{"gene":"RBM5","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2008,"finding":"RBM5 regulates alternative splicing of Fas pre-mRNA by inhibiting the transition between prespliceosomal complexes assembled around exon 6 to mature spliceosomes assembled on flanking introns, promoting sequence-specific pairing of distal splice sites after exon definition rather than affecting early splice site recognition events.","method":"Biochemical spliceosome assembly assays, RNA-protein complex analysis, mutagenesis of OCRE domain","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1/2 / Strong — in vitro spliceosomal complex analysis with mutagenesis, mechanistically distinct model established with multiple orthogonal methods","pmids":["18851835"],"is_preprint":false},{"year":2008,"finding":"RBM5 binds to a U/C-rich sequence immediately upstream of the In100 splicing repressor element in caspase-2 pre-mRNA, and this binding enhances production of the proapoptotic Casp-2L isoform; mutagenesis of the binding site disrupts the ratio of proapoptotic/antiapoptotic isoforms.","method":"Yeast RNA-protein interaction assay, in vitro splicing assay, transfection in cells, mutagenesis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro splicing assay plus mutagenesis plus cellular validation in a single study","pmids":["18840686"],"is_preprint":false},{"year":2016,"finding":"The RBM5 OCRE domain adopts a unique β-sheet fold and directly binds the proline-rich C-terminal tail of spliceosomal SmN/B/B' proteins; NMR structure of the OCRE–SmN peptide complex reveals specific recognition of poly-proline helical motifs; mutation of conserved aromatic residues in OCRE impairs Sm protein binding in vitro and compromises RBM5-mediated FAS/CD95 alternative splicing regulation.","method":"NMR structure determination, biochemical binding assays, mutagenesis, functional splicing assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure with functional mutagenesis and in vitro binding validation, multiple orthogonal methods in one rigorous study","pmids":["27894420"],"is_preprint":false},{"year":2023,"finding":"Crystal/NMR structure of RBM5 RRM1-ZnF1-RRM2 domains in complex with RNA shows that RRM1-ZnF1 cooperate as a single structural module to sandwich target RNA and specifically recognize a GG dinucleotide in a non-canonical fashion; RRM2 is connected by a flexible linker but participates in RNA binding, adopting a closed architecture upon RNA engagement.","method":"X-ray crystallography, NMR, biochemical RNA binding assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus NMR with functional RNA binding validation, multiple orthogonal structural and biochemical methods","pmids":["37454201"],"is_preprint":false},{"year":2012,"finding":"RBM5 solution structure of the second RRM domain (RRM2) reveals it can preferentially bind both CU-rich and GA-rich RNA sequences with affinity in the 10^-5 molar range; both N- and C-terminal regions flanking the β-sheet surface participate in recognition.","method":"NMR solution structure determination, RNA binding assays","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with binding characterization, single lab but rigorous structural method","pmids":["22839758"],"is_preprint":false},{"year":2012,"finding":"RBM5 directly interacts with the DExD/H-box helicase DHX15 and with PRP19 (two spliceosome components); the G-patch domain of RBM5 is required for DHX15 interaction; RBM5 stimulates DHX15 helicase activity in vitro in a G-patch domain-dependent manner.","method":"Co-immunoprecipitation, pull-down assays, in vitro helicase activity assay, domain mutagenesis","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro helicase activity reconstitution with domain mutagenesis establishing mechanistic requirements, single lab","pmids":["22569250"],"is_preprint":false},{"year":2024,"finding":"RBM5 and RBM10 are subunits of the U2 snRNP engaged with intron branch sites across the transcriptome on chromatin; deletion of a conserved RBM5/RBM10 peptide containing a zinc finger motif disrupts U2 snRNP interaction and renders RBM5 inactive for repression of many alternative exons.","method":"Chromatin-associated spliceosome isolation, RNA sequencing of branch-site protected fragments, domain deletion mutagenesis, transcriptome-wide analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — isolation of native spliceosomal complexes combined with mutagenesis and transcriptome-wide functional validation; peer-reviewed and consistent with preprint (PMID:37790489)","pmids":["38537639","37790489"],"is_preprint":false},{"year":2013,"finding":"RBM5, RBM6, and RBM10 antagonistically regulate alternative splicing of the Notch pathway regulator NUMB pre-mRNA; RBM5/RBM6 and RBM10 show distinct positional effects on splicing; modulation of NUMB splicing recapitulates the effects of these factors on cancer cell colony formation and xenograft tumor growth.","method":"Minigene splicing assays, RNA-seq, siRNA knockdown, colony formation, xenograft assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RNA-seq, minigene, functional phenotypic assays) with epistasis demonstrated, replicated across multiple cell systems","pmids":["24332178"],"is_preprint":false},{"year":2013,"finding":"In mouse testes, RBM5 localizes to spermatogonia, spermatocytes, and round spermatids; a missense mutation R263P in the second RRM of RBM5 compromises mRNA binding and causes defective pre-mRNA splicing of target transcripts in round spermatids, leading to spermatid differentiation arrest and male sterility.","method":"Genetic screen, RNA pull-down with microarrays, immunofluorescence/localization, RT-PCR splicing assays, molecular modelling","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model with RRM mutagenesis, RNA target identification by pull-down, and splicing phenotype characterization","pmids":["23935508"],"is_preprint":false},{"year":2012,"finding":"RBM5 promotes AID exon 4 skipping by competing with U2AF65 binding to the polypyrimidine tract at the 3' splice site of intron 3; this competition was demonstrated in vitro; a weak 3' splice site is required for the inhibitory effect.","method":"Minigene splicing assay in HeLa cells, in vitro competition assay for U2AF65 binding","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of competitive U2AF65 displacement plus minigene functional assay, single lab","pmids":["23017209"],"is_preprint":false},{"year":2017,"finding":"RBM10 promotes alternative splicing-coupled nonsense-mediated decay (AS-NMD) of RBM5 mRNA by promoting skipping of RBM5 exon 6 or exon 16; this cross-regulation was validated computationally and experimentally, establishing a mechanism for RBM10-mediated cross-regulation of RBM5 expression.","method":"Computational prediction, RT-PCR splicing validation, NMD reporter assays, overexpression and knockdown experiments","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — combined computational and experimental validation, single lab, two orthogonal methods","pmids":["28586478"],"is_preprint":false},{"year":2017,"finding":"RBM5 post-transcriptionally regulates RBM10 expression via direct interaction with specific RBM10 splice variants, as demonstrated by RNA immunoprecipitation followed by next-generation sequencing (RIP-Seq) and Western blotting.","method":"RIP-Seq, Western blotting, stable cell line with endogenous RBM5 deletion","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP-seq provides genome-wide interaction data, confirmed by Western blot, single lab","pmids":["28662214"],"is_preprint":false},{"year":2018,"finding":"In C. elegans, rbm-5 mutations suppress the temperature-sensitive lethality of a U2AF large subunit (uaf-1) mutant; rbm-5 mutations can suppress or enhance altered splicing of uaf-1-dependent genes in a gene-specific manner, with a preference at weak 3' splice sites; neuronal expression of rbm-5 was sufficient to rescue the suppression.","method":"Genetic epistasis screen, transcriptome analysis, tissue-specific rescue