preprint":false},{"year":2010,"finding":"RBM15B/OTT3 and RBM15 are required for expression of KSHV ORF57 at the posttranscriptional level; knockdown of RBM15 led to nuclear export deficiency of ORF57 RNA. OTT3 and RBM15 ectopic expression augments ORF59 production in the absence of ORF57. KSHV ORF57 interacts directly with the RBM15 C-terminal SPOC domain, reducing RBM15 binding to ORF59 RNA. EBV EB2 and other herpesvirus homologs also interact with RBM15 and OTT3.","method":"RNAi knockdown, nuclear export assay (subcellular RNA fractionation), ectopic expression, direct interaction assays","journal":"Journal of virology / Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two complementary papers (PMID 21106733 and 20828777) using RNAi, fractionation, and interaction assays; single lab but multiple methods","pmids":["21106733","20828777"],"is_preprint":false},{"year":2022,"finding":"RBM15B is transcriptionally activated by transcription factor YY1 and regulates the stability of TRAM2 mRNA in an m6A-dependent manner in hepatocellular carcinoma cells.","method":"ChIP/promoter assay (YY1 binding), m6A-RIP, mRNA stability assay, overexpression/knockdown functional assays","journal":"Frontiers in oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited mechanistic detail in abstract, no reconstitution or mutagenesis described","pmids":["35494016"],"is_preprint":false},{"year":2024,"finding":"RBM15B promotes m6A modification of PCNA mRNA in prostate cancer cells, and the m6A reader YTHDF1 binds these sites to stabilize PCNA mRNA, thereby promoting cell proliferation. RBM15B knockdown decreased m6A levels on PCNA mRNA and reduced mRNA stability.","method":"m6A quantification, RNA immunoprecipitation (RIP), actinomycin D mRNA stability assay, RBM15B knockdown, YTHDF1 binding assay, xenograft model","journal":"Cell biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (m6A-RIP, RIP, stability assay, KD, in vivo xenograft) in a single lab establishing the RBM15B→m6A→YTHDF1→PCNA mRNA stability axis","pmids":["39361104"],"is_preprint":false},{"year":2025,"finding":"RBM15B promotes m6A modification of FNBP1 mRNA; the m6A reader IGF2BP2 recognizes this mark and enhances FNBP1 mRNA stability, promoting glioblastoma progression through a FNBP1-LASP1-Smad3 glycolysis axis.","method":"m6A-RIP, RNA-seq, mRNA stability assay, co-immunoprecipitation, knockdown/overexpression, xenograft models","journal":"Drug development research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, mechanistic details compressed in abstract, no reconstitution or mutagenesis of RBM15B itself","pmids":["41086050"],"is_preprint":false},{"year":2025,"finding":"MEX3A interacts with RBM15B (co-immunoprecipitation) and promotes super-enhancer RNA m6A methylation. RBM15B-binding levels of seRNA m6A are confirmed by MeRIP assay. The MEX3A-RBM15B-IGF2BP3 complex maintains KMT2C mRNA expression and stability, with IGF2BP3/KMT2C promoting H3K4me1 formation.","method":"Co-immunoprecipitation, MeRIP assay, fluorescence in situ hybridization, functional cell assays, in vivo tumor models","journal":"Translational oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single co-IP for the RBM15B interaction, limited mechanistic detail about RBM15B's direct enzymatic role","pmids":["41161249"],"is_preprint":false},{"year":2026,"finding":"RBM15B H47 residue is a key residue for recognition of H3K79me2 histone methylation. Through this chromatin-reading activity, RBM15B guides selective m6A deposition preferentially in 5'UTRs and around start codons of mRNAs transcribed from H3K79me2-marked loci, enhancing translation efficiency of oncogenic transcripts, promoting leukemic stem cell self-renewal, and maintaining MLL-rearranged leukemia.","method":"H3K79me2 recognition assay, m6A-seq/MeRIP-seq, mutagenesis (H47 of RBM15B), translation efficiency assays, leukemic stem cell functional assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — active-site mutagenesis (H47), genome-wide m6A mapping, translation assays, and functional leukemia stem cell assays establishing a novel chromatin-reading/m6A-writing mechanism","pmids":["41629530"],"is_preprint":false},{"year":2026,"finding":"RBM15B mediates m6A modification of FOXM1 mRNA, stabilizing FOXM1 expression. This activates the downstream AURKA/TPX2 axis to promote epithelial-mesenchymal transition in endometrial cancer. RBM15B knockdown inhibited malignant phenotypes and reduced AURKA/TPX2 pathway activation.","method":"RNA pull-down, MeRIP-PCR, dot blot, RNA stability assays, colony formation, Transwell, wound healing assays, functional knockdown","journal":"Cell adhesion & migration","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single m6A-modification mechanism without reconstitution of RBM15B enzymatic activity directly","pmids":["42148505"],"is_preprint":false},{"year":2026,"finding":"RBM15B promotes m6A modification of ITGA1 mRNA, enhancing its stability; this activates the PI3K-Akt pathway to promote glioblastoma progression.","method":"MeRIP assay, actinomycin D mRNA stability