{"gene":"RBM39","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2017,"finding":"Anticancer sulfonamides (E7820, indisulam, CQS) induce proteasomal degradation of RBM39 (CAPERα) via CRL4-DCAF15-mediated ubiquitination. CRISPR-Cas9 knockout of DCAF15 and a single amino acid substitution in RBM39 conferred resistance to sulfonamide-induced RBM39 degradation and cell-growth inhibition.","method":"CRISPR-Cas9 knockout, site-directed mutagenesis, cell viability assays, western blot","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (genetic KO, point mutagenesis, functional rescue), replicated across multiple sulfonamide compounds","pmids":["28437394"],"is_preprint":false},{"year":2019,"finding":"Crystal structure of the DCAF15-DDB1-DDA1-indisulam-RBM39(RRM2) complex at 2.3 Å resolution revealed that DCAF15 embraces the RBM39 RRM2 domain largely via non-polar interactions, with indisulam binding between DCAF15 and RBM39(RRM2) as a molecular glue. An α-helical degron motif in RBM39 RRM2 was defined; only RBM23 and RBM39 share this degron and are degraded by indisulam.","method":"X-ray crystallography (2.3 Å), RBM39 point mutant studies, indisulam analog studies, mass spectrometry of indisulam-treated HCT116 cells","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure with mutagenesis validation and proteomics confirmation in cells","pmids":["31819272"],"is_preprint":false},{"year":2019,"finding":"Cryo-EM structure (4.4 Å) of DDB1-DCAF15-DDA1 bound to RBM39 and E7820 showed DCAF15 adopts a new fold stabilized by DDA1, and extensive protein-protein contacts between the ligase and RBM39 compensate for low-affinity aryl-sulfonamide–DCAF15 interactions. Aryl-sulfonamides neo-functionalize a shallow, non-conserved pocket on DCAF15 to selectively recruit RBM39 and RBM23.","method":"Cryo-EM (4.4 Å), X-ray crystallography of subcomplexes, biochemical reconstitution","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM and crystal structures with functional biochemical validation","pmids":["31686031"],"is_preprint":false},{"year":2019,"finding":"Crystal structure of DDA1-DDB1-DCAF15 in complex with E7820 and RBM39 RRM2 domain showed E7820 packs in a shallow pocket on DCAF15 and the resulting modified interface binds RBM39 through the α1 helix of RRM2. Kinetic analysis revealed that aryl sulfonamide and RBM39 bind to DCAF15 in a synergistic (cooperative) manner.","method":"X-ray crystallography, kinetic binding analysis","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus kinetic experiments, consistent with two independent structural studies","pmids":["31693911"],"is_preprint":false},{"year":2019,"finding":"Domain mapping and mutagenesis identified that RBM39 is recruited to DCAF15 through its RRM2 domain and is ubiquitinated on its N terminus upon indisulam treatment. DCAF15 mutations Q232 or D475 prevent RBM39 recruitment. RBM23 is also recruited and degraded via its RRM2 domain. Indisulam-induced transcriptional and splicing changes (>3,000 genes, intron retention and exon skipping) are attributable to RBM39 loss, not RBM23.","method":"Domain mapping, random mutagenesis, ubiquitination assays, RNA-seq","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (mutagenesis, ubiquitination assay, transcriptomics) in a single rigorous study","pmids":["31693891"],"is_preprint":false},{"year":2001,"finding":"RBM39 (CAPER) was identified as a nuclear coactivator that selectively binds c-Jun (AP-1 component) and estradiol-bound ligand binding domains of ERα and ERβ, and stimulates transactivation by ERα, ERβ, and AP-1 in cotransfection assays. CAPER interaction was identified via its interaction with the general coactivator ASC-2.","method":"Yeast two-hybrid screen, co-immunoprecipitation, luciferase transcription reporter assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal binding assays and functional reporter assays, single lab","pmids":["11704680"],"is_preprint":false},{"year":2005,"finding":"RBM39 (CAPERα) coactivates progesterone receptor-mediated transcription and alters alternative splicing of a calcitonin/CGRP minigene in a hormone-dependent manner. siRNA knockdown of CAPERα affected VEGF isoform splicing. Transcriptional and splicing functions map to distinct, separable domains of the protein.","method":"Luciferase transcription reporter assays, minigene splicing assays, siRNA knockdown, RT-PCR","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (reporter assays, minigene, siRNA, endogenous gene analysis), demonstrated separation of function by domain mapping","pmids":["15694343"],"is_preprint":false},{"year":2014,"finding":"The CAPERα UHM domain interacts with SF3b155 ULM motifs (at 1.7 Å crystal structure). Isothermal titration calorimetry showed high-affinity interaction depends on an intrinsically unstructured SF3b155 domain with seven ULM-like motifs. SF3b155 was identified as the relevant ULM-containing partner of full-length CAPERα in human cell extracts.","method":"X-ray crystallography (1.7 Å), isothermal titration calorimetry, co-immunoprecipitation from cell extracts","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus ITC and Co-IP, multiple orthogonal methods in single study","pmids":["24795046"],"is_preprint":false},{"year":2016,"finding":"Crystal and NMR structures of the RBM39 UHM domain and its complex with U2AF65-ULM were solved. The RBM39-U2AF65 interaction was confirmed by co-immunoprecipitation from human cell extracts, isothermal titration calorimetry, and NMR chemical shift perturbation experiments with purified proteins.","method":"X-ray crystallography, solution NMR, co-immunoprecipitation, isothermal titration calorimetry","journal":"Acta crystallographica Section D","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple structural methods (crystal, NMR) plus orthogonal biochemical validation (Co-IP, ITC)","pmids":["27050129"],"is_preprint":false},{"year":2016,"finding":"Genome-wide CLIP-Seq mapping showed RBM39 binding sites are mainly proximal to 5' and 3' splice sites. RNA-seq of RBM39-knockdown MCF-7 cells identified hundreds of alternative splicing events (predominantly cassette exons) regulated by RBM39, with ~20% of events co-regulated with U2AF65.","method":"CLIP-Seq, RNA-seq, siRNA knockdown","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide CLIP-seq plus RNA-seq with knockdown, orthogonal transcriptomic approaches","pmids":["27354116"],"is_preprint":false},{"year":2017,"finding":"During terminal erythropoiesis, RBM39 associates in a complex with TIA1 and Pcbp1 to activate the protein 4.1R exon 16 3' splice site. This complex interacts with U2AF65 and SF3b155 and promotes U2 snRNP recruitment to the branch point and spliceosome A complex formation.","method":"Co-immunoprecipitation, splicing reporter assays, siRNA knockdown, UV cross-linking","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP complex identification and functional splicing assays, single lab","pmids":["28193846"],"is_preprint":false},{"year":2008,"finding":"CAPERα interacts with the transcription activation domain (TAD) of v-Rel and synergizes v-Rel-mediated transactivation. A dominant-negative mutant of CAPERα enhanced v-Rel-mediated lymphocyte transformation, and siRNA knockdown of CAPERα in v-Rel-transformed lymphocytes enhanced colony formation, identifying CAPERα as a transcriptional coregulator that modulates Rel/NF-κB oncogenic activity.","method":"Co-immunoprecipitation, luciferase reporter assays, dominant-negative overexpression, siRNA knockdown, soft agar colony assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple functional assays (Co-IP, reporter, dominant negative, KD) in single lab","pmids":["18753212"],"is_preprint":false},{"year":2015,"finding":"RBM39 (CAPER) acts as a transcriptional coactivator for ERR-α–mediated Gabpa transcription to drive mitochondrial gene expression and glucose-dependent respiration. CAPER is also a coactivator for NF-κB regulating c-Myc in stress responses. CAPER is required for anaplerotic carbon flux into TCA cycles. These functions are conserved in C. elegans where CAPER loss impairs lifespan and reproduction.","method":"siRNA knockdown, luciferase reporter assays, metabolic flux analysis (isotope tracing), C. elegans genetic studies, ATP measurement","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays (reporter, metabolic, genetic epistasis in model organism), single lab","pmids":["25830341"],"is_preprint":false},{"year":2016,"finding":"RBM39 interacts with the non-receptor tyrosine kinase c-Abl through c-Abl SH2 and SH3 domains. c-Abl phosphorylates RBM39 at Y95 and Y99 (identified by LC/MS/MS and mutational analysis), and c-Abl enhances RBM39 transcriptional coactivation activity for ERα and PRβ in a kinase-dependent manner.","method":"Co-immunoprecipitation, LC/MS/MS phosphoproteomics, site-directed mutagenesis, luciferase reporter assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — mass spectrometry identification of phosphosites with mutagenesis and functional validation, single lab","pmids":["27018250"],"is_preprint":false},{"year":2021,"finding":"RBM39 