{"gene":"RBMX","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2012,"finding":"RBMX accumulates at DNA double-strand break lesions through multiple protein domains in a PARP1-dependent manner and promotes homologous recombination by facilitating proper BRCA2 expression.","method":"Genome-wide siRNA screen, localization imaging at DNA lesions, RNAi knockdown with HR assay readout","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide screen with mechanistic follow-up (PARP1 dependence, BRCA2 expression link, domain analysis), multiple orthogonal methods in a rigorous study","pmids":["22344029"],"is_preprint":false},{"year":2019,"finding":"hnRNPG (RBMX) acts as an m6A reader protein that directly binds the phosphorylated C-terminal domain (CTD) of RNA Polymerase II via its RGG motifs in the low-complexity region, co-transcriptionally associates with RNAPII and nascent pre-mRNA, and regulates alternative splicing transcriptome-wide; m6A near splice sites modulates hnRNPG binding, which in turn influences RNAPII occupancy patterns and promotes exon inclusion.","method":"RNA binding assays, CLIP-seq, ChIP-seq, in vitro CTD binding assays, domain mutant analysis, transcriptome-wide splicing analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (in vitro binding, CLIP-seq, ChIP-seq, mutagenesis) in a single rigorous study establishing the mechanism","pmids":["31445886"],"is_preprint":false},{"year":2002,"finding":"hnRNP-G (RBMX) promotes inclusion of SMN2 exon 7 via a direct protein-protein interaction with the SR-like splicing factor Htra2-beta1, not through non-specific RNA binding; deletion mutant analysis showed the specific protein-protein interaction mediates exon 7 inclusion.","method":"In vivo splicing assays, deletion mutagenesis of hnRNP-G, protein-protein interaction assays with Htra2-beta1","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vivo splicing assay with deletion mutants and direct protein-protein interaction validation, multiple orthogonal approaches","pmids":["12165565"],"is_preprint":false},{"year":2012,"finding":"RBMX maintains centromeric sister chromatid cohesion by associating with cohesin subunits Scc1 and Smc3, and with the cohesion regulator Wapl; RBMX depletion causes premature cohesin loss from centromeres before anaphase with delocalization of the shugoshin complex. RBMX is required for cohesion only in the presence of Wapl, suggesting RBMX acts as a Wapl inhibitor.","method":"RNAi depletion, co-immunoprecipitation with cohesin subunits, chromosome morphology analysis, epistasis with Wapl","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, epistasis with Wapl, defined cellular phenotype (premature chromatid separation), multiple orthogonal methods","pmids":["22832223"],"is_preprint":false},{"year":2020,"finding":"RBMX is an ssDNA-binding protein that, in response to replication stress, binds to ssDNA at adjacent but non-overlapping sites from RPA and recruits TopBP1, thereby activating ATR on repetitive DNA regions; this ssDNA-RBMX-TopBP1 pathway is independent of ssDNA-dsDNA junctions and the 9-1-1 complex.","method":"Super-resolution STORM imaging, ChIP-seq, RNAi depletion, in vitro ssDNA binding, replication stress assays, micronuclei and SCE measurement","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods including super-resolution imaging, ChIP-seq, and in vitro binding with functional validation of a novel pathway","pmids":["32494026"],"is_preprint":false},{"year":2021,"finding":"RBMX RGG/RG motif is methylated by PRMT5, which regulates assembly of RBMX with the SRSF1 splicing factor into higher-order complexes; depletion of RBMX or disruption of the RBMX/SRSF1 complex reduces SRSF1 binding to MDM4 pre-mRNA, leading to MDM4 exon 6 exclusion, lower MDM4 protein, and aberrant p53 pathway activation.","method":"PRMT5 methylation assay of RBMX RGG motif, co-immunoprecipitation of RBMX/SRSF1 complex, RIP for SRSF1-MDM4 pre-mRNA, splicing minigene/endogenous analysis, CRISPR-Cas9 isogenic Shashi-XLID hiPSCs, transcriptomic analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — PTM identified (PRMT5 methylates RBMX RGG motif), protein complex validated, splicing mechanism established with isogenic disease model and transcriptomics","pmids":["34260915"],"is_preprint":false},{"year":2021,"finding":"RBMX and its retrogene RBMXL1 directly bind mRNAs and control nascent transcription of the CBX5 (HP1α) locus; forced CBX5 expression rescues cell growth and apoptosis defects caused by RBMX/L1 loss in myeloid leukemia cells.","method":"RIP for mRNA binding, chromatin accessibility assays, nascent RNA transcription analysis, rescue experiment with forced CBX5 expression, KD in murine and human AML cells","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RIP, chromatin assays, nascent transcription, genetic rescue) in a focused mechanistic study","pmids":["34458856"],"is_preprint":false},{"year":2021,"finding":"RBMX binds hnRNP A1 and competitively inhibits the combination of the RGG motif in hnRNP A1 with sequences