assay, Western blotting (PI3K-Akt pathway), knockdown/overexpression, animal model","journal":"Discover oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited mechanistic characterization of RBM15B enzymatic function directly","pmids":["42020859"],"is_preprint":false},{"year":2026,"finding":"RBM15B promotes m6A modification of ITSN2 mRNA; the m6A reader IGF2BP1 recognizes this modification and stabilizes ITSN2 mRNA, facilitating hepatocellular carcinoma progression. Knockdown of ITSN2 rescued the tumor-promoting phenotype induced by RBM15B overexpression.","method":"m6A dot blot, MeRIP-seq/RNA-seq, RNA immunoprecipitation (RIP-qPCR), rescue assay, in vitro and in vivo functional assays","journal":"Journal of cancer research and clinical oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, multiple methods but limited direct mechanistic characterization of RBM15B's catalytic role","pmids":["41795047"],"is_preprint":false},{"year":2026,"finding":"FOXP2 represses RBM15B expression (ChIP and dual-luciferase assays establish FOXP2 binding to RBM15B promoter). RBM15B mediates m6A modification of KDM4C mRNA (MeRIP), regulating KDM4C expression, which affects H3K9me3 levels at the SLC7A11 promoter to suppress ferroptosis in HCC. Overexpression of RBM15B attenuated ferroptosis and reversed FOXP2-mediated suppression of HCC.","method":"ChIP, dual-luciferase reporter assay, MeRIP, Western blot, functional cell assays, xenograft models","journal":"Applied biochemistry and biotechnology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, mechanistic chain involves several intermediaries with limited direct RBM15B enzymatic characterization","pmids":["41661469"],"is_preprint":false},{"year":2026,"finding":"Cancer-associated fibroblast-derived lactate promotes histone lactylation at the RBM15B locus, upregulating RBM15B expression. RBM15B in turn promotes m6A modification of ANLN mRNA, enhancing its stability and driving pRCC tumor progression. RBM15B knockdown abolished CAF-induced ANLN upregulation.","method":"Lactate level assays, histone lactylation ChIP, MeRIP-qPCR, mRNA stability assay, RNA immunoprecipitation, knockdown experiments, functional cell assays","journal":"International journal of urology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, novel epigenetic regulatory link established but RBM15B's direct enzymatic mechanism not reconstituted","pmids":["42227273"],"is_preprint":false},{"year":2025,"finding":"RBM15B (along with SPEN and RBM15) is directly bound to incoming henipavirus RNA within the first hour of infection (VIR-CLASP), and promotes viral infection. SPEN depletion induces widespread hypomethylation (~98% of differentially modified m6A sites), ~87% of which localize to the viral L mRNA (encoding the RNA-dependent RNA polymerase), implicating the SPEN/RBM15/RBM15B complex in m6A deposition on viral RNA.","method":"Viral Cross-linking and Solid-phase Purification (VIR-CLASP), direct RNA sequencing for m6A mapping, SPEN depletion, functional infection assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — novel VIR-CLASP method with m6A sequencing, but preprint and specific RBM15B contribution not separated from SPEN/RBM15 complex","pmids":["bio_10.1101_2025.11.21.689838"],"is_preprint":true},{"year":2025,"finding":"RBM15B knockdown in CVB3-infected HL-1 cardiomyocytes reduced viral replication (viral plaque assay) and attenuated CVB3-induced apoptosis (Calcein AM/PI staining and Western blotting), indicating an anti-apoptotic and pro-viral role for RBM15B in viral myocarditis.","method":"RNAi knockdown, viral plaque assay, Calcein AM/PI double staining, Western blotting","journal":"Journal of inflammation research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, phenotypic readouts without direct mechanistic pathway placement for RBM15B","pmids":["40546402"],"is_preprint":false}],"current_model":"RBM15B (OTT3) is a SPEN-family nuclear RNA-binding protein that functions as a component of the METTL3/METTL14 m6A methyltransferase writer complex, depositing m6A modifications preferentially in 5'UTRs and around start codons of target mRNAs — a selectivity guided by its direct recognition of the H3K79me2 histone mark via residue H47 — while also acting as an mRNA export cofactor (binding NXF1 and Aly/REF via its C-terminus), a splicing regulator (competing with SR proteins and inhibiting spliceosomal E complex formation to antagonize CDK11p110-cyclin L2α-dependent splicing), and a substrate for transcriptional control by upstream factors (YY1, FOXP2, MEX3A), with its m6A-writer activity stabilizing diverse target mRNAs (TRAM2, PCNA, FNBP1, ITGA1, ITSN2, FOXM1, KDM4C, ANLN) through IGF2BP/YTHDF family reader proteins."