functions as a master transcriptional regulator that interacts with the MLL1 complex to facilitate chromatin binding and H3K4 trimethylation in breast cancer cells. The RRM3 domain of RBM39 acts as a dominant-negative, disrupting the RBM39/MLL1 complex and reducing H3K4me3 and expression of target oncogenic genes.","method":"Co-immunoprecipitation, ChIP-seq, domain deletion/mutagenesis, cell-penetrating peptide experiments","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP-seq and functional domain dissection, single lab","pmids":["34077726"],"is_preprint":false},{"year":2019,"finding":"The lncRNA DARS-AS1 binds RBM39, impeding its interaction with the E3 ubiquitin ligase RNF147, thereby preventing RBM39 proteasomal degradation. This stabilization of RBM39 maintains mTOR signaling in myeloma cells.","method":"RNA immunoprecipitation, co-immunoprecipitation, siRNA/shRNA knockdown, ubiquitination assays, in vivo xenograft","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — RIP and Co-IP showing competitive binding, plus functional rescue experiments, single lab","pmids":["31289203"],"is_preprint":false},{"year":2023,"finding":"NMR solution structures of RBM39 RRM1 and RRM2 bound to their respective RNA targets were determined: RRM1 recognizes RNA stem loops whereas RRM2 binds specifically to single-stranded N(G/U)NUUUG sequences. RBM39 autoregulates its own expression via inclusion of a poison exon into its pre-mRNA, with RRM2 selecting the 3' splice site of the poison exon and the RRM3 and RS domain stabilizing U2 snRNP at the branchpoint.","method":"NMR spectroscopy (solution structures), minigene splicing assays, mutagenesis of cis-acting elements, siRNA knockdown","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structures with functional validation of RNA binding specificity and autoregulation mechanism, multiple orthogonal methods","pmids":["37666821"],"is_preprint":false},{"year":2023,"finding":"Arginine directly binds RBM39 protein to control expression of metabolic genes. RBM39-mediated upregulation of asparagine synthesis leads to enhanced arginine uptake, creating a positive feedback loop. High arginine levels in hepatocellular carcinoma drive oncogenic metabolic reprogramming via RBM39.","method":"Biochemical binding assays (arginine-RBM39 interaction), RNA-seq, metabolomics, genetic knockdown/overexpression, mouse HCC models","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding demonstrated, multiple orthogonal approaches (metabolomics, RNA-seq, genetic models), replicated in murine and patient HCC","pmids":["37804830"],"is_preprint":false},{"year":2022,"finding":"In response to cisplatin (genotoxic stress), c-Jun interacts with RBM39 and prevents RBM39 binding to pre-mRNA, thereby reprogramming alternative splicing genome-wide. This c-Jun–RBM39 interaction drives production of a short COASY isoform lacking exons 4 and 5 that impairs mitochondrial function and decreases cisplatin sensitivity.","method":"Co-immunoprecipitation, RNA-seq, RNA immunoprecipitation, siRNA knockdown, minigene splicing assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of novel interaction, RIP and functional RNA-seq, single lab","pmids":["36477312"],"is_preprint":false},{"year":2004,"finding":"RBM39 (Hcc-1) localizes to the nuclear matrix and binds both double-stranded and single-stranded DNA (higher affinity for ssDNA) and scaffold/matrix attachment region (S/MAR) DNA. Two DEAD-box RNA helicases, BAT1 and DDX39, were identified as RBM39-interacting proteins by yeast two-hybrid. Overexpression of Hcc-1 caused G2/M accumulation and slower growth in HEK293 cells.","method":"Nuclear fractionation, DNA binding assays, yeast two-hybrid, cell cycle analysis (flow cytometry), overexpression","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct biochemical binding assays and genetic screen, single lab, functional cell cycle phenotype","pmids":["15338056"],"is_preprint":false},{"year":2024,"finding":"USP39 is a deubiquitinating enzyme that interacts with RBM39 and co-localizes in the nucleus. USP39 reduces K48-linked polyubiquitin chains on RBM39, enhancing its stability and preventing proteasomal degradation.","method":"Affinity purification-mass spectrometry, co-immunoprecipitation, ubiquitination assays, shRNA knockdown, overexpression","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — AP-MS identification plus biochemical ubiquitination assays and rescue experiments, single lab","pmids":["39260689"],"is_preprint":false},{"year":2016,"finding":"siRNA knockdown of RBM39 in mouse C2C12 cells increased BMP4-dependent transcription. Transcriptome-wide RNA-seq revealed that RBM39 knockdown altered Sin3b exon usage, shifting expression from the long isoform (which recruits HDACs) to the short isoform. BMP4 induced a shift toward the long SIN3B isoform that was prevented by RBM39 knockdown, constituting a negative autoregulatory loop of BMP signaling through RBM39-regulated splicing.","method":"siRNA screen, siRNA knockdown, luciferase reporter, RNA-seq, RT-PCR for isoforms","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA screen with mechanistic RNA-seq follow-up, single lab","pmids":["27324164"],"is_preprint":false},{"year":2024,"finding":"MORC2 binds the RRM1 domain of RBM39, and RBM39 interacts with site 1 of pre-CDK5RAP2 exon 32 via its UHM domain, causing a splicing switch from CDK5RAP2-L to CDK5RAP2-S. CDK5RAP2-S promotes EMT and metastasis by recruiting PHD finger protein 8 to the Slug promoter to remove repressive histone marks.","method":"Co-immunoprecipitation, RNA immunoprecipitation, minigene splicing assay, domain mapping, in vitro/in vivo functional studies","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP domain mapping and RNA binding assays with functional downstream validation, single lab","pmids":["39048555"],"is_preprint":false},{"year":2025,"finding":"PRMT6 methylates RBM39 at R92. This methylation inhibits indisulam-induced ubiquitination and proteasomal degradation of RBM39, thereby increasing RBM39 protein levels and conferring resistance to indisulam in NSCLC. Inhibiting PRMT6 or mutating R92 restores indisulam sensitivity.","method":"Mass spectrometry (phospho/methylo-proteomics), site-directed mutagenesis, ubiquitination assays, PRMT6 inhibitor treatment, xenograft models","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — MS identification of modification site, mutagenesis and functional rescue, single lab","pmids":["40465651"],"is_preprint":false},{"year":2024,"finding":"YAP/TAZ interact with RBM39 (identified by proteome analysis) and RBM39 promotes YAP/TAZ transcriptional activity. YAP/TAZ hyperactivation delays indisulam-induced RBM39 degradation, restoring integrin/collagen expression and activating FAK to confer resistance against indisulam.","method":"Proteome analysis, co-immunoprecipitation, luciferase reporter assays, western blot, in vivo xenograft","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — proteomics discovery plus Co-IP and functional assays, single lab","pmids":["39004623"],"is_preprint":false},{"year":2025,"finding":"RBM39 scaffolds an m6A-dependent RNA decay complex by recruiting the m6A reader YTHDC1 and RNA helicase DDX5, forming a tripartite complex that accelerates Tat (HIV-1) RNA decay and enforces viral quiescence. Genetic or pharmacological degradation of RBM39 reactivates latent HIV-1.","method":"Proteomics, co-immunoprecipitation, RNA decay assays, RBM39 knockdown/degradation, latency reactivation assays","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomic identification with Co-IP validation and functional RNA decay/reactivation assays, single lab","pmids":["41218081"],"is_preprint":false},{"year":2021,"finding":"In PRRSV-infected cells, RBM39 alters phosphorylation of c-Jun to inhibit the AP-1 pathway, promoting viral proliferation. RBM39 undergoes nucleocytoplasmic translocation from nucleus to cytoplasm. The three RRM domains of RBM39 are required for supporting PRRSV proliferation. RBM39 directly binds several PRRSV RNA segments (nsp4, nsp5, nsp7, nsp10-12, M and N genes).","method":"siRNA knockdown, phosphorylation assays, co-immunoprecipitation, RNA immunoprecipitation, confocal microscopy, viral replication assays","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple assays (RIP, Co-IP, localization) in a single lab, porcine cell context","pmids":["34079549"],"is_preprint":false},{"year":2024,"finding":"CMGC kinase inhibition (including DYRK1A) or CDK9 inhibition disrupts cotranscriptional splicing by altering SF3B1 and Pol II association and changing Pol II pausing, leading to inclusion of a poison exon in RBM39 pre-mRNA, which is recognized by NMD for degradation. This reduces RBM39 protein levels and inhibits B-ALL growth.","method":"Kinase inhibitor treatment, CRISPR knockout, RNA-seq, ChIP/CUT&RUN, NMD assays","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic dissection of cotranscriptional regulation with multiple genomic approaches, single lab","pmids":["39316649"],"is_preprint":false},{"year":2026,"finding":"CDK13 