experiments","journal":"RNA biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in C. elegans with transcriptome-wide splicing analysis, single lab","pmids":["30295127"],"is_preprint":false},{"year":2010,"finding":"RBM5 augments p53 transcriptional activity: RBM5 overexpression increases mRNA and protein levels of endogenous p53 target genes, and shRNA knockdown decreases them; RBM5 affects p53 protein but not mRNA levels after DNA damage, suggesting a post-transcriptional mechanism of p53 stabilization.","method":"Reporter gene assays, shRNA knockdown, Western blotting, RT-PCR, overexpression studies","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assays plus KD/OE with specific molecular readouts, single lab, two orthogonal methods","pmids":["20309933"],"is_preprint":false},{"year":2006,"finding":"Stable overexpression of RBM5/H37 in A549 lung cancer cells induces G1 cell cycle arrest (decreased cyclin A and phospho-RB) and apoptosis via the mitochondrial pathway (increased Bax, cytochrome c release, caspase-9 and caspase-3 activation); Bax siRNA knockdown reduces RBM5-mediated apoptosis, placing Bax functionally downstream of RBM5.","method":"Stable transfection, Western blotting, mitochondrial membrane potential assay, cytochrome c fractionation, caspase activity assays, siRNA epistasis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via Bax siRNA plus multiple apoptosis pathway readouts, single lab","pmids":["16585163"],"is_preprint":false},{"year":2007,"finding":"RBM5 is a phosphoprotein; phosphatase treatment decreases its apparent molecular mass; phosphorylation changes reversibly with growth factor addition/deprivation; mutagenesis and immunoprecipitation indicate serine 69 is phosphorylated under normal growth conditions (not by Akt kinase), with no evidence of phosphotyrosines.","method":"Phosphatase treatment (CIP), immunoprecipitation, site-directed mutagenesis, Western blotting","journal":"Cell biochemistry and function","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphatase treatment plus mutagenesis of specific residue, single lab","pmids":["16927403"],"is_preprint":false},{"year":2014,"finding":"The two RRM domains (aa 98-178 and 231-315) of RBM5 are required for RNA binding; a mutant lacking both RRMs (RBM5-ΔRRM) fails to bind RNA, shows compromised caspase-2 alternative splicing activity, and lacks cell proliferation inhibition and apoptosis induction in A549 cells.","method":"Domain deletion mutagenesis, RNA binding assays, splicing assays, cell proliferation and apoptosis assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain deletion mutagenesis with functional and RNA-binding readouts, single lab","pmids":["24486491"],"is_preprint":false},{"year":2000,"finding":"LUCA15/RBM5 protein localizes to the nucleus and binds poly(G) RNA homopolymers in vitro; ectopic expression of LUCA15 in HT1080 fibrosarcoma cells suppresses cell growth; LUCA15 mRNA is downregulated by constitutively active Ras(G12V).","method":"Epitope-tag localization, in vitro RNA binding assay, ectopic expression cell growth assay","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization and in vitro binding plus functional growth suppression assay, single lab","pmids":["11029660"],"is_preprint":false},{"year":2011,"finding":"The RanBP2-type zinc finger 1 (Zf1) of RBM5 adopts a defined solution structure; NMR screening identified a small molecule (compound 1) that binds within the RNA binding pocket of the Zf1 domain, competing with RNA binding.","method":"NMR solution structure, NMR fragment screening, competitive binding assay","journal":"Chembiochem : a European journal of chemical biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — NMR structure with binding competition demonstrated, single lab","pmids":["22162216"],"is_preprint":false},{"year":2020,"finding":"The RanBP2-type zinc finger 1 (Zf1) of RBM5 harbors a non-canonical cysteine that kinetically destabilizes the zinc coordination; mutation of this cysteine establishes high-affinity zinc coordination, indicating that the native Zf1 has intrinsically dynamic metal exchange kinetics.","method":"NMR structure/dynamics analysis, metal-exchange kinetics, site-directed mutagenesis","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — NMR and mutagenesis in a single lab, establishes structural dynamics mechanism","pmids":["32450081"],"is_preprint":false},{"year":2022,"finding":"The L. monocytogenes virulence factor InlP translocates into human cell nuclei, interacts directly with RBM5 (identified by yeast two-hybrid, immunoprecipitation, and pull-down), inhibits RBM5-induced cell death, and stimulates formation of RBM5-containing nuclear granules where the SC35 speckle protein redistributes.","method":"Yeast two-hybrid, co-immunoprecipitation, pull-down, ectopic expression, cell death assay, immunofluorescence","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP/pull-down plus functional cell death assay and localization imaging, single lab","pmids":["36535993"],"is_preprint":false},{"year":2024,"finding":"In AML cells, RBM5 functions through a noncanonical transcriptional regulation mechanism (dependent on DNA-binding domains) rather than RNA splicing to maintain HOXA9 transcription; acute degradation of RBM5 via an auxin-inducible degron immediately reduces HOXA9 transcription; ectopic HOXA9 rescues impaired proliferation upon RBM5 loss.","method":"Genome-wide CRISPR/Cas9 screen, domain CRISPR screening, shRNA knockdown, auxin-inducible protein degradation, epistasis rescue experiments","journal":"Genome biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — orthogonal genetic methods (CRISPR, degron, epistasis) but noncanonical mechanism with limited biochemical characterization of direct DNA binding","pmids":["38216972"],"is_preprint":false},{"year":2024,"finding":"RBM5 binds directly to PTEN mRNA and stabilizes its expression; RBM5 overexpression increases PTEN protein, decreases PI3K and p-AKT, and suppresses glycolysis, proliferation, and metastasis of CRC cells; PTEN knockdown partially reverses RBM5-mediated suppression.","method":"RNA immunoprecipitation (RIP), half-life RT-PCR, dual-luciferase reporter assay, Western blotting, xenograft model, siRNA epistasis","journal":"World journal of gastrointestinal oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP assay plus mRNA stability and epistasis experiments, single lab","pmids":["39072172"],"is_preprint":false},{"year":2024,"finding":"RBM5 interacts with the m6A demethylase FTO in normal (cisplatin-sensitive) NSCLC cells but not in cisplatin-resistant cells; loss of RBM5 causes FTO to aberrantly methylate 5'-UTRs of resistance-associated transcripts, silencing their translation.","method":"RIP-seq, co-immunoprecipitation, translational activity assays, in vivo/in vitro m6A methylation analysis","journal":"Journal of cellular physiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — RIP-seq interaction data plus co-IP in single lab; mechanistic detail on RBM5-FTO interaction is limited in the abstract","pmids":["38742685"],"is_preprint":false},{"year":2024,"finding":"CHIP (E3 ubiquitin ligase) mediates ubiquitination and degradation of non-phosphorylated eIF2α; this promotes transcriptional upregulation of RBM5 (via ATF), and elevated RBM5 suppresses A549 cell proliferation and migration; this places RBM5 downstream of the PERK-eIF2α pathway under ER stress.","method":"In vitro ubiquitination assay, co-immunoprecipitation, reporter assay, siRNA knockdown, Western blotting","journal":"The Journal of biological chemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway epistasis established but RBM5 is downstream endpoint with limited direct mechanistic characterization, single lab","pmids":["38272235"],"is_preprint":false},{"year":2025,"finding":"RBM5 recruits lncRNA MGC32805 and together they promote exclusion of FAS exon 6, decreasing apoptotic mFAS and increasing anti-apoptotic ΔFAS isoforms; RBM5 ZnF-C2H2 residues Leu650 and Arg681 recognize a 'GUACG' motif in