},"narrative":{"mechanistic_narrative":"RBM15B (OTT3) is a non-shuttling nuclear SPEN-family RNA-binding protein, with N-terminal RNA recognition motifs and a C-terminal SPOC domain, that operates at the interface of mRNA processing, nuclear export, and m6A deposition [PMID:16129689]. Through its C-terminal region it directly engages the mRNA export receptor NXF1 and the export factor Aly/REF, and it self-associates and localizes to the splicing factor compartment and nuclear envelope, linking it to post-transcriptional regulation [PMID:19586903]. As a splicing regulator, RBM15B competes with SR proteins, co-elutes with CDK11p110, cyclin L2α, and SR proteins in a ~1-MDa nuclear complex, and inhibits formation of the functional spliceosomal E complex, thereby antagonizing CDK11p110-cyclin L2α-dependent splicing [PMID:21044963]. Its defining recent role is as a component of the m6A methyltransferase writer machinery: RBM15B reads the H3K79me2 histone mark via residue H47 to guide selective m6A deposition into 5'UTRs and around start codons of transcripts from H3K79me2-marked loci, enhancing translation of oncogenic mRNAs and sustaining MLL-rearranged leukemia stem cells [PMID:41629530]. This chromatin-coupled m6A-writing activity stabilizes diverse target mRNAs through IGF2BP- and YTHDF-family readers — for example PCNA via YTHDF1 [PMID:39361104] and ITSN2 via IGF2BP1 [PMID:41795047]. RBM15B is also exploited by viruses, acting with RBM15/SPEN to bind incoming viral RNA and support infection [PMID:21106733, PMID:20828777].","teleology":[{"year":2005,"claim":"Established RBM15B/OTT3 as a SPEN-family nuclear RNA-binding protein with a distinct domain architecture and a function in splicing regulation, defining the protein's basic identity.","evidence":"Yeast two-hybrid, co-localization, domain mapping, and beta-globin/beta-thalassemia splicing reporter assays","pmids":["16129689"],"confidence":"Medium","gaps":["No genome-wide RNA targets identified","SPOC domain partners only partially mapped (EBV EB2; weak SMRT)","Catalytic or scaffolding role within any complex undefined"]},{"year":2009,"claim":"Connected RBM15B to the mRNA export machinery, showing its C-terminus directly binds NXF1 and Aly/REF, positioning it as a post-transcriptional/export cofactor rather than a splicing factor alone.","evidence":"Reciprocal co-immunoprecipitation, mutational mapping, and subcellular fractionation/microscopy","pmids":["19586903"],"confidence":"High","gaps":["Specific exported mRNA cargoes not defined","Functional consequence of export-factor binding on endogenous transcripts unresolved"]},{"year":2010,"claim":"Defined a mechanism by which RBM15B negatively regulates splicing — competing with SR proteins and blocking spliceosomal E complex assembly within a ~1-MDa CDK11p110/cyclin L2α complex.","evidence":"Size exclusion chromatography, co-IP, in vitro pulldown, domain mapping, in vitro and in vivo splicing assays","pmids":["21044963"],"confidence":"High","gaps":["Endogenous splicing targets not enumerated","How splicing role integrates with later m6A-writing role unknown"]},{"year":2010,"claim":"Showed RBM15B/RBM15 are co-opted in herpesvirus gene expression and that viral proteins (KSHV ORF57, EBV EB2) target the SPOC domain, revealing the protein as a node hijacked for viral RNA fate.","evidence":"RNAi knockdown, nuclear RNA fractionation export assays, ectopic expression, direct interaction assays","pmids":["21106733","20828777"],"confidence":"Medium","gaps":["Mechanism of RNA export deficiency on knockdown not fully resolved","RBM15B-specific (vs RBM15) contribution not separated"]},{"year":2025,"claim":"Extended RBM15B's pro-viral role to direct binding of incoming viral RNA and m6A deposition, implicating the SPEN/RBM15/RBM15B writer complex in modifying viral transcripts during early infection.","evidence":"VIR-CLASP, direct RNA sequencing for m6A, SPEN depletion, infection assays (preprint); plus CVB3 cardiomyocyte knockdown phenotyping","pmids":["bio_10.1101_2025.11.21.689838","40546402"],"confidence":"Low","gaps":["RBM15B-specific contribution not separated from SPEN/RBM15","Preprint, not peer-reviewed","Direct enzymatic step not reconstituted"]},{"year":2025,"claim":"Placed RBM15B as an m6A writer that stabilizes specific oncogenic mRNAs through defined reader proteins, establishing a recurrent RBM15B→m6A→reader→mRNA-stability axis across cancers.","evidence":"MeRIP/m6A-RIP, RIP, actinomycin D stability assays, knockdown/overexpression, and xenografts across PCNA-YTHDF1, FNBP1-IGF2BP2, ITSN2-IGF2BP1, and KMT2C-IGF2BP3 studies","pmids":["39361104","41086050","41795047","41161249"],"confidence":"Medium","gaps":["Direct catalytic activity of RBM15B not reconstituted in most studies","Target selectivity rules not defined per study","Most chains involve single labs and indirect readouts"]},{"year":2026,"claim":"Resolved how RBM15B achieves m6A target selectivity — H47-dependent recognition of H3K79me2 couples chromatin state to 5'UTR/start-codon m6A deposition and translational enhancement, defining a chromatin-reading/m6A-writing mechanism.","evidence":"H3K79me2 recognition assays, MeRIP-seq, H47 active-site mutagenesis, translation efficiency assays, leukemic stem cell functional assays","pmids":["41629530"],"confidence":"High","gaps":["Structural basis of H3K79me2 recognition not detailed","Relationship between this chromatin-coupled writing