directly phosphorylates RBM39 at serine 117 (identified by phosphoproteomic analysis). This phosphorylation enhances RBM39's ability to bind and stabilize RAD50 mRNA, increasing RAD50 protein levels and promoting DNA damage repair, thereby driving cisplatin resistance in endometrial cancer.","method":"Phosphoproteomics (LC-MS/MS), site-directed mutagenesis (S117A), RIP assays, mRNA stability assays (actinomycin D), in vivo xenograft","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — MS-identified phosphosite with mutagenesis and RNA binding functional assays, single lab","pmids":["41997449"],"is_preprint":false},{"year":2025,"finding":"RBM39 regulates alternative splicing of EZH2 pre-mRNA; RBM39 depletion suppresses EZH2 expression. RBM39-regulated EZH2 controls WNT7B/β-catenin activity, establishing an RBM39-EZH2-β-catenin signaling axis in cholangiocarcinoma.","method":"CRISPR/Cas9 and shRNA depletion, RNA-seq splicing analysis, western blot, in vivo xenograft","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"Low","confidence_rationale":"Tier 2–3 / Weak — single lab, KD phenotype with downstream pathway inference from RNA-seq","pmids":["39278404"],"is_preprint":false},{"year":2025,"finding":"RBM39 binds the 3'-UTR of FANCD2 mRNA (validated by RIP-qPCR and motif mutagenesis) and extends FANCD2 mRNA half-life (actinomycin D assay), thereby stabilizing FANCD2 protein and promoting DNA repair in esophageal cancer.","method":"RNA immunoprecipitation (RIP-qPCR), motif mutagenesis, mRNA stability assay (actinomycin D), FANCD2 overexpression rescue","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA binding validated by RIP and mutagenesis, functional rescue experiments, single lab","pmids":["40752539"],"is_preprint":false},{"year":2025,"finding":"RBM39 binds RFX1 pre-mRNA (identified by RIP-seq) and regulates alternative splicing of RFX1 exon 2. Skipping of exon 2 produces an N-terminal truncated RFX1 lacking transcriptional repression activity on oncogenic collagen genes, leading to activation of the FAK/PI3K/AKT signaling pathway in HCC.","method":"RIP-seq, minigene splicing assay, RT-PCR, CRISPR/shRNA knockdown, in vivo xenograft","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP-seq with minigene validation and downstream pathway functional assays, single lab","pmids":["40033026"],"is_preprint":false},{"year":2025,"finding":"RBM39 depletion reduced expression of IRF3, RIG-I, and MDA5 (transcription and/or splicing affected), as well as IFN receptor subunits IFNAR and STAT1/2, impairing TLR3, RIG-I/MDA5, and type I/III IFN responses in hepatocytes. A genome-wide CRISPR/Cas9 screen identified RBM39 as a required factor for TLR3 pathway activation.","method":"Genome-wide CRISPR/Cas9 screen, siRNA knockdown, indisulam treatment, RNA-seq, mass spectrometry","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen with validation by two independent methods and transcriptomic/proteomic characterization, single lab","pmids":["40330464"],"is_preprint":false},{"year":2025,"finding":"RBM39 promotes base excision repair (BER) in HCC by binding OGG1 mRNA and stabilizing it, increasing OGG1 expression and BER efficiency under oxidative stress. This was demonstrated using a BER reporter assay and RBM39 knockdown/degradation experiments.","method":"BER reporter assay, RNA immunoprecipitation, mRNA stability assay, siRNA knockdown, indisulam treatment, xenograft model","journal":"Cell proliferation","confidence":"Low","confidence_rationale":"Tier 2–3 / Weak — RIP and functional reporter, single lab, limited mechanistic depth","pmids":["40364450"],"is_preprint":false},{"year":2025,"finding":"RBM39 regulates MEK5 pre-mRNA splicing; RBM39 knockdown causes aberrant MEK5 isoforms with exon loss that are non-functional and prone to proteasomal degradation. Full-length MEK5 is required for multiple myeloma cell survival.","method":"shRNA knockdown, RNA-seq splicing analysis, RT-PCR isoform analysis, western blot, in vivo xenograft","journal":"Blood advances","confidence":"Low","confidence_rationale":"Tier 2–3 / Weak — single lab, splicing change identified by RNA-seq with limited mechanistic reconstitution","pmids":["40048740"],"is_preprint":false},{"year":2025,"finding":"Rbm39 enhances hepatocyte nuclear factor 4α (Hnf4α) transcriptional activity to upregulate Apob transcription, while suppressing Fabp4 transcription through regulation of alternative splicing of Hif-1α, thereby maintaining hepatic lipid homeostasis.","method":"AAV-mediated Rbm39 overexpression/knockdown, RNA-seq, dual-luciferase reporter assays, alternative splicing analysis, RT-PCR","journal":"Biochimica et biophysica acta Molecular basis of disease","confidence":"Low","confidence_rationale":"Tier 2–3 / Weak — reporter assays and RNA-seq in vivo model, single lab, limited mechanistic reconstitution","pmids":["40147697"],"is_preprint":false},{"year":2011,"finding":"CAPER-α expression correlates inversely with the VEGF165/VEGF189 mRNA ratio in Ewing sarcoma cells. Transfection of CAPER-α cDNA or siRNA knockdown altered VEGF isoform splicing (VEGF189 vs VEGF165). CAPER-α expression was regulated by EWS/FLI-1 through a protein-protein interaction.","method":"cDNA transfection, siRNA knockdown, RT-PCR isoform analysis, co-immunoprecipitation (protein-protein interaction), in vivo tumor growth assay","journal":"Cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP of EWS/FLI-1 interaction plus functional splicing assays, single lab","pmids":["22009261"],"is_preprint":false}],"current_model":"RBM39 is a multifunctional nuclear RNA-binding protein and transcriptional coactivator that (1) regulates alternative pre-mRNA splicing by binding near 5' and 3' splice sites through its RRM domains and interacting with core spliceosome components (U2AF65 via UHM-ULM interaction, SF3b155, U2 snRNP), (2) coactivates transcription by ERα, ERβ, AP-1/c-Jun, NF-κB, and other transcription factors, (3) can stabilize specific mRNAs (e.g., OGG1, FANCD2, RAD50) by binding their 3'-UTRs, (4) autoregulates its own expression via a poison exon, (5) is subject to modification by c-Abl (phosphorylation at Y95/Y99), CDK13 (phosphorylation at S117), and PRMT6 (methylation at R92), the last of which protects it from degradation, (6) is stabilized by USP39-mediated deubiquitination and destabilized by RNF147-mediated ubiquitination, and (7) is selectively degraded by aryl sulfonamide molecular glues (indisulam, E7820, tasisulam) that act as 'molecular glue' to recruit RBM39's RRM2 α-helical degron to the CRL4-DCAF15 E3 ligase complex for ubiquitination and proteasomal destruction."},"narrative":{"mechanistic_narrative":"RBM39 (CAPERα/Hcc-1) is a multifunctional nuclear RNA-binding protein that operates both as a regulator of alternative pre-mRNA splicing and as a transcriptional coactivator [PMID:11704680, PMID:15694343, PMID:27354116]. Through its tandem RRM domains it binds RNA in a structurally distinct manner—RRM1 recognizes stem-loop elements while RRM2 binds single-stranded N(G/U)NUUUG motifs—and CLIP-Seq maps its binding predominantly to sequences flanking 5' and 3' splice sites, where it controls cassette-exon and other alternative splicing events [PMID:27354116, PMID:37666821]. RBM39 engages the core 3' splice site machinery through its UHM domain, which binds ULM motifs in U2AF65 and SF3b155 to promote U2 snRNP recruitment and spliceosome A-complex assembly [PMID:24795046, PMID:27050129, PMID:28193846]. It autoregulates its own abundance by directing inclusion of an NMD-targeted poison exon into its own transcript [PMID:37666821, PMID:39316649]. Independently, RBM39 acts as a coactivator that potentiates transactivation by ERα/ERβ, AP-1/c-Jun, progesterone receptor, NF-κB/Rel, ERRα, and YAP/TAZ, and facilitates chromatin activation via the MLL1 complex and H3K4 trimethylation, with transcriptional and splicing functions mapping to separable domains [PMID:11704680, PMID:15694343, PMID:18753212, PMID:25830341, PMID:34077726, PMID:39004623]. RBM39 protein levels are tightly controlled by post-translational modification and ubiquitin signaling: c-Abl phosphorylates Y95/Y99 and CDK13 phosphorylates S117 to modulate its coactivator and mRNA-stabilizing activities, PRMT6 methylation at R92 and USP39 deubiquitination stabilize it, and RNF147 destabilizes it [PMID:27018250, PMID:39260689, PMID:40465651, PMID:41997449, PMID:31289203]. RBM39 is the selective neo-substrate of aryl-sulfonamide molecular glues (indisulam, E7820, CQS), which occupy a shallow, non-conserved pocket on the CRL4 substrate receptor DCAF15 and cooperatively recruit an α-helical degron within RBM39's RRM2 domain for ubiquitination and proteasomal degradation—a property shared only with the paralog RBM23 [PMID:28437394, PMID:31819272, PMID:31686031, PMID:31693911, PMID:31693891].","teleology":[{"year":2001,"claim":"Established RBM39 as a transcriptional coactivator, defining its first molecular function beyond a nuclear protein of unknown role.","evidence":"Yeast two-hybrid, Co-IP and luciferase reporter assays showing selective binding