MGC32805; His665 and Leu668 of RBM5 bind the FAS exon 6 adjacent element 'GAACAAA'; MGC32805 blocks the PRPF19 binding site (Lys645) on RBM5, preventing its ubiquitination and degradation.","method":"Mutagenesis, RNA pull-down, co-immunoprecipitation, minigene splicing assay, xenograft model, ubiquitination assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-level mutagenesis with multiple interaction assays and functional splicing readouts, single lab","pmids":["40571778"],"is_preprint":false},{"year":2023,"finding":"RBM5 binds directly to CARM1 mRNA and participates in alternative splicing-coupled nonsense-mediated decay (AS-NMD) to downregulate CARM1 expression in bladder cancer cells; reduced RBM5 leads to CARM1 upregulation, which activates the PRKACA/GSK3β/Wnt-β-catenin axis.","method":"RNA immunoprecipitation, AS-NMD reporter assays, Western blotting, pathway epistasis","journal":"Cancers","confidence":"Low","confidence_rationale":"Tier 3 / Weak — RIP assay with pathway readouts, single lab, limited mechanistic resolution of direct AS-NMD event in abstract","pmids":["38201567"],"is_preprint":false}],"current_model":"RBM5 is a multi-domain nuclear RNA-binding protein (containing RRM1, ZnF1/RanBP2-type, RRM2, G-patch, OCRE, and ZnF-C2H2 domains) that functions primarily as a splicing regulator: it associates with the U2 snRNP at intron branch sites transcriptome-wide and represses alternative exon inclusion; it regulates splice-site pairing of Fas/CD95 pre-mRNA (via OCRE-mediated contacts with spliceosomal SmN/B/B' proteins), promotes proapoptotic caspase-2 isoform production (by binding a U/C-rich intronic element and competing with splicing repressors), and antagonizes RBM10 in controlling NUMB alternative splicing to suppress cancer cell proliferation; its G-patch domain stimulates the helicase activity of the spliceosome component DHX15; it also stabilizes p53 post-transcriptionally and modulates target mRNA stability, and RBM5 itself is subject to regulation by phosphorylation, by RBM10-driven AS-NMD, and by ubiquitination via PRPF19."},"narrative":{"mechanistic_narrative":"RBM5 is a multi-domain nuclear RNA-binding protein that functions as a sequence-specific regulator of alternative pre-mRNA splicing and, through it, controls apoptosis and cell proliferation [PMID:18851835, PMID:38537639, PMID:37790489, PMID:24332178]. Transcriptome-wide, RBM5 (together with RBM10) is engaged with the U2 snRNP at intron branch sites via a conserved zinc-finger-containing peptide, and this association is required for its repression of many alternative exons [PMID:38537639, PMID:37790489]. Its modular architecture underlies this activity: a cooperative RRM1–ZnF1 module sandwiches target RNA and recognizes a GG dinucleotide, with RRM2 contributing additional CU/GA-rich RNA contacts, while the OCRE domain adopts a unique β-sheet fold that binds the proline-rich tails of spliceosomal SmN/B/B' proteins to govern splice-site pairing of FAS/CD95 pre-mRNA [PMID:27894420, PMID:37454201, PMID:22839758]. RBM5 acts mechanistically at the spliceosome by inhibiting the transition from prespliceosomal to mature complexes around the regulated exon and by competing with U2AF65 at weak 3' splice sites [PMID:18851835, PMID:23017209], and its G-patch domain directly stimulates the helicase activity of DHX15 [PMID:22569250]. Through these activities it promotes the proapoptotic caspase-2L isoform by binding a U/C-rich element upstream of the In100 repressor [PMID:18840686], regulates FAS exon 6 inclusion (in cooperation with lncRNA MGC32805 and antagonized by RBM10) [PMID:40571778], and antagonizes RBM10 in NUMB splicing to suppress cancer cell proliferation and tumor growth [PMID:24332178]. Beyond splicing, RBM5 stabilizes p53 protein post-transcriptionally and induces G1 arrest and mitochondrial apoptosis acting upstream of Bax [PMID:20309933, PMID:16585163]. RBM5 expression is itself cross-regulated by RBM10-driven AS-NMD and its protein activity is controlled by phosphorylation and by PRPF19-mediated ubiquitination [PMID:28586478, PMID:16927403, PMID:40571778]. In vivo, a missense mutation in RRM2 disrupts RNA binding and causes spermatid differentiation arrest and male sterility in mouse [PMID:23935508].","teleology":[{"year":2000,"claim":"Establishing RBM5 as a nuclear RNA-binding protein with growth-suppressive activity set the foundation for its role as a tumor suppressor acting on RNA.","evidence":"Epitope-tag localization, in vitro poly(G) RNA binding, and ectopic expression growth assays in fibrosarcoma cells","pmids":["11029660"],"confidence":"Medium","gaps":["RNA targets undefined","molecular mechanism of growth suppression not established","splicing role not yet identified"]},{"year":2006,"claim":"Defining the apoptotic output of RBM5 placed it functionally upstream of the mitochondrial cell-death pathway, explaining its tumor-suppressor phenotype.","evidence":"Stable overexpression in A549 cells with caspase/cytochrome c readouts and Bax siRNA epistasis","pmids":["16585163"],"confidence":"Medium","gaps":["direct molecular targets linking RBM5 to Bax not identified","single cell line","does not distinguish splicing from non-splicing mechanism"]},{"year":2008,"claim":"Two parallel studies converted RBM5 from a generic RNA-binder into a sequence-specific splicing regulator, showing it controls apoptotic isoform choice of FAS and caspase-2.","evidence":"In vitro spliceosome assembly assays with OCRE mutagenesis (FAS) and yeast RNA interaction plus in vitro/cellular splicing assays with binding-site mutagenesis (caspase-2)","pmids":["18851835","18840686"],"confidence":"High","gaps":["protein partners mediating the spliceosomal arrest not fully resolved","genome-wide target spectrum unknown"]},{"year":2010,"claim":"Connecting RBM5 to post-transcriptional p53 stabilization expanded its tumor-suppressor activity beyond splicing into protein-level control of a master regulator.","evidence":"Reporter assays, shRNA knockdown and overexpression with p53 target gene readouts after DNA damage","pmids":["20309933"],"confidence":"Medium","gaps":["direct mechanism of p53 protein stabilization unknown","no direct binding partner identified"]},{"year":2012,"claim":"Structural and biochemical dissection assigned discrete functions to RBM5 domains: RRM2 RNA recognition, Zf1 RNA binding/druggability, and G-patch-dependent stimulation of the DHX15 helicase within the spliceosome.","evidence":"NMR solution structures of RRM2 and Zf1, fragment screening, co-IP/pull-down with DHX15 and PRP19, and in vitro helicase assays with domain mutagenesis","pmids":["22839758","22162216","22569250"],"confidence":"High","gaps":["how DHX15 stimulation maps onto specific splicing events not resolved","Zf1 ligand has no cellular validation"]},{"year":2012,"claim":"Identifying U2AF65 competition at weak 3' splice sites provided a concrete biochemical mechanism for RBM5-mediated exon skipping.","evidence":"Minigene splicing in HeLa and in vitro U2AF65 competition assays on AID pre-mRNA","pmids":["23017209"],"confidence":"High","gaps":["generality across endogenous targets not shown in this study","structural basis of competition not defined"]},{"year":2013,"claim":"RBM5 was shown to govern proliferation through splicing of the Notch regulator NUMB, antagonizing RBM10, and an in vivo mutation established its physiological splicing role in spermatogenesis.","evidence":"Minigene/RNA-seq/knockdown plus colony-formation and xenograft assays (NUMB); mouse genetic R263P RRM2 mutant with RNA pull-down and splicing phenotyping (testis)","pmids":["24332178","23935508"],"confidence":"High","gaps":["positional rules distinguishing RBM5 from RBM10 not fully mechanistic","in vivo target set incompletely defined"]},{"year":2016,"claim":"Solving the OCRE–SmN complex structure revealed how RBM5 physically contacts the spliceosome to dictate FAS splice-site pairing.","evidence":"NMR structure of OCRE–SmN peptide complex with aromatic-residue mutagenesis and functional splicing