flanking PKM exon 9, resulting in reduced PKM2 and elevated PKM1 levels, thereby attenuating glycolysis and tumor progression in bladder cancer.","method":"Co-immunoprecipitation of RBMX and hnRNP A1, PKM splicing analysis, RNAi and overexpression with functional assays in vitro and in vivo","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and splicing assays with functional rescue, single lab, multiple methods","pmids":["33564070"],"is_preprint":false},{"year":2018,"finding":"RBMX associates with satellite I noncoding RNA specifically during M phase and is a component of the centromere ncRNP complex; knockdown of RBMX or satellite I RNA causes premature sister chromatid separation, and satellite I RNA stabilizes RBMX and Sororin levels in the ncRNP complex.","method":"Purification of satellite I ncRNP complex by LC/MS, RNAi knockdown, cell cycle synchronization, immunofluorescence","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-based complex purification, RNAi phenotype, but single lab with limited orthogonal validation of mechanism","pmids":["29383807"],"is_preprint":false},{"year":2010,"finding":"hnRNP G (RBMX) contains at least three functionally distinct domains: an N-terminal RRM, a centrally positioned Nascent Transcripts Targeting Domain (NTD, residues 186–236) required for recruitment to active transcription units independently of RNA sequence specificity, and a C-terminal auxiliary RNA-binding domain (RBD, 58 residues) that recognizes an RNA hairpin motif.","method":"Deletion analysis in Xenopus oocytes, injection of domain mutants, RNA binding assays with characterized RNA probe","journal":"Nucleus","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain deletion analysis with functional readout in an amphibian oocyte system, single lab, two orthogonal approaches","pmids":["21327109"],"is_preprint":false},{"year":2011,"finding":"hnRNPG (RBMX) inhibits splicing of tau exon 10 and interacts with SRp75 and hnRNPE2; SRp75 binds the proximal downstream intron of tau exon 10 at the FTDP-17 hotspot region, and hnRNPG forms a complex with SRp75 to regulate exon 10 splicing.","method":"Co-transfection splicing assays, co-immunoprecipitation, RNAi","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP and splicing assays with RNAi, single lab, multiple methods","pmids":["21723381"],"is_preprint":false},{"year":2006,"finding":"RBMX acts as a transcriptional regulator of the SREBP-1c gene promoter in mouse liver in response to high-fructose diet, as demonstrated by EMSA (anti-RBMX antibody displaces fructose-induced bands) and by the fact that overexpression or suppression of RBMX regulates SREBP-1c promoter activity in rat hepatoma cells.","method":"MALDI-TOF mass spectrometry identification, EMSA with anti-RBMX antibody, overexpression and siRNA suppression with SREBP-1c promoter assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — EMSA and functional promoter assays with gain/loss of function, single lab","pmids":["17188681"],"is_preprint":false},{"year":2009,"finding":"RBMX interacts with SAFB1 (scaffold attachment factor B1), and both proteins bind the upstream region of the Srebp-1c gene; SAFB1 is required for RBMX-induced Srebp-1c promoter activity, and the effect of SAFB1 overexpression on the Srebp-1c promoter is only observed in the presence of RBMX.","method":"Yeast two-hybrid screen, co-immunoprecipitation, chromatin immunoprecipitation (ChIP), RNAi, promoter activity assay","journal":"BMB reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — yeast two-hybrid confirmed by Co-IP and ChIP, multiple methods, single lab","pmids":["19403048"],"is_preprint":false},{"year":2008,"finding":"RBMX associates with ARTS-1 (aminopeptidase regulator of TNFR1 shedding) by co-immunoprecipitation, and RNAi knockdown of RBMX reduces both constitutive release of TNFR1 exosome-like vesicles and IL-1β-mediated inducible proteolytic cleavage of TNFR1 ectodomains; conversely, RBMX overexpression increases both forms of TNFR1 release.","method":"Co-immunoprecipitation, RNAi knockdown, RBMX overexpression, TNFR1 release assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP with reciprocal gain/loss of function, single lab, multiple approaches","pmids":["18445477"],"is_preprint":false},{"year":2022,"finding":"hnRNP G (RBMX) binds a purine-rich splicing enhancer sequence in HPV16 pre-mRNA and promotes splicing to splice site SA2709, enhancing E2 mRNA production; the splicing-enhancing function maps to amino acids 236–286 and involves interaction with splicing factor U2AF65. Additionally, DDR reduces sumoylation of hnRNP G and this enhances hnRNP G interactions with HPV16 E2 mRNAs and U2AF65. hnRNP G also promotes intron retention in the HPV16 E6 coding region to inhibit spliced E7 oncogene mRNA production.","method":"Mutational analysis of splicing enhancer, RNA binding assays, co-immunoprecipitation with U2AF65, domain deletion mapping, sumoylation assay, keratinocyte differentiation and DDR treatments","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping, Co-IP, mutation