to c-Jun and ER ligand-binding domains and stimulation of ERα/ERβ/AP-1 transactivation","pmids":["11704680"],"confidence":"Medium","gaps":["Did not address whether splicing and coactivation are linked","No structural basis for receptor binding"]},{"year":2004,"claim":"Showed RBM39 is a nuclear-matrix DNA/RNA-associated protein with helicase partners and a cell-cycle phenotype, broadening it beyond transcription.","evidence":"Nuclear fractionation, DNA-binding assays, yeast two-hybrid (BAT1, DDX39) and flow cytometry in HEK293 cells","pmids":["15338056"],"confidence":"Medium","gaps":["Functional significance of DNA/S-MAR binding unresolved","Helicase interactions not validated reciprocally in cells"]},{"year":2005,"claim":"Demonstrated that RBM39 couples transcriptional coactivation and alternative splicing through separable domains, unifying its dual identity.","evidence":"Reporter assays, calcitonin/CGRP and VEGF minigene/endogenous splicing analyses with siRNA in a single study","pmids":["15694343"],"confidence":"High","gaps":["Did not map RNA-binding specificity","Spliceosome contacts not identified"]},{"year":2014,"claim":"Provided the structural basis for RBM39's incorporation into the spliceosome by defining its UHM–ULM interactions with SF3b155.","evidence":"1.7 Å crystal structure, ITC and Co-IP from human cell extracts","pmids":["24795046"],"confidence":"High","gaps":["Did not establish which splicing events require this contact in vivo"]},{"year":2016,"claim":"Defined the second core spliceosomal contact (U2AF65) and mapped RBM39's genome-wide RNA binding and splicing program, establishing it as a bona fide splicing regulator near splice sites.","evidence":"Crystal/NMR structures of UHM–U2AF65, ITC, Co-IP, and CLIP-seq/RNA-seq with knockdown in MCF-7","pmids":["27050129","27354116"],"confidence":"High","gaps":["Direct RNA-binding sequence specificity not yet structurally defined","U2AF65 vs SF3b155 functional division unclear"]},{"year":2017,"claim":"Identified RBM39 as the cellular target of anticancer aryl-sulfonamides via DCAF15-dependent degradation, transforming it into a pharmacologically actionable node.","evidence":"CRISPR-Cas9 DCAF15 knockout, RBM39 point mutagenesis, viability assays and western blot across multiple sulfonamides","pmids":["28437394"],"confidence":"High","gaps":["Atomic mechanism of glue-induced recruitment not yet resolved","Degron location undefined at the time"]},{"year":2019,"claim":"Resolved at atomic and near-atomic resolution how aryl-sulfonamides act as molecular glues, defining the RRM2 α-helical degron and the cooperative, non-conserved DCAF15 pocket recruiting RBM39 (and only RBM23).","evidence":"X-ray (2.3 Å, 1.7 Å) and cryo-EM (4.4 Å) structures, kinetic binding analysis, domain mapping, ubiquitination assays and RNA-seq","pmids":["31819272","31686031","31693911","31693891"],"confidence":"High","gaps":["Why only RBM39/RBM23 carry a glue-competent degron not generalized","N-terminal ubiquitination site context vs degron geometry not fully reconciled"]},{"year":2021,"claim":"Linked RBM39 coactivation to chromatin modification, showing it recruits the MLL1 complex to drive H3K4me3 at oncogenic loci.","evidence":"Co-IP, ChIP-seq, domain deletion and cell-penetrating dominant-negative RRM3 peptide in breast cancer cells","pmids":["34077726"],"confidence":"Medium","gaps":["Single-lab; direct MLL1 contact surface not structurally defined","Genome-wide MLL1 co-occupancy with RBM39 limited"]},{"year":2023,"claim":"Defined RBM39's intrinsic RNA-recognition code and the structural mechanism of its poison-exon autoregulation, explaining how it tunes its own levels.","evidence":"NMR solution structures of RRM1/RRM2 bound to RNA, minigene splicing assays and mutagenesis","pmids":["37666821"],"confidence":"High","gaps":["How RRM3/RS domain stabilizes U2 snRNP not structurally resolved"]},{"year":2023,"claim":"Connected RBM39 to nutrient sensing and oncogenic metabolic reprogramming, showing arginine directly binds RBM39 to regulate metabolic gene expression.","evidence":"Biochemical arginine-binding assays, metabolomics, RNA-seq, genetic models in murine and patient HCC","pmids":["37804830"],"confidence":"High","gaps":["Arginine-binding surface on RBM39 not mapped","Whether sensing alters splicing vs coactivation unclear"]},{"year":2024,"claim":"Mapped the upstream ubiquitin/modification network controlling RBM39 stability beyond the sulfonamide axis, identifying USP39, PRMT6 and CDK kinases as regulators of its abundance.","evidence":"AP-MS/Co-IP and ubiquitination assays (USP39), MS-identified methylation/phosphosites with mutagenesis and rescue (PRMT6 R92, CDK13 S117), and CMGC/CDK9 inhibition driving poison-exon NMD","pmids":["39260689","40465651","41997449","39316649"],"confidence":"Medium","gaps":["Each regulator validated in a single lab/context","Interplay between competing modifications not integrated","RNF147 ligase mechanism not structurally defined"]},{"year":2025,"claim":"Extended RBM39 function to mRNA stabilization and decay scaffolding, showing it binds specific 3'-UTRs to stabilize DNA-repair transcripts and assembles an m6A-dependent decay complex.","evidence":"RIP-qPCR, motif mutagenesis and actinomycin D stability assays (FANCD2, OGG1, RAD50) and Co-IP/RNA decay assays for a YTHDC1–DDX5 tripartite complex on HIV-1 Tat RNA","pmids":["40752539","40364450","41997449","41218081"],"confidence":"Medium","gaps":["Whether stabilization and degradation use the same RRM contacts unclear","Determinants of stabilize-vs-decay outcome unknown"]},{"year":null,"claim":"How RBM39 integrates its splicing, transcriptional coactivation, mRNA-stability and metabolic-sensing functions into a unified regulatory logic—and how its post-translational modification network biases between these outputs—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of full-length RBM39 with multiple partners","No unifying model linking modification state to functional choice","Many downstream target events validated only in single cancer contexts"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[9,16,17,30,31]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5,6,11,12,14]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[9,10,16]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7,8,10,25]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[19]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,19,20]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[9,16]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[9,16]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,6,14]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,4,20,23]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[12,17]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,17,31]}],"complexes":["CRL4-DCAF15 E3 ligase (neo-substrate)","spliceosome (U2 snRNP-associated)","MLL1 complex","RBM39-YTHDC1-DDX5 RNA decay complex"],"partners":["U2AF65","SF3B1 (SF3B155)","DCAF15","USP39","YTHDC1","DDX5","C-JUN","C-ABL"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14498","full_name":"RNA-binding protein 39","aliases":["CAPER alpha","CAPERalpha","Hepatocellular carcinoma protein 1","RNA-binding motif protein 39","RNA-binding region-containing protein 2","Splicing factor HCC1"],"length_aa":530,"mass_kda":59.4,"function":"RNA-binding protein that acts as a pre-mRNA splicing factor (PubMed:15694343, PubMed:24795046, PubMed:28302793, PubMed:28437394, PubMed:31271494). Acts by promoting exon inclusion via regulation of exon cassette splicing (PubMed:31271494). Also acts as a transcriptional coactivator for steroid nuclear receptors ESR1/ER-alpha and ESR2/ER-beta, and JUN/AP-1, independently of the pre-mRNA splicing factor activity (By similarity)","subcellular_location":"Nucleus speckle","url":"https://www.uniprot.org/uniprotkb/Q14498/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/RBM39","classification":"Common 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DCAF15","url":"https://www.omim.org/entry/620109"},{"mim_id":"611911","title":"IRON-SULFUR CLUSTER ASSEMBLY ENZYME; ISCU","url":"https://www.omim.org/entry/611911"},{"mim_id":"604739","title":"RNA-BINDING MOTIF PROTEIN 39; RBM39","url":"https://www.omim.org/entry/604739"},{"mim_id":"603988","title":"ZINC FINGER PROTEIN 106; ZNF106","url":"https://www.omim.org/entry/603988"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear speckles","reliability":"Supported"},{"location":"Microtubules","reliability":"Additional"},{"location":"Centriolar satellite","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":162.0}],"url":"https://www.proteinatlas.org/search/RBM39"},"hgnc":{"alias_symbol":["CC1.3","HCC1","CAPER","fSAP59","CAPERalpha"],"prev_symbol":["RNPC2"]},"alphafold":{"accession":"Q14498","domains":[{"cath_id":"3.30.70.330","chopping":"146-240","consensus_level":"high","plddt":85.6341,"start":146,"end":240},{"cath_id":"3.30.70.330","chopping":"245-324","consensus_level":"high","plddt":86.7103,"start":245,"end":324},{"cath_id":"3.30.70.330","chopping":"424-517","consensus_level":"high","plddt":84.6968,"start":424,"end":517}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14498","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14498-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14498-F1-predicted_aligned_error_v6.png","plddt_mean":66.