assays","pmids":["27894420"],"confidence":"High","gaps":["how Sm contact translates into the kinetic spliceosomal block not fully resolved"]},{"year":2017,"claim":"Reciprocal cross-regulation between RBM5 and RBM10 was established, with RBM10 triggering AS-NMD of RBM5 and RBM5 binding specific RBM10 variants, defining a feedback circuit between the paralogs.","evidence":"Computational prediction with RT-PCR/NMD reporters (RBM10→RBM5) and RIP-seq plus Western blot (RBM5→RBM10)","pmids":["28586478","28662214"],"confidence":"Medium","gaps":["physiological contexts of the circuit not defined","single-lab studies"]},{"year":2018,"claim":"Genetic epistasis in C. elegans confirmed a conserved functional relationship between RBM5 and U2AF, reinforcing the U2AF-competition model at weak 3' splice sites.","evidence":"rbm-5/uaf-1 genetic suppression screen with transcriptome analysis and neuronal tissue-specific rescue","pmids":["30295127"],"confidence":"Medium","gaps":["gene-specific suppress-vs-enhance behavior not mechanistically explained","ortholog system"]},{"year":2024,"claim":"Native spliceosome isolation placed RBM5/RBM10 directly on the U2 snRNP at branch sites transcriptome-wide, unifying prior single-target studies into a genome-scale repression mechanism.","evidence":"Chromatin-associated spliceosome isolation, branch-site RNA-seq, and conserved-peptide deletion mutagenesis","pmids":["38537639","37790489"],"confidence":"High","gaps":["how branch-site engagement selects which exons are repressed not fully resolved"]},{"year":2024,"claim":"Multiple studies extended RBM5 into non-splicing and disease-context roles—mRNA stabilization (PTEN), m6A regulation via FTO, ER-stress pathway output, and a noncanonical DNA-binding-dependent maintenance of HOXA9 transcription in AML.","evidence":"RIP/half-life/luciferase and xenograft (PTEN); RIP-seq/co-IP and methylation assays (FTO); ubiquitination/epistasis (eIF2α); CRISPR/degron/domain screens (HOXA9)","pmids":["39072172","38742685","38272235","38216972"],"confidence":"Medium","gaps":["direct DNA binding by RBM5 not biochemically demonstrated","FTO and eIF2α links are low-confidence single-lab findings","relationship between splicing and these noncanonical roles unclear"]},{"year":2025,"claim":"A detailed domain-level model showed how a lncRNA cofactor and PRPF19 jointly tune RBM5's FAS-splicing activity and its own stability.","evidence":"Domain mutagenesis mapping ZnF-C2H2 and other residues, RNA pull-down, co-IP, minigene splicing, ubiquitination assays, and xenograft (MGC32805/FAS/PRPF19)","pmids":["40571778"],"confidence":"Medium","gaps":["generality of lncRNA-assisted recruitment to other targets unknown","single-lab study"]},{"year":null,"claim":"How RBM5 partitions between its canonical U2 snRNP/branch-site splicing function and its reported noncanonical roles (DNA-binding transcriptional control, mRNA stability, m6A regulation) remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["no biochemical demonstration of direct DNA binding","no unified model integrating splicing and non-splicing activities","structural basis of full-length RNA target selection in cells undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[3,4,6,17]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[17,8]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[6,20]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,6]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,14]}],"complexes":["U2 snRNP"],"partners":["DHX15","PRPF19","RBM10","SNRPB","U2AF2","FTO"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P52756","full_name":"RNA-binding protein 5","aliases":["Protein G15","Putative tumor suppressor LUCA15","RNA-binding motif protein 5","Renal carcinoma antigen NY-REN-9"],"length_aa":815,"mass_kda":92.2,"function":"Component of the spliceosome A complex. Binds to ssRNA containing the consensus sequence 5'-AGGUAA-3' (PubMed:21256132). Regulates alternative splicing of a number of mRNAs. May modulate splice site pairing after recruitment of the U1 and U2 snRNPs to the 5' and 3' splice sites of the intron. May both positively and negatively regulate apoptosis by regulating the alternative splicing of several genes involved in this process, including FAS and CASP2/caspase-2. In the case of FAS, promotes exclusion of exon 6 thereby producing a soluble form of FAS that inhibits apoptosis. In the case of CASP2/caspase-2, promotes exclusion of exon 9 thereby producing a catalytically active form of CASP2/Caspase-2 that induces apoptosis","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P52756/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RBM5","classification":"Not 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Animal","url":"https://pubmed.ncbi.nlm.nih.gov/26659391","citation_count":5,"is_preprint":false},{"pmid":"32450081","id":"PMC_32450081","title":"Conformational Dynamics from Ambiguous Zinc Coordination in the RanBP2-Type Zinc Finger of RBM5.","date":"2020","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/32450081","citation_count":5,"is_preprint":false},{"pmid":"33469971","id":"PMC_33469971","title":"Domain-wise differentiation of Mycobacterium tuberculosis H37 Rv hypothetical proteins: A roadmap to discover bacterial survival potentials.","date":"2021","source":"Biotechnology and applied biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33469971","citation_count":5,"is_preprint":false},{"pmid":"39072172","id":"PMC_39072172","title":"RBM5 suppresses proliferation, metastasis and glycolysis of colorectal cancer cells via stabilizing phosphatase and tensin homolog mRNA.","date":"2024","source":"World journal of gastrointestinal oncology","url":"https://pubmed.ncbi.nlm.nih.gov/39072172","citation_count":4,"is_preprint":false},{"pmid":"22882865","id":"PMC_22882865","title":"Downregulating activated epidermal growth factor receptor has no effect on RBM5 expression.","date":"2012","source":"Chinese medical journal","url":"https://pubmed.ncbi.nlm.nih.gov/22882865","citation_count":4,"is_preprint":false},{"pmid":"40522493","id":"PMC_40522493","title":"Plasma expression of antisense LncRNAs RBM5-AS1, VPS9D1-AS1 and STEAP3-AS1 as novel biomarkers for colorectal cancer diagnosis.","date":"2025","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/40522493","citation_count":4,"is_preprint":false},{"pmid":"38272235","id":"PMC_38272235","title":"CHIP suppresses the proliferation and migration of A549 cells by mediating the ubiquitination of eIF2α and upregulation of tumor suppressor RBM5.","date":"2024","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38272235","citation_count":4,"is_preprint":false},{"pmid":"18038152","id":"PMC_18038152","title":"Promoter methylation study of the H37/RBM5 tumor suppressor gene from the 3p21.3 human lung cancer tumor suppressor locus.","date":"2007","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18038152","citation_count":4,"is_preprint":false},{"pmid":"31966706","id":"PMC_31966706","title":"Association of RBM5 rs2013208 SNP with serum lipid levels in two Chinese ethnic groups.","date":"2017","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31966706","citation_count":4,"is_preprint":false},{"pmid":"32691412","id":"PMC_32691412","title":"Comprehensive analysis of GTP cyclohydrolase I activity in Mycobacterium tuberculosis H37 Rv via in silico studies.","date":"2020","source":"Biotechnology and applied biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32691412","citation_count":4,"is_preprint":false},{"pmid":"37848418","id":"PMC_37848418","title":"Neuronal RBM5 modulates cell signaling responses to traumatic and hypoxic-ischemic injury in a sex-dependent manner.","date":"2023","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/37848418","citation_count":3,"is_preprint":false},{"pmid":"37790489","id":"PMC_37790489","title":"The apoptotic splicing regulators RBM5 and RBM10 are subunits of the U2 snRNP engaged with intron branch sites on chromatin.