Affinage

RBM15B

Putative RNA-binding protein 15B · UniProt Q8NDT2

Round 2 corrected
Length
890 aa
Mass
97.2 kDa
Annotated
2026-04-28
43 papers in source corpus 14 papers cited in narrative 14 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2005 Medium

    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

    PMID:16129689

    Open questions at the time
    • Endogenous splicing targets were not identified
    • Mechanism of splicing repression was not resolved
    • Biological relevance of EB2 interaction to viral lifecycle was not tested
  2. 2009 Medium

    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

    PMID:19586903

    Open questions at the time
    • No RNA export cargo was identified for RBM15B-NXF1
    • Functional redundancy with paralogue RBM15 in export was not resolved
  3. 2010 High

    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

    PMID:21044963 PMID:21106733

    Open questions at the time
    • 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
  4. 2016 High

    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

    PMID:27602518

    Open questions at the time
    • 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
  5. 2022 Medium

    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

    PMID:35494016 PMID:39361104 PMID:41086050 PMID:41161249 PMID:41661469 PMID:41795047

    Open questions at the time
    • 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
  6. 2026 High

    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

    PMID:41629530

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 5 GO:0098772 molecular function regulator activity 3 GO:0042393 histone binding 1
Localization
GO:0005634 nucleus 3 GO:0005654 nucleoplasm 2
Pathway
R-HSA-1643685 Disease 4 R-HSA-8953854 Metabolism of RNA 4 R-HSA-74160 Gene expression (Transcription) 2
Partners
ALYREFCDK11BIGF2BP1METTL3MEX3ANXF1RBM15SRSF1
Complex memberships
CDK11(p110)–cyclin L2α–SR protein complexm6A methyltransferase writer complex

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 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. Yeast two-hybrid screen, co-immunoprecipitation, subcellular localization by transfection/imaging, splicing reporter assays The Journal of biological chemistry Medium 16129689
2009 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. Co-immunoprecipitation, mutational analysis, subcellular localization studies, biochemical fractionation The Journal of biological chemistry Medium 19586903
2010 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. Co-immunoprecipitation, RNA immunoprecipitation, nucleocytoplasmic fractionation, domain mapping, overexpression/knockdown assays Journal of virology Medium 21106733
2010 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. Size exclusion chromatography, co-immunoprecipitation, in vitro pulldown, in vitro splicing assay, in vivo splicing assay, domain mapping The Journal of biological chemistry High 21044963
2016 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. RNAi knockdown, m6A sequencing (MeRIP), gene silencing reporter assays, co-immunoprecipitation Nature High 27602518
2022 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. ChIP assay (YY1 binding to RBM15B promoter), m6A assay, RNA stability assay, overexpression/knockdown with proliferation and invasion readouts Frontiers in oncology Medium 35494016
2024 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. RNA immunoprecipitation (RIP), m6A quantification, mRNA stability assay (actinomycin D), knockdown/rescue experiments, xenograft model Cell biochemistry and biophysics Medium 39361104
2025 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. Co-immunoprecipitation, methylated RNA immunoprecipitation (MeRIP), FISH, knockdown/overexpression functional assays, in vivo xenograft Translational oncology Medium 41161249
2025 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. siRNA knockdown, viral plaque assay, Calcein AM/PI viability staining, Western blotting, MeRIP-seq/RNA-seq Journal of inflammation research Low 40546402
2025 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. MeRIP, RNA immunoprecipitation, co-immunoprecipitation, knockdown/overexpression, xenograft model Drug development research Medium 41086050
2026 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. ChIP-seq, MeRIP-seq, mutagenesis of H47 residue, polysome profiling (translation efficiency), knockdown/CRISPR, leukemic stem cell self-renewal assays The EMBO journal High 41629530
2026 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. ChIP assay, dual-luciferase reporter assay, MeRIP, Western blotting, ferroptosis markers, xenograft model Applied biochemistry and biotechnology Medium 41661469
2026 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. MeRIP-seq, RNA-seq, RNA immunoprecipitation (RIP-qPCR), mRNA stability assay, rescue/overexpression assays, xenograft model Journal of cancer research and clinical oncology Medium 41795047
2025 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. VIR-CLASP (viral crosslinking and solid-phase purification), direct RNA sequencing for m6A profiling, siRNA depletion bioRxivpreprint Low bio_10.1101_2025.11.21.689838