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RBM39","jax_strain_url":"https://www.jax.org/strain/search?query=RBM39"},"sequence":{"accession":"Q14498","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14498.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14498/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14498"}},"corpus_meta":[{"pmid":"28437394","id":"PMC_28437394","title":"Selective 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CRISPR-Cas9 knockout of DCAF15 and a single amino acid substitution in RBM39 conferred resistance to sulfonamide-induced RBM39 degradation and cell-growth inhibition.\",\n      \"method\": \"CRISPR-Cas9 knockout, site-directed mutagenesis, cell viability assays, western blot\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (genetic KO, point mutagenesis, functional rescue), replicated across multiple sulfonamide compounds\",\n      \"pmids\": [\"28437394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Crystal structure of the DCAF15-DDB1-DDA1-indisulam-RBM39(RRM2) complex at 2.3 Å resolution revealed that DCAF15 embraces the RBM39 RRM2 domain largely via non-polar interactions, with indisulam binding between DCAF15 and RBM39(RRM2) as a molecular glue. An α-helical degron motif in RBM39 RRM2 was defined; only RBM23 and RBM39 share this degron and are degraded by indisulam.\",\n      \"method\": \"X-ray crystallography (2.3 Å), RBM39 point mutant studies, indisulam analog studies, mass spectrometry of indisulam-treated HCT116 cells\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure with mutagenesis validation and proteomics confirmation in cells\",\n      \"pmids\": [\"31819272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cryo-EM structure (4.4 Å) of DDB1-DCAF15-DDA1 bound to RBM39 and E7820 showed DCAF15 adopts a new fold stabilized by DDA1, and extensive protein-protein contacts between the ligase and RBM39 compensate for low-affinity aryl-sulfonamide–DCAF15 interactions. Aryl-sulfonamides neo-functionalize a shallow, non-conserved pocket on DCAF15 to selectively recruit RBM39 and RBM23.\",\n      \"method\": \"Cryo-EM (4.4 Å), X-ray crystallography of subcomplexes, biochemical reconstitution\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM and crystal structures with functional biochemical validation\",\n      \"pmids\": [\"31686031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Crystal structure of DDA1-DDB1-DCAF15 in complex with E7820 and RBM39 RRM2 domain showed E7820 packs in a shallow pocket on DCAF15 and the resulting modified interface binds RBM39 through the α1 helix of RRM2. Kinetic analysis revealed that aryl sulfonamide and RBM39 bind to DCAF15 in a synergistic (cooperative) manner.\",\n      \"method\": \"X-ray crystallography, kinetic binding analysis\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus kinetic experiments, consistent with two independent structural studies\",\n      \"pmids\": [\"31693911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Domain mapping and mutagenesis identified that RBM39 is recruited to DCAF15 through its RRM2 domain and is ubiquitinated on its N terminus upon indisulam treatment. DCAF15 mutations Q232 or D475 prevent RBM39 recruitment. RBM23 is also recruited and degraded via its RRM2 domain. Indisulam-induced transcriptional and splicing changes (>3,000 genes, intron retention and exon skipping) are attributable to RBM39 loss, not RBM23.\",\n      \"method\": \"Domain mapping, random mutagenesis, ubiquitination assays, RNA-seq\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (mutagenesis, ubiquitination assay, transcriptomics) in a single rigorous study\",\n      \"pmids\": [\"31693891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"RBM39 (CAPER) was identified as a nuclear coactivator that selectively binds c-Jun (AP-1 component) and estradiol-bound ligand binding domains of ERα and ERβ, and stimulates transactivation by ERα, ERβ, and AP-1 in cotransfection assays. CAPER interaction was identified via its interaction with the general coactivator ASC-2.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, luciferase transcription reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal binding assays and functional reporter assays, single lab\",\n      \"pmids\": [\"11704680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RBM39 (CAPERα) coactivates progesterone receptor-mediated transcription and alters alternative splicing of a calcitonin/CGRP minigene in a hormone-dependent manner. siRNA knockdown of CAPERα affected VEGF isoform splicing. Transcriptional and splicing functions map to distinct, separable domains of the protein.\",\n      \"method\": \"Luciferase transcription reporter assays, minigene splicing assays, siRNA knockdown, RT-PCR\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (reporter assays, minigene, siRNA, endogenous gene analysis), demonstrated separation of function by domain mapping\",\n      \"pmids\": [\"15694343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The CAPERα UHM domain interacts with SF3b155 ULM motifs (at 1.7 Å crystal structure). Isothermal titration calorimetry showed high-affinity interaction depends on an intrinsically unstructured SF3b155 domain with seven ULM-like motifs. SF3b155 was identified as the relevant ULM-containing partner of full-length CAPERα in human cell extracts.\",\n      \"method\": \"X-ray crystallography (1.7 Å), isothermal titration calorimetry, co-immunoprecipitation from cell extracts\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus ITC and Co-IP, multiple orthogonal methods in single study\",\n      \"pmids\": [\"24795046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal and NMR structures of the RBM39 UHM domain and its complex with U2AF65-ULM were solved. The RBM39-U2AF65 interaction was confirmed by co-immunoprecipitation from human cell extracts, isothermal titration calorimetry, and NMR chemical shift perturbation experiments with purified proteins.\",\n      \"method\": \"X-ray crystallography, solution NMR, co-immunoprecipitation, isothermal titration calorimetry\",\n      \"journal\": \"Acta crystallographica Section D\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple structural methods (crystal, NMR) plus orthogonal biochemical validation (Co-IP, ITC)\",\n      \"pmids\": [\"27050129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Genome-wide CLIP-Seq mapping showed RBM39 binding sites are mainly proximal to 5' and 3' splice sites. RNA-seq of RBM39-knockdown MCF-7 cells identified hundreds of alternative splicing events (predominantly cassette exons) regulated by RBM39, with ~20% of events co-regulated with U2AF65.\",\n      \"method\": \"CLIP-Seq, RNA-seq, siRNA knockdown\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide CLIP-seq plus RNA-seq with knockdown, orthogonal transcriptomic approaches\",\n      \"pmids\": [\"27354116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"During terminal erythropoiesis, RBM39 associates in a complex with TIA1 and Pcbp1 to activate the protein 4.1R exon 16 3' splice site. This complex interacts with U2AF65 and SF3b155 and promotes U2 snRNP recruitment to the branch point and spliceosome A complex formation.\",\n      \"method\": \"Co-immunoprecipitation, splicing reporter assays, siRNA knockdown, UV cross-linking\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP complex identification and functional splicing assays, single lab\",\n      \"pmids\": [\"28193846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CAPERα interacts with the transcription activation domain (TAD) of v-Rel and synergizes v-Rel-mediated transactivation. A dominant-negative mutant of CAPERα enhanced v-Rel-mediated lymphocyte transformation, and siRNA knockdown of CAPERα in v-Rel-transformed lymphocytes enhanced colony formation, identifying CAPERα as a transcriptional coregulator that modulates Rel/NF-κB oncogenic activity.\",\n      \"method\": \"Co-immunoprecipitation, luciferase reporter assays, dominant-negative overexpression, siRNA knockdown, soft agar colony assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple functional assays (Co-IP, reporter, dominant negative, KD) in single lab\",\n      \"pmids\": [\"18753212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RBM39 (CAPER) acts as a transcriptional coactivator for ERR-α–mediated Gabpa transcription to drive mitochondrial gene expression and glucose-dependent respiration. CAPER is also a coactivator for NF-κB regulating c-Myc in stress responses. CAPER is required for anaplerotic carbon flux into TCA cycles. These functions are conserved in C. elegans where CAPER loss impairs lifespan and reproduction.