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37790489","citation_count":3,"is_preprint":false},{"pmid":"32975902","id":"PMC_32975902","title":"OCRE Domains of Splicing Factors RBM5 and RBM10: Tyrosine Ring-Flip Frequencies Determined by Integrated Use of 1 H NMR Spectroscopy and Molecular Dynamics Simulations.","date":"2020","source":"Chembiochem : a European journal of chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/32975902","citation_count":3,"is_preprint":false},{"pmid":"31957826","id":"PMC_31957826","title":"LncRNA LINP1 promotes proliferation and inhibits apoptosis of gastric cancer cells by repressing RBM5.","date":"2020","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31957826","citation_count":3,"is_preprint":false},{"pmid":"40571778","id":"PMC_40571778","title":"RBM5 recruiting MGC32805 in a sandwich mode and inducing ΔFAS neoantigen and triggering FAS properties switch: implication in colorectal cancer.","date":"2025","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/40571778","citation_count":2,"is_preprint":false},{"pmid":"38619681","id":"PMC_38619681","title":"ZNF554 Inhibits Endometrial Cancer Progression via Regulating RBM5 and Inactivating WNT/β-Catenin Signaling Pathway.","date":"2024","source":"Current medical science","url":"https://pubmed.ncbi.nlm.nih.gov/38619681","citation_count":2,"is_preprint":false},{"pmid":"38031049","id":"PMC_38031049","title":"Elucidating the role of RBM5 in osteoclastogenesis: a novel potential therapeutic target for osteoporosis.","date":"2023","source":"BMC musculoskeletal disorders","url":"https://pubmed.ncbi.nlm.nih.gov/38031049","citation_count":2,"is_preprint":false},{"pmid":"38402723","id":"PMC_38402723","title":"PEI, a new transfection method, augments the inhibitory effect of RBM5 on prostate cancer.","date":"2024","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/38402723","citation_count":2,"is_preprint":false},{"pmid":"25355266","id":"PMC_25355266","title":"[Construction of RBM5 vector, establishment of stably transfected A549 cell line and preliminary research on the function of RBM5 gene].","date":"2014","source":"Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/25355266","citation_count":2,"is_preprint":false},{"pmid":"36536516","id":"PMC_36536516","title":"RNA-binding protein PUM2 promotes T-cell acute lymphoblastic leukemia via competitively binding to RBM5 3'UTR with miR-28-5p.","date":"2023","source":"European journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/36536516","citation_count":1,"is_preprint":false},{"pmid":"39161132","id":"PMC_39161132","title":"Circular RNA LDLRAD3 promotes gastric cancer progression by upregulating COL4A5 through sponging miR-h37.","date":"2024","source":"Journal of the Chinese Medical Association : JCMA","url":"https://pubmed.ncbi.nlm.nih.gov/39161132","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50406,"output_tokens":6404,"usd":0.123639,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15220,"output_tokens":4381,"usd":0.092813,"stage2_stop_reason":"end_turn"},"total_usd":0.216452,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"RBM5 regulates alternative splicing of Fas pre-mRNA by inhibiting the transition between prespliceosomal complexes assembled around exon 6 to mature spliceosomes assembled on flanking introns, promoting sequence-specific pairing of distal splice sites after exon definition rather than affecting early splice site recognition events.\",\n      \"method\": \"Biochemical spliceosome assembly assays, RNA-protein complex analysis, mutagenesis of OCRE domain\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 / Strong — in vitro spliceosomal complex analysis with mutagenesis, mechanistically distinct model established with multiple orthogonal methods\",\n      \"pmids\": [\"18851835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"RBM5 binds to a U/C-rich sequence immediately upstream of the In100 splicing repressor element in caspase-2 pre-mRNA, and this binding enhances production of the proapoptotic Casp-2L isoform; mutagenesis of the binding site disrupts the ratio of proapoptotic/antiapoptotic isoforms.\",\n      \"method\": \"Yeast RNA-protein interaction assay, in vitro splicing assay, transfection in cells, mutagenesis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro splicing assay plus mutagenesis plus cellular validation in a single study\",\n      \"pmids\": [\"18840686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The RBM5 OCRE domain adopts a unique β-sheet fold and directly binds the proline-rich C-terminal tail of spliceosomal SmN/B/B' proteins; NMR structure of the OCRE–SmN peptide complex reveals specific recognition of poly-proline helical motifs; mutation of conserved aromatic residues in OCRE impairs Sm protein binding in vitro and compromises RBM5-mediated FAS/CD95 alternative splicing regulation.\",\n      \"method\": \"NMR structure determination, biochemical binding assays, mutagenesis, functional splicing assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure with functional mutagenesis and in vitro binding validation, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"27894420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Crystal/NMR structure of RBM5 RRM1-ZnF1-RRM2 domains in complex with RNA shows that RRM1-ZnF1 cooperate as a single structural module to sandwich target RNA and specifically recognize a GG dinucleotide in a non-canonical fashion; RRM2 is connected by a flexible linker but participates in RNA binding, adopting a closed architecture upon RNA engagement.\",\n      \"method\": \"X-ray crystallography, NMR, biochemical RNA binding assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus NMR with functional RNA binding validation, multiple orthogonal structural and biochemical methods\",\n      \"pmids\": [\"37454201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RBM5 solution structure of the second RRM domain (RRM2) reveals it can preferentially bind both CU-rich and GA-rich RNA sequences with affinity in the 10^-5 molar range; both N- and C-terminal regions flanking the β-sheet surface participate in recognition.\",\n      \"method\": \"NMR solution structure determination, RNA binding assays\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with binding characterization, single lab but rigorous structural method\",\n      \"pmids\": [\"22839758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RBM5 directly interacts with the DExD/H-box helicase DHX15 and with PRP19 (two spliceosome components); the G-patch domain of RBM5 is required for DHX15 interaction; RBM5 stimulates DHX15 helicase activity in vitro in a G-patch domain-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, pull-down assays, in vitro helicase activity assay, domain mutagenesis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro helicase activity reconstitution with domain mutagenesis establishing mechanistic requirements, single lab\",\n      \"pmids\": [\"22569250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RBM5 and RBM10 are subunits of the U2 snRNP engaged with intron branch sites across the transcriptome on chromatin; deletion of a conserved RBM5/RBM10 peptide containing a zinc finger motif disrupts U2 snRNP interaction and renders RBM5 inactive for repression of many alternative exons.\",\n      \"method\": \"Chromatin-associated spliceosome isolation, RNA sequencing of branch-site protected fragments, domain deletion mutagenesis, transcriptome-wide analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — isolation of native spliceosomal complexes combined with mutagenesis and transcriptome-wide functional validation; peer-reviewed and consistent with preprint (PMID:37790489)\",\n      \"pmids\": [\"38537639\", \"37790489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RBM5, RBM6, and RBM10 antagonistically regulate alternative splicing of the Notch pathway regulator NUMB pre-mRNA; RBM5/RBM6 and RBM10 show distinct positional effects on splicing; modulation of NUMB splicing recapitulates the effects of these factors on cancer cell colony formation and xenograft tumor growth.