Source papers

Stage 0 corpus · 43 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2016 m(6)A RNA methylation promotes XIST-mediated transcriptional repression. Nature 1441 27602518
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2012 The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Molecular cell 973 22681889
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2014 HIV latency. Specific HIV integration sites are linked to clonal expansion and persistence of infected cells. Science (New York, N.Y.) 732 24968937
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
2005 Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways. Proceedings of the National Academy of Sciences of the United States of America 383 16009940
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
1993 Rapid cDNA sequencing (expressed sequence tags) from a directionally cloned human infant brain cDNA library. Nature genetics 299 8401585
2011 Toward an understanding of the protein interaction network of the human liver. Molecular systems biology 207 21988832
2013 Quantitative dissection and stoichiometry determination of the human SET1/MLL histone methyltransferase complexes. Molecular and cellular biology 180 23508102
2019 H4K20me0 recognition by BRCA1-BARD1 directs homologous recombination to sister chromatids. Nature cell biology 162 30804502
2014 The central role of EED in the orchestration of polycomb group complexes. Nature communications 131 24457600
2007 Toward a confocal subcellular atlas of the human proteome. Molecular & cellular proteomics : MCP 114 18029348
2022 EZH2 depletion potentiates MYC degradation inhibiting neuroblastoma and small cell carcinoma tumor formation. Nature communications 99 35013218
2017 CHD3 and CHD4 form distinct NuRD complexes with different yet overlapping functionality. Nucleic acids research 91 28977666
2005 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. The Journal of biological chemistry 81 16129689
2009 The RNA-binding motif protein 15B (RBM15B/OTT3) acts as cofactor of the nuclear export receptor NXF1. The Journal of biological chemistry 48 19586903
2010 Kaposi's sarcoma-associated herpesvirus ORF57 interacts with cellular RNA export cofactors RBM15 and OTT3 to promote expression of viral ORF59. Journal of virology 45 21106733
2022 YY1-Targeted RBM15B Promotes Hepatocellular Carcinoma Cell Proliferation and Sorafenib Resistance by Promoting TRAM2 Expression in an m6A-Dependent Manner. Frontiers in oncology 24 35494016
2010 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. The Journal of biological chemistry 18 21044963
2010 Requirement of UAP56, URH49, RBM15, and OTT3 in the expression of Kaposi sarcoma-associated herpesvirus ORF57. Virology 12 20828777
2024 RBM15B Promotes Prostate Cancer Cell Proliferation via PCNA m6A Modification. Cell biochemistry and biophysics 7 39361104
2025 MEX3A-mediated super-enhancer RNA m6A methylation promotes aggressiveness of breast cancer via regulating RBM15B/IGF2BP3/KMT2C signaling. Translational oncology 1 41161249
2026 RBM15B recognizes H3K79me2 to guide selective m6A-modification of mRNA and enhance oncoprotein translation in MLL-r leukemia. The EMBO journal 0 41629530
2026 Mechanism of FOXP2 in the Hepatocellular Carcinoma Progression via Ferroptosis Through RBM15B-Mediated m6A Modification. Applied biochemistry and biotechnology 0 41661469
2026 RBM15B promotes hepatocellular carcinoma progression via IGF2BP1-mediated ITSN2 mRNA stabilization. Journal of cancer research and clinical oncology 0 41795047
2025 Comprehensive Analysis of Differences in N6-Methyladenosine RNA Methylation Groups in CVB3-Induced Viral Myocarditis and Identification of the Anti-Apoptotic Role of RBM15B. Journal of inflammation research 0 40546402
2025 RBM15B/IGF2BP2-m6A Mediated Upregulation of FNBP1 Promotes the Progression of Glioblastoma by Promoting Smad3-Mediated Glycolysis. Drug development research 0 41086050