and the earlier splicing/export roles unresolved"]},{"year":2026,"claim":"Mapped upstream transcriptional and epigenetic control of RBM15B (YY1 activation, FOXP2 repression, CAF-lactate-driven histone lactylation) feeding into m6A stabilization of FOXM1, KDM4C, ITGA1, and ANLN, embedding RBM15B in tumor regulatory circuits.","evidence":"ChIP/promoter and dual-luciferase assays, histone lactylation ChIP, MeRIP, mRNA stability assays, and functional/xenograft models","pmids":["35494016","42148505","41661469","42020859","42227273"],"confidence":"Low","gaps":["Single-lab studies with limited direct enzymatic characterization","Multiple intermediaries inferred rather than reconstituted","Direct vs indirect RBM15B effects on each target not separated"]},{"year":null,"claim":"How RBM15B's distinct activities — splicing antagonism, mRNA export, and chromatin-guided m6A writing — are coordinated on shared transcripts, and the structural and biochemical basis of its direct catalytic contribution to the methyltransferase complex, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of RBM15B within the METTL3/METTL14 writer complex","Direct catalytic vs scaffolding role not reconstituted in vitro","Integration of splicing/export and m6A functions on the same RNAs untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,2,8]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[8]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[8,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[1]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,2,8]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[8]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,8]}],"complexes":["METTL3/METTL14 m6A writer complex","CDK11p110-cyclin L2α-SR protein splicing complex"],"partners":["NXF1","ALYREF","RBM15","CDK11B","MEX3A","SPEN"],"other_free_text":[]}},"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":82,"is_preprint":false},{"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":49,"is_preprint":false},{"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},{"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":27,"is_preprint":false},{"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},{"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},{"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":9,"is_preprint":false},{"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":1,"is_preprint":false},{"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},{"pmid":"41086050","id":"PMC_41086050","title":"RBM15B/IGF2BP2-m6A Mediated Upregulation of FNBP1 Promotes the Progression of Glioblastoma by Promoting Smad3-Mediated Glycolysis.","date":"2025","source":"Drug development research","url":"https://pubmed.ncbi.nlm.nih.gov/41086050","citation_count":0,"is_preprint":false},{"pmid":"42020859","id":"PMC_42020859","title":"RBM15B enhancing ITGA1 mRNA stability can accelerate glioblastoma tumorigenesis via the PI3K-Akt pathway.","date":"2026","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/42020859","citation_count":0,"is_preprint":false},{"pmid":"41795047","id":"PMC_41795047","title":"RBM15B promotes hepatocellular carcinoma progression via IGF2BP1-mediated ITSN2 mRNA stabilization.","date":"2026","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41795047","citation_count":0,"is_preprint":false},{"pmid":"42148505","id":"PMC_42148505","title":"RBM15B-mediated m6A modification of FOXM1 activates the AURKA/TPX2 axis to promote epithelial-mesenchymal transition-driven endometrial cancer progression.","date":"2026","source":"Cell adhesion & migration","url":"https://pubmed.ncbi.nlm.nih.gov/42148505","citation_count":0,"is_preprint":false},{"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 journal","url":"https://pubmed.ncbi.nlm.nih.gov/41629530","citation_count":0,"is_preprint":false},{"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},{"pmid":"42227273","id":"PMC_42227273","title":"Cancer-Associated Fibroblasts Promote Development of Papillary Renal Cell Carcinoma by Inducing Histone Lactylation of RBM15B to Modify in an m6A-Dependent Manner on ANLN.","date":"2026","source":"International journal of urology : official journal of the Japanese Urological Association","url":"https://pubmed.ncbi.nlm.nih.gov/42227273","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.21.689838","title":"Early Host-Virus RNA Interactions Reveal SPEN-Driven m  <sup>6</sup>  A Regulation as a Major Determinant of Henipavirus Infection","date":"2025-11-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.21.689838","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11646,"output_tokens":4498,"usd":0.051204,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12321,"output_tokens":3544,"usd":0.075103,"stage2_stop_reason":"end_turn"},"total_usd":0.126307,"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\": \"OTT3 (RBM15B) was identified as a new member of the SPEN family with N-terminal RNA recognition motifs and a C-terminal SPOC domain. It is a non-shuttling nuclear protein. Its SPOC domain interacts with EBV EB2 (mapped to the 40 N-terminal amino acids of EB2), but the OTT3 SPOC domain shows far weaker interaction with SMRT corepressors compared to SHARP. OTT3 represses accumulation of alternatively spliced beta-thalassemia mRNAs but has no effect on constitutively spliced beta-globin mRNA, establishing a role in splicing regulation.