\",\n      \"method\": \"Minigene splicing assays, RNA-seq, siRNA knockdown, colony formation, xenograft assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RNA-seq, minigene, functional phenotypic assays) with epistasis demonstrated, replicated across multiple cell systems\",\n      \"pmids\": [\"24332178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In mouse testes, RBM5 localizes to spermatogonia, spermatocytes, and round spermatids; a missense mutation R263P in the second RRM of RBM5 compromises mRNA binding and causes defective pre-mRNA splicing of target transcripts in round spermatids, leading to spermatid differentiation arrest and male sterility.\",\n      \"method\": \"Genetic screen, RNA pull-down with microarrays, immunofluorescence/localization, RT-PCR splicing assays, molecular modelling\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model with RRM mutagenesis, RNA target identification by pull-down, and splicing phenotype characterization\",\n      \"pmids\": [\"23935508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RBM5 promotes AID exon 4 skipping by competing with U2AF65 binding to the polypyrimidine tract at the 3' splice site of intron 3; this competition was demonstrated in vitro; a weak 3' splice site is required for the inhibitory effect.\",\n      \"method\": \"Minigene splicing assay in HeLa cells, in vitro competition assay for U2AF65 binding\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of competitive U2AF65 displacement plus minigene functional assay, single lab\",\n      \"pmids\": [\"23017209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RBM10 promotes alternative splicing-coupled nonsense-mediated decay (AS-NMD) of RBM5 mRNA by promoting skipping of RBM5 exon 6 or exon 16; this cross-regulation was validated computationally and experimentally, establishing a mechanism for RBM10-mediated cross-regulation of RBM5 expression.\",\n      \"method\": \"Computational prediction, RT-PCR splicing validation, NMD reporter assays, overexpression and knockdown experiments\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — combined computational and experimental validation, single lab, two orthogonal methods\",\n      \"pmids\": [\"28586478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RBM5 post-transcriptionally regulates RBM10 expression via direct interaction with specific RBM10 splice variants, as demonstrated by RNA immunoprecipitation followed by next-generation sequencing (RIP-Seq) and Western blotting.\",\n      \"method\": \"RIP-Seq, Western blotting, stable cell line with endogenous RBM5 deletion\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP-seq provides genome-wide interaction data, confirmed by Western blot, single lab\",\n      \"pmids\": [\"28662214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In C. elegans, rbm-5 mutations suppress the temperature-sensitive lethality of a U2AF large subunit (uaf-1) mutant; rbm-5 mutations can suppress or enhance altered splicing of uaf-1-dependent genes in a gene-specific manner, with a preference at weak 3' splice sites; neuronal expression of rbm-5 was sufficient to rescue the suppression.\",\n      \"method\": \"Genetic epistasis screen, transcriptome analysis, tissue-specific rescue experiments\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in C. elegans with transcriptome-wide splicing analysis, single lab\",\n      \"pmids\": [\"30295127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RBM5 augments p53 transcriptional activity: RBM5 overexpression increases mRNA and protein levels of endogenous p53 target genes, and shRNA knockdown decreases them; RBM5 affects p53 protein but not mRNA levels after DNA damage, suggesting a post-transcriptional mechanism of p53 stabilization.\",\n      \"method\": \"Reporter gene assays, shRNA knockdown, Western blotting, RT-PCR, overexpression studies\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assays plus KD/OE with specific molecular readouts, single lab, two orthogonal methods\",\n      \"pmids\": [\"20309933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Stable overexpression of RBM5/H37 in A549 lung cancer cells induces G1 cell cycle arrest (decreased cyclin A and phospho-RB) and apoptosis via the mitochondrial pathway (increased Bax, cytochrome c release, caspase-9 and caspase-3 activation); Bax siRNA knockdown reduces RBM5-mediated apoptosis, placing Bax functionally downstream of RBM5.\",\n      \"method\": \"Stable transfection, Western blotting, mitochondrial membrane potential assay, cytochrome c fractionation, caspase activity assays, siRNA epistasis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via Bax siRNA plus multiple apoptosis pathway readouts, single lab\",\n      \"pmids\": [\"16585163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RBM5 is a phosphoprotein; phosphatase treatment decreases its apparent molecular mass; phosphorylation changes reversibly with growth factor addition/deprivation; mutagenesis and immunoprecipitation indicate serine 69 is phosphorylated under normal growth conditions (not by Akt kinase), with no evidence of phosphotyrosines.\",\n      \"method\": \"Phosphatase treatment (CIP), immunoprecipitation, site-directed mutagenesis, Western blotting\",\n      \"journal\": \"Cell biochemistry and function\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphatase treatment plus mutagenesis of specific residue, single lab\",\n      \"pmids\": [\"16927403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The two RRM domains (aa 98-178 and 231-315) of RBM5 are required for RNA binding; a mutant lacking both RRMs (RBM5-ΔRRM) fails to bind RNA, shows compromised caspase-2 alternative splicing activity, and lacks cell proliferation inhibition and apoptosis induction in A549 cells.\",\n      \"method\": \"Domain deletion mutagenesis, RNA binding assays, splicing assays, cell proliferation and apoptosis assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain deletion mutagenesis with functional and RNA-binding readouts, single lab\",\n      \"pmids\": [\"24486491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"LUCA15/RBM5 protein localizes to the nucleus and binds poly(G) RNA homopolymers in vitro; ectopic expression of LUCA15 in HT1080 fibrosarcoma cells suppresses cell growth; LUCA15 mRNA is downregulated by constitutively active Ras(G12V).\",\n      \"method\": \"Epitope-tag localization, in vitro RNA binding assay, ectopic expression cell growth assay\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization and in vitro binding plus functional growth suppression assay, single lab\",\n      \"pmids\": [\"11029660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The RanBP2-type zinc finger 1 (Zf1) of RBM5 adopts a defined solution structure; NMR screening identified a small molecule (compound 1) that binds within the RNA binding pocket of the Zf1 domain, competing with RNA binding.\",\n      \"method\": \"NMR solution structure, NMR fragment screening, competitive binding assay\",\n      \"journal\": \"Chembiochem : a European journal of chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with binding competition demonstrated, single lab\",\n      \"pmids\": [\"22162216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The RanBP2-type zinc finger 1 (Zf1) of RBM5 harbors a non-canonical cysteine that kinetically destabilizes the zinc coordination; mutation of this cysteine establishes high-affinity zinc coordination, indicating that the native Zf1 has intrinsically dynamic metal exchange kinetics.\",\n      \"method\": \"NMR structure/dynamics analysis, metal-exchange kinetics, site-directed mutagenesis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR and mutagenesis in a single lab, establishes structural dynamics mechanism\",\n      \"pmids\": [\"32450081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The L. monocytogenes virulence factor InlP translocates into human cell nuclei, interacts directly with RBM5 (identified by yeast two-hybrid, immunoprecipitation, and pull-down), inhibits RBM5-induced cell death, and stimulates formation of RBM5-containing nuclear granules where the SC35 speckle protein redistributes.