\",\n      \"method\": \"siRNA knockdown, luciferase reporter assays, metabolic flux analysis (isotope tracing), C. elegans genetic studies, ATP measurement\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays (reporter, metabolic, genetic epistasis in model organism), single lab\",\n      \"pmids\": [\"25830341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RBM39 interacts with the non-receptor tyrosine kinase c-Abl through c-Abl SH2 and SH3 domains. c-Abl phosphorylates RBM39 at Y95 and Y99 (identified by LC/MS/MS and mutational analysis), and c-Abl enhances RBM39 transcriptional coactivation activity for ERα and PRβ in a kinase-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, LC/MS/MS phosphoproteomics, site-directed mutagenesis, luciferase reporter assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mass spectrometry identification of phosphosites with mutagenesis and functional validation, single lab\",\n      \"pmids\": [\"27018250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RBM39 functions as a master transcriptional regulator that interacts with the MLL1 complex to facilitate chromatin binding and H3K4 trimethylation in breast cancer cells. The RRM3 domain of RBM39 acts as a dominant-negative, disrupting the RBM39/MLL1 complex and reducing H3K4me3 and expression of target oncogenic genes.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, domain deletion/mutagenesis, cell-penetrating peptide experiments\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP-seq and functional domain dissection, single lab\",\n      \"pmids\": [\"34077726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The lncRNA DARS-AS1 binds RBM39, impeding its interaction with the E3 ubiquitin ligase RNF147, thereby preventing RBM39 proteasomal degradation. This stabilization of RBM39 maintains mTOR signaling in myeloma cells.\",\n      \"method\": \"RNA immunoprecipitation, co-immunoprecipitation, siRNA/shRNA knockdown, ubiquitination assays, in vivo xenograft\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — RIP and Co-IP showing competitive binding, plus functional rescue experiments, single lab\",\n      \"pmids\": [\"31289203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NMR solution structures of RBM39 RRM1 and RRM2 bound to their respective RNA targets were determined: RRM1 recognizes RNA stem loops whereas RRM2 binds specifically to single-stranded N(G/U)NUUUG sequences. RBM39 autoregulates its own expression via inclusion of a poison exon into its pre-mRNA, with RRM2 selecting the 3' splice site of the poison exon and the RRM3 and RS domain stabilizing U2 snRNP at the branchpoint.\",\n      \"method\": \"NMR spectroscopy (solution structures), minigene splicing assays, mutagenesis of cis-acting elements, siRNA knockdown\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structures with functional validation of RNA binding specificity and autoregulation mechanism, multiple orthogonal methods\",\n      \"pmids\": [\"37666821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Arginine directly binds RBM39 protein to control expression of metabolic genes. RBM39-mediated upregulation of asparagine synthesis leads to enhanced arginine uptake, creating a positive feedback loop. High arginine levels in hepatocellular carcinoma drive oncogenic metabolic reprogramming via RBM39.\",\n      \"method\": \"Biochemical binding assays (arginine-RBM39 interaction), RNA-seq, metabolomics, genetic knockdown/overexpression, mouse HCC models\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding demonstrated, multiple orthogonal approaches (metabolomics, RNA-seq, genetic models), replicated in murine and patient HCC\",\n      \"pmids\": [\"37804830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In response to cisplatin (genotoxic stress), c-Jun interacts with RBM39 and prevents RBM39 binding to pre-mRNA, thereby reprogramming alternative splicing genome-wide. This c-Jun–RBM39 interaction drives production of a short COASY isoform lacking exons 4 and 5 that impairs mitochondrial function and decreases cisplatin sensitivity.\",\n      \"method\": \"Co-immunoprecipitation, RNA-seq, RNA immunoprecipitation, siRNA knockdown, minigene splicing assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of novel interaction, RIP and functional RNA-seq, single lab\",\n      \"pmids\": [\"36477312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"RBM39 (Hcc-1) localizes to the nuclear matrix and binds both double-stranded and single-stranded DNA (higher affinity for ssDNA) and scaffold/matrix attachment region (S/MAR) DNA. Two DEAD-box RNA helicases, BAT1 and DDX39, were identified as RBM39-interacting proteins by yeast two-hybrid. Overexpression of Hcc-1 caused G2/M accumulation and slower growth in HEK293 cells.\",\n      \"method\": \"Nuclear fractionation, DNA binding assays, yeast two-hybrid, cell cycle analysis (flow cytometry), overexpression\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct biochemical binding assays and genetic screen, single lab, functional cell cycle phenotype\",\n      \"pmids\": [\"15338056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP39 is a deubiquitinating enzyme that interacts with RBM39 and co-localizes in the nucleus. USP39 reduces K48-linked polyubiquitin chains on RBM39, enhancing its stability and preventing proteasomal degradation.\",\n      \"method\": \"Affinity purification-mass spectrometry, co-immunoprecipitation, ubiquitination assays, shRNA knockdown, overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — AP-MS identification plus biochemical ubiquitination assays and rescue experiments, single lab\",\n      \"pmids\": [\"39260689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"siRNA knockdown of RBM39 in mouse C2C12 cells increased BMP4-dependent transcription. Transcriptome-wide RNA-seq revealed that RBM39 knockdown altered Sin3b exon usage, shifting expression from the long isoform (which recruits HDACs) to the short isoform. BMP4 induced a shift toward the long SIN3B isoform that was prevented by RBM39 knockdown, constituting a negative autoregulatory loop of BMP signaling through RBM39-regulated splicing.\",\n      \"method\": \"siRNA screen, siRNA knockdown, luciferase reporter, RNA-seq, RT-PCR for isoforms\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA screen with mechanistic RNA-seq follow-up, single lab\",\n      \"pmids\": [\"27324164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MORC2 binds the RRM1 domain of RBM39, and RBM39 interacts with site 1 of pre-CDK5RAP2 exon 32 via its UHM domain, causing a splicing switch from CDK5RAP2-L to CDK5RAP2-S. CDK5RAP2-S promotes EMT and metastasis by recruiting PHD finger protein 8 to the Slug promoter to remove repressive histone marks.\",\n      \"method\": \"Co-immunoprecipitation, RNA immunoprecipitation, minigene splicing assay, domain mapping, in vitro/in vivo functional studies\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP domain mapping and RNA binding assays with functional downstream validation, single lab\",\n      \"pmids\": [\"39048555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PRMT6 methylates RBM39 at R92. This methylation inhibits indisulam-induced ubiquitination and proteasomal degradation of RBM39, thereby increasing RBM39 protein levels and conferring resistance to indisulam in NSCLC. Inhibiting PRMT6 or mutating R92 restores indisulam sensitivity.\",\n      \"method\": \"Mass spectrometry (phospho/methylo-proteomics), site-directed mutagenesis, ubiquitination assays, PRMT6 inhibitor treatment, xenograft models\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — MS identification of modification site, mutagenesis and functional rescue, single lab\",\n      \"pmids\": [\"40465651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YAP/TAZ interact with RBM39 (identified by proteome analysis) and RBM39 promotes YAP/TAZ transcriptional activity. YAP/TAZ hyperactivation delays indisulam-induced RBM39 degradation, restoring integrin/collagen expression and activating FAK to confer resistance against indisulam.\",\n      \"method\": \"Proteome analysis, co-immunoprecipitation, luciferase reporter assays, western blot, in vivo xenograft\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — proteomics discovery plus Co-IP and functional assays, single lab\",\n      \"pmids\": [\"39004623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBM39 scaffolds an m6A-dependent RNA decay complex by recruiting the m6A reader YTHDC1 and RNA helicase DDX5, forming a tripartite complex that accelerates Tat (HIV-1) RNA decay and enforces viral quiescence. Genetic or pharmacological degradation of RBM39 reactivates latent HIV-1.\",\n      \"method\": \"Proteomics, co-immunoprecipitation, RNA decay assays, RBM39 knockdown/degradation, latency reactivation assays\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomic identification with Co-IP validation and functional RNA decay/reactivation assays, single lab\",\n      \"pmids\": [\"41218081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In PRRSV-infected cells, RBM39 alters phosphorylation of c-Jun to inhibit the AP-1 pathway, promoting viral proliferation. RBM39 undergoes nucleocytoplasmic translocation from nucleus to cytoplasm. The three RRM domains of RBM39 are required for supporting PRRSV proliferation. RBM39 directly binds several PRRSV RNA segments (nsp4, nsp5, nsp7, nsp10-12, M and N genes).