\",\n      \"method\": \"Yeast two-hybrid screen, transfection/co-localization, domain mapping, splicing assays with beta-globin/beta-thalassemia reporters\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (yeast two-hybrid, co-localization, domain mapping, functional splicing assay) in a single lab; foundational characterization paper\",\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 export factor Aly/REF via its C-terminal region. Mutational analysis mapped the NXF1-binding activity to the C-terminal portion of OTT3. RBM15B and OTT3 also interact with each other in vivo. OTT3 associates with the splicing factor compartment and the nuclear envelope.\",\n      \"method\": \"Co-immunoprecipitation, mutational analysis, subcellular localization (fluorescence microscopy), biochemical fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, mutational mapping, subcellular localization, functional comparison across paralogs in a single rigorous study\",\n      \"pmids\": [\"19586903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RBM15B/OTT3 acts as a functional competitor of SR proteins (SF2/ASF, 9G8) and antagonizes the positive effect of the CDK11p110-cyclin L2α complex on splicing. RBM15B co-elutes with CDK11p110, cyclin L2α, and SR proteins in a ~1-MDa nuclear complex. Two distinct domains of RBM15B mediate direct interactions with the N-terminal extension of CDK11p110, cyclin L2α, and SR proteins. RBM15B inhibits formation of the functional spliceosomal E complex in vitro and in vivo.\",\n      \"method\": \"Size exclusion chromatography, co-immunoprecipitation, in vitro pulldown assays, domain mapping, in vitro and in vivo splicing assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro reconstitution of splicing inhibition combined with co-IP, pulldown, domain mapping, and both in vitro and in vivo functional assays in a single study\",\n      \"pmids\": [\"21044963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RBM15B/OTT3 and RBM15 are required for expression of KSHV ORF57 at the posttranscriptional level; knockdown of RBM15 led to nuclear export deficiency of ORF57 RNA. OTT3 and RBM15 ectopic expression augments ORF59 production in the absence of ORF57. KSHV ORF57 interacts directly with the RBM15 C-terminal SPOC domain, reducing RBM15 binding to ORF59 RNA. EBV EB2 and other herpesvirus homologs also interact with RBM15 and OTT3.\",\n      \"method\": \"RNAi knockdown, nuclear export assay (subcellular RNA fractionation), ectopic expression, direct interaction assays\",\n      \"journal\": \"Journal of virology / Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two complementary papers (PMID 21106733 and 20828777) using RNAi, fractionation, and interaction assays; single lab but multiple methods\",\n      \"pmids\": [\"21106733\", \"20828777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RBM15B is transcriptionally activated by transcription factor YY1 and regulates the stability of TRAM2 mRNA in an m6A-dependent manner in hepatocellular carcinoma cells.\",\n      \"method\": \"ChIP/promoter assay (YY1 binding), m6A-RIP, mRNA stability assay, overexpression/knockdown functional assays\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited mechanistic detail in abstract, no reconstitution or mutagenesis described\",\n      \"pmids\": [\"35494016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RBM15B promotes m6A modification of PCNA mRNA in prostate cancer cells, and the m6A reader YTHDF1 binds these sites to stabilize PCNA mRNA, thereby promoting cell proliferation. RBM15B knockdown decreased m6A levels on PCNA mRNA and reduced mRNA stability.\",\n      \"method\": \"m6A quantification, RNA immunoprecipitation (RIP), actinomycin D mRNA stability assay, RBM15B knockdown, YTHDF1 binding assay, xenograft model\",\n      \"journal\": \"Cell biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (m6A-RIP, RIP, stability assay, KD, in vivo xenograft) in a single lab establishing the RBM15B→m6A→YTHDF1→PCNA mRNA stability axis\",\n      \"pmids\": [\"39361104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBM15B promotes m6A modification of FNBP1 mRNA; the m6A reader IGF2BP2 recognizes this mark and enhances FNBP1 mRNA stability, promoting glioblastoma progression through a FNBP1-LASP1-Smad3 glycolysis axis.\",\n      \"method\": \"m6A-RIP, RNA-seq, mRNA stability assay, co-immunoprecipitation, knockdown/overexpression, xenograft models\",\n      \"journal\": \"Drug development research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, mechanistic details compressed in abstract, no reconstitution or mutagenesis of RBM15B itself\",\n      \"pmids\": [\"41086050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MEX3A interacts with RBM15B (co-immunoprecipitation) and promotes super-enhancer RNA m6A methylation. RBM15B-binding levels of seRNA m6A are confirmed by MeRIP assay. The MEX3A-RBM15B-IGF2BP3 complex maintains KMT2C mRNA expression and stability, with IGF2BP3/KMT2C promoting H3K4me1 formation.