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, pull-down, ectopic expression, cell death assay, immunofluorescence\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP/pull-down plus functional cell death assay and localization imaging, single lab\",\n      \"pmids\": [\"36535993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In AML cells, RBM5 functions through a noncanonical transcriptional regulation mechanism (dependent on DNA-binding domains) rather than RNA splicing to maintain HOXA9 transcription; acute degradation of RBM5 via an auxin-inducible degron immediately reduces HOXA9 transcription; ectopic HOXA9 rescues impaired proliferation upon RBM5 loss.\",\n      \"method\": \"Genome-wide CRISPR/Cas9 screen, domain CRISPR screening, shRNA knockdown, auxin-inducible protein degradation, epistasis rescue experiments\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — orthogonal genetic methods (CRISPR, degron, epistasis) but noncanonical mechanism with limited biochemical characterization of direct DNA binding\",\n      \"pmids\": [\"38216972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RBM5 binds directly to PTEN mRNA and stabilizes its expression; RBM5 overexpression increases PTEN protein, decreases PI3K and p-AKT, and suppresses glycolysis, proliferation, and metastasis of CRC cells; PTEN knockdown partially reverses RBM5-mediated suppression.\",\n      \"method\": \"RNA immunoprecipitation (RIP), half-life RT-PCR, dual-luciferase reporter assay, Western blotting, xenograft model, siRNA epistasis\",\n      \"journal\": \"World journal of gastrointestinal oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP assay plus mRNA stability and epistasis experiments, single lab\",\n      \"pmids\": [\"39072172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RBM5 interacts with the m6A demethylase FTO in normal (cisplatin-sensitive) NSCLC cells but not in cisplatin-resistant cells; loss of RBM5 causes FTO to aberrantly methylate 5'-UTRs of resistance-associated transcripts, silencing their translation.\",\n      \"method\": \"RIP-seq, co-immunoprecipitation, translational activity assays, in vivo/in vitro m6A methylation analysis\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RIP-seq interaction data plus co-IP in single lab; mechanistic detail on RBM5-FTO interaction is limited in the abstract\",\n      \"pmids\": [\"38742685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CHIP (E3 ubiquitin ligase) mediates ubiquitination and degradation of non-phosphorylated eIF2α; this promotes transcriptional upregulation of RBM5 (via ATF), and elevated RBM5 suppresses A549 cell proliferation and migration; this places RBM5 downstream of the PERK-eIF2α pathway under ER stress.\",\n      \"method\": \"In vitro ubiquitination assay, co-immunoprecipitation, reporter assay, siRNA knockdown, Western blotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway epistasis established but RBM5 is downstream endpoint with limited direct mechanistic characterization, single lab\",\n      \"pmids\": [\"38272235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBM5 recruits lncRNA MGC32805 and together they promote exclusion of FAS exon 6, decreasing apoptotic mFAS and increasing anti-apoptotic ΔFAS isoforms; RBM5 ZnF-C2H2 residues Leu650 and Arg681 recognize a 'GUACG' motif in MGC32805; His665 and Leu668 of RBM5 bind the FAS exon 6 adjacent element 'GAACAAA'; MGC32805 blocks the PRPF19 binding site (Lys645) on RBM5, preventing its ubiquitination and degradation.\",\n      \"method\": \"Mutagenesis, RNA pull-down, co-immunoprecipitation, minigene splicing assay, xenograft model, ubiquitination assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-level mutagenesis with multiple interaction assays and functional splicing readouts, single lab\",\n      \"pmids\": [\"40571778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RBM5 binds directly to CARM1 mRNA and participates in alternative splicing-coupled nonsense-mediated decay (AS-NMD) to downregulate CARM1 expression in bladder cancer cells; reduced RBM5 leads to CARM1 upregulation, which activates the PRKACA/GSK3β/Wnt-β-catenin axis.\",\n      \"method\": \"RNA immunoprecipitation, AS-NMD reporter assays, Western blotting, pathway epistasis\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RIP assay with pathway readouts, single lab, limited mechanistic resolution of direct AS-NMD event in abstract\",\n      \"pmids\": [\"38201567\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RBM5 is a multi-domain nuclear RNA-binding protein (containing RRM1, ZnF1/RanBP2-type, RRM2, G-patch, OCRE, and ZnF-C2H2 domains) that functions primarily as a splicing regulator: it associates with the U2 snRNP at intron branch sites transcriptome-wide and represses alternative exon inclusion; it regulates splice-site pairing of Fas/CD95 pre-mRNA (via OCRE-mediated contacts with spliceosomal SmN/B/B' proteins), promotes proapoptotic caspase-2 isoform production (by binding a U/C-rich intronic element and competing with splicing repressors), and antagonizes RBM10 in controlling NUMB alternative splicing to suppress cancer cell proliferation; its G-patch domain stimulates the helicase activity of the spliceosome component DHX15; it also stabilizes p53 post-transcriptionally and modulates target mRNA stability, and RBM5 itself is subject to regulation by phosphorylation, by RBM10-driven AS-NMD, and by ubiquitination via PRPF19.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RBM5 is a multi-domain nuclear RNA-binding protein that functions as a sequence-specific regulator of alternative pre-mRNA splicing and, through it, controls apoptosis and cell proliferation [#0, #6, #7]. Transcriptome-wide, RBM5 (together with RBM10) is engaged with the U2 snRNP at intron branch sites via a conserved zinc-finger-containing peptide, and this association is required for its repression of many alternative exons [#6]. Its modular architecture underlies this activity: a cooperative RRM1–ZnF1 module sandwiches target RNA and recognizes a GG dinucleotide, with RRM2 contributing additional CU/GA-rich RNA contacts, while the OCRE domain adopts a unique β-sheet fold that binds the proline-rich tails of spliceosomal SmN/B/B' proteins to govern splice-site pairing of FAS/CD95 pre-mRNA [#2, #3, #4]. RBM5 acts mechanistically at the spliceosome by inhibiting the transition from prespliceosomal to mature complexes around the regulated exon and by competing with U2AF65 at weak 3' splice sites [#0, #9], and its G-patch domain directly stimulates the helicase activity of DHX15 [#5]. Through these activities it promotes the proapoptotic caspase-2L isoform by binding a U/C-rich element upstream of the In100 repressor [#1], regulates FAS exon 6 inclusion (in cooperation with lncRNA MGC32805 and antagonized by RBM10) [#25], and antagonizes RBM10 in NUMB splicing to suppress cancer cell proliferation and tumor growth [#7]. Beyond splicing, RBM5 stabilizes p53 protein post-transcriptionally and induces G1 arrest and mitochondrial apoptosis acting upstream of Bax [#13, #14]. RBM5 expression is itself cross-regulated by RBM10-driven AS-NMD and its protein activity is controlled by phosphorylation and by PRPF19-mediated ubiquitination [#10, #15, #25]. In vivo, a missense mutation in RRM2 disrupts RNA binding and causes spermatid differentiation arrest and male sterility in mouse [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing RBM5 as a nuclear RNA-binding protein with growth-suppressive activity set the foundation for its role as a tumor suppressor acting on RNA.