\",\n      \"method\": \"siRNA knockdown, phosphorylation assays, co-immunoprecipitation, RNA immunoprecipitation, confocal microscopy, viral replication assays\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple assays (RIP, Co-IP, localization) in a single lab, porcine cell context\",\n      \"pmids\": [\"34079549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CMGC kinase inhibition (including DYRK1A) or CDK9 inhibition disrupts cotranscriptional splicing by altering SF3B1 and Pol II association and changing Pol II pausing, leading to inclusion of a poison exon in RBM39 pre-mRNA, which is recognized by NMD for degradation. This reduces RBM39 protein levels and inhibits B-ALL growth.\",\n      \"method\": \"Kinase inhibitor treatment, CRISPR knockout, RNA-seq, ChIP/CUT&RUN, NMD assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic dissection of cotranscriptional regulation with multiple genomic approaches, single lab\",\n      \"pmids\": [\"39316649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CDK13 directly phosphorylates RBM39 at serine 117 (identified by phosphoproteomic analysis). This phosphorylation enhances RBM39's ability to bind and stabilize RAD50 mRNA, increasing RAD50 protein levels and promoting DNA damage repair, thereby driving cisplatin resistance in endometrial cancer.\",\n      \"method\": \"Phosphoproteomics (LC-MS/MS), site-directed mutagenesis (S117A), RIP assays, mRNA stability assays (actinomycin D), in vivo xenograft\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — MS-identified phosphosite with mutagenesis and RNA binding functional assays, single lab\",\n      \"pmids\": [\"41997449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBM39 regulates alternative splicing of EZH2 pre-mRNA; RBM39 depletion suppresses EZH2 expression. RBM39-regulated EZH2 controls WNT7B/β-catenin activity, establishing an RBM39-EZH2-β-catenin signaling axis in cholangiocarcinoma.\",\n      \"method\": \"CRISPR/Cas9 and shRNA depletion, RNA-seq splicing analysis, western blot, in vivo xenograft\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — single lab, KD phenotype with downstream pathway inference from RNA-seq\",\n      \"pmids\": [\"39278404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBM39 binds the 3'-UTR of FANCD2 mRNA (validated by RIP-qPCR and motif mutagenesis) and extends FANCD2 mRNA half-life (actinomycin D assay), thereby stabilizing FANCD2 protein and promoting DNA repair in esophageal cancer.\",\n      \"method\": \"RNA immunoprecipitation (RIP-qPCR), motif mutagenesis, mRNA stability assay (actinomycin D), FANCD2 overexpression rescue\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA binding validated by RIP and mutagenesis, functional rescue experiments, single lab\",\n      \"pmids\": [\"40752539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBM39 binds RFX1 pre-mRNA (identified by RIP-seq) and regulates alternative splicing of RFX1 exon 2. Skipping of exon 2 produces an N-terminal truncated RFX1 lacking transcriptional repression activity on oncogenic collagen genes, leading to activation of the FAK/PI3K/AKT signaling pathway in HCC.\",\n      \"method\": \"RIP-seq, minigene splicing assay, RT-PCR, CRISPR/shRNA knockdown, in vivo xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP-seq with minigene validation and downstream pathway functional assays, single lab\",\n      \"pmids\": [\"40033026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBM39 depletion reduced expression of IRF3, RIG-I, and MDA5 (transcription and/or splicing affected), as well as IFN receptor subunits IFNAR and STAT1/2, impairing TLR3, RIG-I/MDA5, and type I/III IFN responses in hepatocytes. A genome-wide CRISPR/Cas9 screen identified RBM39 as a required factor for TLR3 pathway activation.\",\n      \"method\": \"Genome-wide CRISPR/Cas9 screen, siRNA knockdown, indisulam treatment, RNA-seq, mass spectrometry\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen with validation by two independent methods and transcriptomic/proteomic characterization, single lab\",\n      \"pmids\": [\"40330464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBM39 promotes base excision repair (BER) in HCC by binding OGG1 mRNA and stabilizing it, increasing OGG1 expression and BER efficiency under oxidative stress. This was demonstrated using a BER reporter assay and RBM39 knockdown/degradation experiments.\",\n      \"method\": \"BER reporter assay, RNA immunoprecipitation, mRNA stability assay, siRNA knockdown, indisulam treatment, xenograft model\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — RIP and functional reporter, single lab, limited mechanistic depth\",\n      \"pmids\": [\"40364450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBM39 regulates MEK5 pre-mRNA splicing; RBM39 knockdown causes aberrant MEK5 isoforms with exon loss that are non-functional and prone to proteasomal degradation. Full-length MEK5 is required for multiple myeloma cell survival.\",\n      \"method\": \"shRNA knockdown, RNA-seq splicing analysis, RT-PCR isoform analysis, western blot, in vivo xenograft\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — single lab, splicing change identified by RNA-seq with limited mechanistic reconstitution\",\n      \"pmids\": [\"40048740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Rbm39 enhances hepatocyte nuclear factor 4α (Hnf4α) transcriptional activity to upregulate Apob transcription, while suppressing Fabp4 transcription through regulation of alternative splicing of Hif-1α, thereby maintaining hepatic lipid homeostasis.\",\n      \"method\": \"AAV-mediated Rbm39 overexpression/knockdown, RNA-seq, dual-luciferase reporter assays, alternative splicing analysis, RT-PCR\",\n      \"journal\": \"Biochimica et biophysica acta Molecular basis of disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — reporter assays and RNA-seq in vivo model, single lab, limited mechanistic reconstitution\",\n      \"pmids\": [\"40147697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CAPER-α expression correlates inversely with the VEGF165/VEGF189 mRNA ratio in Ewing sarcoma cells. Transfection of CAPER-α cDNA or siRNA knockdown altered VEGF isoform splicing (VEGF189 vs VEGF165). CAPER-α expression was regulated by EWS/FLI-1 through a protein-protein interaction.\",\n      \"method\": \"cDNA transfection, siRNA knockdown, RT-PCR isoform analysis, co-immunoprecipitation (protein-protein interaction), in vivo tumor growth assay\",\n      \"journal\": \"Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP of EWS/FLI-1 interaction plus functional splicing assays, single lab\",\n      \"pmids\": [\"22009261\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RBM39 is a multifunctional nuclear RNA-binding protein and transcriptional coactivator that (1) regulates alternative pre-mRNA splicing by binding near 5' and 3' splice sites through its RRM domains and interacting with core spliceosome components (U2AF65 via UHM-ULM interaction, SF3b155, U2 snRNP), (2) coactivates transcription by ERα, ERβ, AP-1/c-Jun, NF-κB, and other transcription factors, (3) can stabilize specific mRNAs (e.g., OGG1, FANCD2, RAD50) by binding their 3'-UTRs, (4) autoregulates its own expression via a poison exon, (5) is subject to modification by c-Abl (phosphorylation at Y95/Y99), CDK13 (phosphorylation at S117), and PRMT6 (methylation at R92), the last of which protects it from degradation, (6) is stabilized by USP39-mediated deubiquitination and destabilized by RNF147-mediated ubiquitination, and (7) is selectively degraded by aryl sulfonamide molecular glues (indisulam, E7820, tasisulam) that act as 'molecular glue' to recruit RBM39's RRM2 α-helical degron to the CRL4-DCAF15 E3 ligase complex for ubiquitination and proteasomal destruction.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RBM39 (CAPERα/Hcc-1) is a multifunctional nuclear RNA-binding protein that operates both as a regulator of alternative pre-mRNA splicing and as a transcriptional coactivator [#5, #6, #9]. Through its tandem RRM domains it binds RNA in a structurally distinct manner—RRM1 recognizes stem-loop elements while RRM2 binds single-stranded N(G/U)NUUUG motifs—and CLIP-Seq maps its binding predominantly to sequences flanking 5' and 3' splice sites, where it controls cassette-exon and other alternative splicing events [#9, #16]. RBM39 engages the core 3' splice site machinery through its UHM domain, which binds ULM motifs in U2AF65 and SF3b155 to promote U2 snRNP recruitment and spliceosome A-complex assembly [#7, #8, #10]. It autoregulates its own abundance by directing inclusion of an NMD-targeted poison exon into its own transcript [#16, #27]. Independently, RBM39 acts as a coactivator that potentiates transactivation by ERα/ERβ, AP-1/c-Jun, progesterone receptor, NF-κB/Rel, ERRα, and YAP/TAZ, and facilitates chromatin activation via the MLL1 complex and H3K4 trimethylation, with transcriptional and splicing functions mapping to separable domains [#5, #6, #11, #12, #14, #24]. RBM39 protein levels are tightly controlled by post-translational modification and ubiquitin signaling: c-Abl phosphorylates Y95/Y99 and CDK13 phosphorylates S117 to modulate its coactivator and mRNA-stabilizing activities, PRMT6 methylation at R92 and USP39 deubiquitination stabilize it, and RNF147 destabilizes it [#13, #20, #23, #28, #15]. RBM39 is the selective neo-substrate of aryl-sulfonamide molecular glues (indisulam, E7820, CQS), which occupy a shallow, non-conserved pocket on the CRL4 substrate receptor DCAF15 and cooperatively recruit an α-helical degron within RBM39's RRM2 domain for ubiquitination and proteasomal degradation—a property shared only with the paralog RBM23 [#0, #1, #2, #3, #4].