\",\n      \"method\": \"Co-immunoprecipitation, MeRIP assay, fluorescence in situ hybridization, functional cell assays, in vivo tumor models\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single co-IP for the RBM15B interaction, limited mechanistic detail about RBM15B's direct enzymatic role\",\n      \"pmids\": [\"41161249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RBM15B H47 residue is a key residue for recognition of H3K79me2 histone methylation. Through this chromatin-reading activity, RBM15B guides selective m6A deposition preferentially in 5'UTRs and around start codons of mRNAs transcribed from H3K79me2-marked loci, enhancing translation efficiency of oncogenic transcripts, promoting leukemic stem cell self-renewal, and maintaining MLL-rearranged leukemia.\",\n      \"method\": \"H3K79me2 recognition assay, m6A-seq/MeRIP-seq, mutagenesis (H47 of RBM15B), translation efficiency assays, leukemic stem cell functional assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — active-site mutagenesis (H47), genome-wide m6A mapping, translation assays, and functional leukemia stem cell assays establishing a novel chromatin-reading/m6A-writing mechanism\",\n      \"pmids\": [\"41629530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RBM15B mediates m6A modification of FOXM1 mRNA, stabilizing FOXM1 expression. This activates the downstream AURKA/TPX2 axis to promote epithelial-mesenchymal transition in endometrial cancer. RBM15B knockdown inhibited malignant phenotypes and reduced AURKA/TPX2 pathway activation.\",\n      \"method\": \"RNA pull-down, MeRIP-PCR, dot blot, RNA stability assays, colony formation, Transwell, wound healing assays, functional knockdown\",\n      \"journal\": \"Cell adhesion & migration\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single m6A-modification mechanism without reconstitution of RBM15B enzymatic activity directly\",\n      \"pmids\": [\"42148505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RBM15B promotes m6A modification of ITGA1 mRNA, enhancing its stability; this activates the PI3K-Akt pathway to promote glioblastoma progression.\",\n      \"method\": \"MeRIP assay, actinomycin D mRNA stability assay, Western blotting (PI3K-Akt pathway), knockdown/overexpression, animal model\",\n      \"journal\": \"Discover oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited mechanistic characterization of RBM15B enzymatic function directly\",\n      \"pmids\": [\"42020859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RBM15B promotes m6A modification of ITSN2 mRNA; the m6A reader IGF2BP1 recognizes this modification and stabilizes ITSN2 mRNA, facilitating hepatocellular carcinoma progression. Knockdown of ITSN2 rescued the tumor-promoting phenotype induced by RBM15B overexpression.\",\n      \"method\": \"m6A dot blot, MeRIP-seq/RNA-seq, RNA immunoprecipitation (RIP-qPCR), rescue assay, in vitro and in vivo functional assays\",\n      \"journal\": \"Journal of cancer research and clinical oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, multiple methods but limited direct mechanistic characterization of RBM15B's catalytic role\",\n      \"pmids\": [\"41795047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FOXP2 represses RBM15B expression (ChIP and dual-luciferase assays establish FOXP2 binding to RBM15B promoter). RBM15B mediates m6A modification of KDM4C mRNA (MeRIP), regulating KDM4C expression, which affects H3K9me3 levels at the SLC7A11 promoter to suppress ferroptosis in HCC. Overexpression of RBM15B attenuated ferroptosis and reversed FOXP2-mediated suppression of HCC.\",\n      \"method\": \"ChIP, dual-luciferase reporter assay, MeRIP, Western blot, functional cell assays, xenograft models\",\n      \"journal\": \"Applied biochemistry and biotechnology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, mechanistic chain involves several intermediaries with limited direct RBM15B enzymatic characterization\",\n      \"pmids\": [\"41661469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Cancer-associated fibroblast-derived lactate promotes histone lactylation at the RBM15B locus, upregulating RBM15B expression. RBM15B in turn promotes m6A modification of ANLN mRNA, enhancing its stability and driving pRCC tumor progression. RBM15B knockdown abolished CAF-induced ANLN upregulation.