\",\n      \"evidence\": \"Epitope-tag localization, in vitro poly(G) RNA binding, and ectopic expression growth assays in fibrosarcoma cells\",\n      \"pmids\": [\"11029660\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RNA targets undefined\", \"molecular mechanism of growth suppression not established\", \"splicing role not yet identified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defining the apoptotic output of RBM5 placed it functionally upstream of the mitochondrial cell-death pathway, explaining its tumor-suppressor phenotype.\",\n      \"evidence\": \"Stable overexpression in A549 cells with caspase/cytochrome c readouts and Bax siRNA epistasis\",\n      \"pmids\": [\"16585163\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct molecular targets linking RBM5 to Bax not identified\", \"single cell line\", \"does not distinguish splicing from non-splicing mechanism\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Two parallel studies converted RBM5 from a generic RNA-binder into a sequence-specific splicing regulator, showing it controls apoptotic isoform choice of FAS and caspase-2.\",\n      \"evidence\": \"In vitro spliceosome assembly assays with OCRE mutagenesis (FAS) and yeast RNA interaction plus in vitro/cellular splicing assays with binding-site mutagenesis (caspase-2)\",\n      \"pmids\": [\"18851835\", \"18840686\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"protein partners mediating the spliceosomal arrest not fully resolved\", \"genome-wide target spectrum unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connecting RBM5 to post-transcriptional p53 stabilization expanded its tumor-suppressor activity beyond splicing into protein-level control of a master regulator.\",\n      \"evidence\": \"Reporter assays, shRNA knockdown and overexpression with p53 target gene readouts after DNA damage\",\n      \"pmids\": [\"20309933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct mechanism of p53 protein stabilization unknown\", \"no direct binding partner identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Structural and biochemical dissection assigned discrete functions to RBM5 domains: RRM2 RNA recognition, Zf1 RNA binding/druggability, and G-patch-dependent stimulation of the DHX15 helicase within the spliceosome.\",\n      \"evidence\": \"NMR solution structures of RRM2 and Zf1, fragment screening, co-IP/pull-down with DHX15 and PRP19, and in vitro helicase assays with domain mutagenesis\",\n      \"pmids\": [\"22839758\", \"22162216\", \"22569250\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how DHX15 stimulation maps onto specific splicing events not resolved\", \"Zf1 ligand has no cellular validation\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identifying U2AF65 competition at weak 3' splice sites provided a concrete biochemical mechanism for RBM5-mediated exon skipping.\",\n      \"evidence\": \"Minigene splicing in HeLa and in vitro U2AF65 competition assays on AID pre-mRNA\",\n      \"pmids\": [\"23017209\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"generality across endogenous targets not shown in this study\", \"structural basis of competition not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"RBM5 was shown to govern proliferation through splicing of the Notch regulator NUMB, antagonizing RBM10, and an in vivo mutation established its physiological splicing role in spermatogenesis.\",\n      \"evidence\": \"Minigene/RNA-seq/knockdown plus colony-formation and xenograft assays (NUMB); mouse genetic R263P RRM2 mutant with RNA pull-down and splicing phenotyping (testis)\",\n      \"pmids\": [\"24332178\", \"23935508\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"positional rules distinguishing RBM5 from RBM10 not fully mechanistic\", \"in vivo target set incompletely defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Solving the OCRE–SmN complex structure revealed how RBM5 physically contacts the spliceosome to dictate FAS splice-site pairing.\",\n      \"evidence\": \"NMR structure of OCRE–SmN peptide complex with aromatic-residue mutagenesis and functional splicing assays\",\n      \"pmids\": [\"27894420\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how Sm contact translates into the kinetic spliceosomal block not fully resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Reciprocal cross-regulation between RBM5 and RBM10 was established, with RBM10 triggering AS-NMD of RBM5 and RBM5 binding specific RBM10 variants, defining a feedback circuit between the paralogs.\",\n      \"evidence\": \"Computational prediction with RT-PCR/NMD reporters (RBM10→RBM5) and RIP-seq plus Western blot (RBM5→RBM10)\",\n      \"pmids\": [\"28586478\", \"28662214\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"physiological contexts of the circuit not defined\", \"single-lab studies\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Genetic epistasis in C. elegans confirmed a conserved functional relationship between RBM5 and U2AF, reinforcing the U2AF-competition model at weak 3' splice sites.\",\n      \"evidence\": \"rbm-5/uaf-1 genetic suppression screen with transcriptome analysis and neuronal tissue-specific rescue\",\n      \"pmids\": [\"30295127\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"gene-specific suppress-vs-enhance behavior not mechanistically explained\", \"ortholog system\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Native spliceosome isolation placed RBM5/RBM10 directly on the U2 snRNP at branch sites transcriptome-wide, unifying prior single-target studies into a genome-scale repression mechanism.\",\n      \"evidence\": \"Chromatin-associated spliceosome isolation, branch-site RNA-seq, and conserved-peptide deletion mutagenesis\",\n      \"pmids\": [\"38537639\", \"37790489\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how branch-site engagement selects which exons are repressed not fully resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Multiple studies extended RBM5 into non-splicing and disease-context roles—mRNA stabilization (PTEN), m6A regulation via FTO, ER-stress pathway output, and a noncanonical DNA-binding-dependent maintenance of HOXA9 transcription in AML.\",\n      \"evidence\": \"RIP/half-life/luciferase and xenograft (PTEN); RIP-seq/co-IP and methylation assays (FTO); ubiquitination/epistasis (eIF2α); CRISPR/degron/domain screens (HOXA9)\",\n      \"pmids\": [\"39072172\", \"38742685\", \"38272235\", \"38216972\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct DNA binding by RBM5 not biochemically demonstrated\", \"FTO and eIF2α links are low-confidence single-lab findings\", \"relationship between splicing and these noncanonical roles unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A detailed domain-level model showed how a lncRNA cofactor and PRPF19 jointly tune RBM5's FAS-splicing activity and its own stability.\",\n      \"evidence\": \"Domain mutagenesis mapping ZnF-C2H2 and other residues, RNA pull-down, co-IP, minigene splicing, ubiquitination assays, and xenograft (MGC32805/FAS/PRPF19)\",\n      \"pmids\": [\"40571778\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"generality of lncRNA-assisted recruitment to other targets unknown\", \"single-lab study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RBM5 partitions between its canonical U2 snRNP/branch-site splicing function and its reported noncanonical roles (DNA-binding transcriptional control, mRNA stability, m6A regulation) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"no biochemical demonstration of direct DNA binding\", \"no unified model integrating splicing and non-splicing activities\", \"structural basis of full-length RNA target selection in cells undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [3, 4, 6, 17]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [17, 8]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [6, 20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 14]}\n    ],\n    \"complexes\": [\n      \"U2 snRNP\"\n    ],\n    \"partners\": [\n      \"DHX15\",\n      \"PRPF19\",\n      \"RBM10\",\n      \"SNRPB\",\n      \"U2AF2\",\n      \"FTO\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}