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established RBM39 as a transcriptional coactivator, defining its first molecular function beyond a nuclear protein of unknown role.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP and luciferase reporter assays showing selective binding to c-Jun and ER ligand-binding domains and stimulation of ERα/ERβ/AP-1 transactivation\",\n      \"pmids\": [\"11704680\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not address whether splicing and coactivation are linked\", \"No structural basis for receptor binding\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed RBM39 is a nuclear-matrix DNA/RNA-associated protein with helicase partners and a cell-cycle phenotype, broadening it beyond transcription.\",\n      \"evidence\": \"Nuclear fractionation, DNA-binding assays, yeast two-hybrid (BAT1, DDX39) and flow cytometry in HEK293 cells\",\n      \"pmids\": [\"15338056\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of DNA/S-MAR binding unresolved\", \"Helicase interactions not validated reciprocally in cells\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated that RBM39 couples transcriptional coactivation and alternative splicing through separable domains, unifying its dual identity.\",\n      \"evidence\": \"Reporter assays, calcitonin/CGRP and VEGF minigene/endogenous splicing analyses with siRNA in a single study\",\n      \"pmids\": [\"15694343\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map RNA-binding specificity\", \"Spliceosome contacts not identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided the structural basis for RBM39's incorporation into the spliceosome by defining its UHM–ULM interactions with SF3b155.\",\n      \"evidence\": \"1.7 Å crystal structure, ITC and Co-IP from human cell extracts\",\n      \"pmids\": [\"24795046\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish which splicing events require this contact in vivo\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the second core spliceosomal contact (U2AF65) and mapped RBM39's genome-wide RNA binding and splicing program, establishing it as a bona fide splicing regulator near splice sites.\",\n      \"evidence\": \"Crystal/NMR structures of UHM–U2AF65, ITC, Co-IP, and CLIP-seq/RNA-seq with knockdown in MCF-7\",\n      \"pmids\": [\"27050129\", \"27354116\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct RNA-binding sequence specificity not yet structurally defined\", \"U2AF65 vs SF3b155 functional division unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified RBM39 as the cellular target of anticancer aryl-sulfonamides via DCAF15-dependent degradation, transforming it into a pharmacologically actionable node.\",\n      \"evidence\": \"CRISPR-Cas9 DCAF15 knockout, RBM39 point mutagenesis, viability assays and western blot across multiple sulfonamides\",\n      \"pmids\": [\"28437394\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic mechanism of glue-induced recruitment not yet resolved\", \"Degron location undefined at the time\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved at atomic and near-atomic resolution how aryl-sulfonamides act as molecular glues, defining the RRM2 α-helical degron and the cooperative, non-conserved DCAF15 pocket recruiting RBM39 (and only RBM23).\",\n      \"evidence\": \"X-ray (2.3 Å, 1.7 Å) and cryo-EM (4.4 Å) structures, kinetic binding analysis, domain mapping, ubiquitination assays and RNA-seq\",\n      \"pmids\": [\"31819272\", \"31686031\", \"31693911\", \"31693891\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why only RBM39/RBM23 carry a glue-competent degron not generalized\", \"N-terminal ubiquitination site context vs degron geometry not fully reconciled\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked RBM39 coactivation to chromatin modification, showing it recruits the MLL1 complex to drive H3K4me3 at oncogenic loci.\",\n      \"evidence\": \"Co-IP, ChIP-seq, domain deletion and cell-penetrating dominant-negative RRM3 peptide in breast cancer cells\",\n      \"pmids\": [\"34077726\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab; direct MLL1 contact surface not structurally defined\", \"Genome-wide MLL1 co-occupancy with RBM39 limited\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined RBM39's intrinsic RNA-recognition code and the structural mechanism of its poison-exon autoregulation, explaining how it tunes its own levels.\",\n      \"evidence\": \"NMR solution structures of RRM1/RRM2 bound to RNA, minigene splicing assays and mutagenesis\",\n      \"pmids\": [\"37666821\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RRM3/RS domain stabilizes U2 snRNP not structurally resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected RBM39 to nutrient sensing and oncogenic metabolic reprogramming, showing arginine directly binds RBM39 to regulate metabolic gene expression.\",\n      \"evidence\": \"Biochemical arginine-binding assays, metabolomics, RNA-seq, genetic models in murine and patient HCC\",\n      \"pmids\": [\"37804830\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Arginine-binding surface on RBM39 not mapped\", \"Whether sensing alters splicing vs coactivation unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mapped the upstream ubiquitin/modification network controlling RBM39 stability beyond the sulfonamide axis, identifying USP39, PRMT6 and CDK kinases as regulators of its abundance.\",\n      \"evidence\": \"AP-MS/Co-IP and ubiquitination assays (USP39), MS-identified methylation/phosphosites with mutagenesis and rescue (PRMT6 R92, CDK13 S117), and CMGC/CDK9 inhibition driving poison-exon NMD\",\n      \"pmids\": [\"39260689\", \"40465651\", \"41997449\", \"39316649\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Each regulator validated in a single lab/context\", \"Interplay between competing modifications not integrated\", \"RNF147 ligase mechanism not structurally defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended RBM39 function to mRNA stabilization and decay scaffolding, showing it binds specific 3'-UTRs to stabilize DNA-repair transcripts and assembles an m6A-dependent decay complex.\",\n      \"evidence\": \"RIP-qPCR, motif mutagenesis and actinomycin D stability assays (FANCD2, OGG1, RAD50) and Co-IP/RNA decay assays for a YTHDC1–DDX5 tripartite complex on HIV-1 Tat RNA\",\n      \"pmids\": [\"40752539\", \"40364450\", \"41997449\", \"41218081\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether stabilization and degradation use the same RRM contacts unclear\", \"Determinants of stabilize-vs-decay outcome unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RBM39 integrates its splicing, transcriptional coactivation, mRNA-stability and metabolic-sensing functions into a unified regulatory logic—and how its post-translational modification network biases between these outputs—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of full-length RBM39 with multiple partners\", \"No unifying model linking modification state to functional choice\", \"Many downstream target events validated only in single cancer contexts\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [9, 16, 17, 30, 31]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5, 6, 11, 12, 14]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [9, 10, 16]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7, 8, 10, 25]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 19, 20]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [9, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [9, 16]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 6, 14]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 4, 20, 23]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [12, 17]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 17, 31]}\n    ],\n    \"complexes\": [\"CRL4-DCAF15 E3 ligase (neo-substrate)\", \"spliceosome (U2 snRNP-associated)\", \"MLL1 complex\", \"RBM39-YTHDC1-DDX5 RNA decay complex\"],\n    \"partners\": [\"U2AF65\", \"SF3B1 (SF3b155)\", \"DCAF15\", \"USP39\", \"YTHDC1\", \"DDX5\", \"c-Jun\", \"c-Abl\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}