\",\n      \"method\": \"Lactate level assays, histone lactylation ChIP, MeRIP-qPCR, mRNA stability assay, RNA immunoprecipitation, knockdown experiments, functional cell assays\",\n      \"journal\": \"International journal of urology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, novel epigenetic regulatory link established but RBM15B's direct enzymatic mechanism not reconstituted\",\n      \"pmids\": [\"42227273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBM15B (along with SPEN and RBM15) is directly bound to incoming henipavirus RNA within the first hour of infection (VIR-CLASP), and promotes viral infection. SPEN depletion induces widespread hypomethylation (~98% of differentially modified m6A sites), ~87% of which localize to the viral L mRNA (encoding the RNA-dependent RNA polymerase), implicating the SPEN/RBM15/RBM15B complex in m6A deposition on viral RNA.\",\n      \"method\": \"Viral Cross-linking and Solid-phase Purification (VIR-CLASP), direct RNA sequencing for m6A mapping, SPEN depletion, functional infection assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — novel VIR-CLASP method with m6A sequencing, but preprint and specific RBM15B contribution not separated from SPEN/RBM15 complex\",\n      \"pmids\": [\"bio_10.1101_2025.11.21.689838\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBM15B knockdown in CVB3-infected HL-1 cardiomyocytes reduced viral replication (viral plaque assay) and attenuated CVB3-induced apoptosis (Calcein AM/PI staining and Western blotting), indicating an anti-apoptotic and pro-viral role for RBM15B in viral myocarditis.\",\n      \"method\": \"RNAi knockdown, viral plaque assay, Calcein AM/PI double staining, Western blotting\",\n      \"journal\": \"Journal of inflammation research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, phenotypic readouts without direct mechanistic pathway placement for RBM15B\",\n      \"pmids\": [\"40546402\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RBM15B (OTT3) is a SPEN-family nuclear RNA-binding protein that functions as a component of the METTL3/METTL14 m6A methyltransferase writer complex, depositing m6A modifications preferentially in 5'UTRs and around start codons of target mRNAs — a selectivity guided by its direct recognition of the H3K79me2 histone mark via residue H47 — while also acting as an mRNA export cofactor (binding NXF1 and Aly/REF via its C-terminus), a splicing regulator (competing with SR proteins and inhibiting spliceosomal E complex formation to antagonize CDK11p110-cyclin L2α-dependent splicing), and a substrate for transcriptional control by upstream factors (YY1, FOXP2, MEX3A), with its m6A-writer activity stabilizing diverse target mRNAs (TRAM2, PCNA, FNBP1, ITGA1, ITSN2, FOXM1, KDM4C, ANLN) through IGF2BP/YTHDF family reader proteins.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RBM15B (OTT3) is a non-shuttling nuclear SPEN-family RNA-binding protein, with N-terminal RNA recognition motifs and a C-terminal SPOC domain, that operates at the interface of mRNA processing, nuclear export, and m6A deposition [#0]. Through its C-terminal region it directly engages the mRNA export receptor NXF1 and the export factor Aly/REF, and it self-associates and localizes to the splicing factor compartment and nuclear envelope, linking it to post-transcriptional regulation [#1]. As a splicing regulator, RBM15B competes with SR proteins, co-elutes with CDK11p110, cyclin L2\\u03b1, and SR proteins in a ~1-MDa nuclear complex, and inhibits formation of the functional spliceosomal E complex, thereby antagonizing CDK11p110-cyclin L2\\u03b1-dependent splicing [#2]. Its defining recent role is as a component of the m6A methyltransferase writer machinery: RBM15B reads the H3K79me2 histone mark via residue H47 to guide selective m6A deposition into 5'UTRs and around start codons of transcripts from H3K79me2-marked loci, enhancing translation of oncogenic mRNAs and sustaining MLL-rearranged leukemia stem cells [#8]. This chromatin-coupled m6A-writing activity stabilizes diverse target mRNAs through IGF2BP- and YTHDF-family readers \\u2014 for example PCNA via YTHDF1 [#5] and ITSN2 via IGF2BP1 [#11]. RBM15B is also exploited by viruses, acting with RBM15/SPEN to bind incoming viral RNA and support infection [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established RBM15B/OTT3 as a SPEN-family nuclear RNA-binding protein with a distinct domain architecture and a function in splicing regulation, defining the protein's basic identity.\",\n      \"evidence\": \"Yeast two-hybrid, co-localization, domain mapping, and beta-globin/beta-thalassemia splicing reporter assays\",\n      \"pmids\": [\"16129689\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No genome-wide RNA targets identified\", \"SPOC domain partners only partially mapped (EBV EB2; weak SMRT)\", \"Catalytic or scaffolding role within any complex undefined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected RBM15B to the mRNA export machinery, showing its C-terminus directly binds NXF1 and Aly/REF, positioning it as a post-transcriptional/export cofactor rather than a splicing factor alone.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, mutational mapping, and subcellular fractionation/microscopy\",\n      \"pmids\": [\"19586903\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific exported mRNA cargoes not defined\", \"Functional consequence of export-factor binding on endogenous transcripts unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined a mechanism by which RBM15B negatively regulates splicing \\u2014 competing with SR proteins and blocking spliceosomal E complex assembly within a ~1-MDa CDK11p110/cyclin L2\\u03b1 complex.\",\n      \"evidence\": \"Size exclusion chromatography, co-IP, in vitro pulldown, domain mapping, in vitro and in vivo splicing assays\",\n      \"pmids\": [\"21044963\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous splicing targets not enumerated\", \"How splicing role integrates with later m6A-writing role unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed RBM15B/RBM15 are co-opted in herpesvirus gene expression and that viral proteins (KSHV ORF57, EBV EB2) target the SPOC domain, revealing the protein as a node hijacked for viral RNA fate.\",\n      \"evidence\": \"RNAi knockdown, nuclear RNA fractionation export assays, ectopic expression, direct interaction assays\",\n      \"pmids\": [\"21106733\", \"20828777\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of RNA export deficiency on knockdown not fully resolved\", \"RBM15B-specific (vs RBM15) contribution not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended RBM15B's pro-viral role to direct binding of incoming viral RNA and m6A deposition, implicating the SPEN/RBM15/RBM15B writer complex in modifying viral transcripts during early infection.\",\n      \"evidence\": \"VIR-CLASP, direct RNA sequencing for m6A, SPEN depletion, infection assays (preprint); plus CVB3 cardiomyocyte knockdown phenotyping\",\n      \"pmids\": [\"bio_10.1101_2025.11.21.689838\", \"40546402\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"RBM15B-specific contribution not separated from SPEN/RBM15\", \"Preprint, not peer-reviewed\", \"Direct enzymatic step not reconstituted\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed RBM15B as an m6A writer that stabilizes specific oncogenic mRNAs through defined reader proteins, establishing a recurrent RBM15B\\u2192m6A\\u2192reader\\u2192mRNA-stability axis across cancers.\",\n      \"evidence\": \"MeRIP/m6A-RIP, RIP, actinomycin D stability assays, knockdown/overexpression, and xenografts across PCNA-YTHDF1, FNBP1-IGF2BP2, ITSN2-IGF2BP1, and KMT2C-IGF2BP3 studies\",\n      \"pmids\": [\"39361104\", \"41086050\", \"41795047\", \"41161249\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct catalytic activity of RBM15B not reconstituted in most studies\", \"Target selectivity rules not defined per study\", \"Most chains involve single labs and indirect readouts\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Resolved how RBM15B achieves m6A target selectivity \\u2014 H47-dependent recognition of H3K79me2 couples chromatin state to 5'UTR/start-codon m6A deposition and translational enhancement, defining a chromatin-reading/m6A-writing mechanism.\",\n      \"evidence\": \"H3K79me2 recognition assays, MeRIP-seq, H47 active-site mutagenesis, translation efficiency assays, leukemic stem cell functional assays\",\n      \"pmids\": [\"41629530\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of H3K79me2 recognition not detailed\", \"Relationship between this chromatin-coupled writing and the earlier splicing/export roles unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Mapped upstream transcriptional and epigenetic control of RBM15B (YY1 activation, FOXP2 repression, CAF-lactate-driven histone lactylation) feeding into m6A stabilization of FOXM1, KDM4C, ITGA1, and ANLN, embedding RBM15B in tumor regulatory circuits.\",\n      \"evidence\": \"ChIP/promoter and dual-luciferase assays, histone lactylation ChIP, MeRIP, mRNA stability assays, and functional/xenograft models\",\n      \"pmids\": [\"35494016\", \"42148505\", \"41661469\", \"42020859\", \"42227273\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single-lab studies with limited direct enzymatic characterization\", \"Multiple intermediaries inferred rather than reconstituted\", \"Direct vs indirect RBM15B effects on each target not separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RBM15B's distinct activities \\u2014 splicing antagonism, mRNA export, and chromatin-guided m6A writing \\u2014 are coordinated on shared transcripts, and the structural and biochemical basis of its direct catalytic contribution to the methyltransferase complex, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of RBM15B within the METTL3/METTL14 writer complex\", \"Direct catalytic vs scaffolding role not reconstituted in vitro\", \"Integration of splicing/export and m6A functions on the same RNAs untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 2, 8]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [8, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 2, 8]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 8]}\n    ],\n    \"complexes\": [\"METTL3/METTL14 m6A writer complex\", \"CDK11p110-cyclin L2\\u03b1-SR protein splicing complex\"],\n    \"partners\": [\"NXF1\", \"ALYREF\", \"RBM15\", \"CDK11B\", \"MEX3A\", \"SPEN\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}