of splicing enhancer and functional readout, single lab with multiple orthogonal methods","pmids":["35357488"],"is_preprint":false},{"year":2019,"finding":"NORAD localizes predominantly to the cytoplasm (not nucleus) with or without DNA damage, and genetic rescue experiments showed PUM binding (not RBMX binding) is required for NORAD-mediated maintenance of genomic stability; RBMX binding to NORAD is dispensable for this function.","method":"RNA FISH, cellular fractionation, genetic rescue experiments with PUM-binding mutant and RBMX-binding mutant NORAD","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (FISH, fractionation, genetic rescue) consistently showing RBMX binding to NORAD is NOT required for genome stability; replicated across approaches","pmids":["31343408"],"is_preprint":false},{"year":2023,"finding":"RBMX binds TERRA (telomeric repeat-containing RNA) and simultaneously binds the nuclear exosome targeting protein ZCCHC8; RBMX depletion elevates TERRA levels, enhances telomere R-loop formation, and slows TERRA degradation, indicating RBMX promotes TERRA degradation by facilitating its transport to the nuclear exosome.","method":"RNA immunoprecipitation, co-immunoprecipitation of RBMX and ZCCHC8, RBMX depletion with TERRA level measurement, R-loop analysis, replication stress assays","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — RIP and Co-IP with functional readouts, single lab, multiple methods","pmids":["37756323"],"is_preprint":false},{"year":2015,"finding":"RBMX interacts with Borna disease virus (BDV) nucleoprotein in the nucleus; knockdown of RBMX disrupts formation of viral nuclear inclusion bodies (vSPOTs) and reduces BDV transcription and replication.","method":"Co-immunoprecipitation of RBMX with BDV nucleoprotein, RNAi knockdown, fluorescence imaging of vSPOTs, BDV transcription/replication assay","journal":"The Journal of general virology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and functional knockdown with defined phenotypic readout, single lab","pmids":["26333388"],"is_preprint":false},{"year":2007,"finding":"RBMX (hnRNP-G) forms a complex with ZAP3, PP1, SAM68, CIA, and NF110/45 in the nucleus; the interaction of hnRNP-G with ZAP3 and SAM68 is lost upon digestion of endogenous nucleic acid, indicating these interactions are nucleic acid-dependent.","method":"Proteomic analysis (mass spectrometry) of ZAP3 complex, nucleic acid digestion experiment to test interaction dependency","journal":"Biochimica et biophysica acta","confidence":"Low","confidence_rationale":"Tier 3 / Weak — MS-based interactome from ZAP3 pulldown, single method, RBMX not the primary focus","pmids":["17890166"],"is_preprint":false},{"year":2024,"finding":"DeSUMOylation of RBMX in diabetic kidney disease alters exosomal miRNA content; RBMX binds miR-26a, miR-23c, and miR-874 within exosomes, and these miRNAs protect against mitochondrial damage by targeting CERS6 mRNA.","method":"Co-immunoprecipitation, SUMOylation assays, RNA immunoprecipitation, confocal microscopy, AAV-mediated Rbmx overexpression in mice","journal":"Journal of advanced research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — multiple assays but complex multi-step mechanism, single lab, limited orthogonal validation","pmids":["39341454"],"is_preprint":false},{"year":2024,"finding":"The SOCS5 SH2 domain (with critical residues Y413 and D443) directly binds the RBMX RRM domain; SOCS5-RBMX co-stimulate the SREBP1 promoter to induce de novo lipogenesis, and SH2 domain mutations reverse this effect.","method":"Co-immunoprecipitation, GST-pulldown, SREBP1 promoter assay, domain mutation analysis","journal":"NPJ precision oncology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal Co-IP and GST-pulldown with domain mapping and promoter functional assay, single lab","pmids":["38429411"],"is_preprint":false},{"year":2025,"finding":"Mycobacterial phosphatase PstP dephosphorylates RBMX at serine 189 (S189), which influences the alternative splicing of PLA2G7, resulting in increased levels of a PLA2G7 transcript containing exon 9 that potentiates inflammatory responses.","method":"Multi-omics (proteomics, phosphoproteomics, transcriptomics, interactomics), site-specific dephosphorylation analysis of RBMX S189 by PstP","journal":"iMetaOmics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multi-omics identification with phosphosite specificity, but limited direct functional validation of RBMX S189 in splicing, single study","pmids":["41675711"],"is_preprint":false},{"year":2025,"finding":"RBMX influences allele-dependent differences in DDIT4 protein expression at a 3'UTR SNP (rs1053639); RBMX binds DDIT4 3'UTR in an allele-specific manner (RNA-EMSA, RIP, smiFISH), and RBMX depletion reduces DDIT4 protein in TT clones to AA levels, modulating mTORC1 repression under ER stress.","method":"RNA-EMSA, RIP, smiFISH, RBMX depletion, CRISPR genome editing for allele comparison, polysome profiling","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (EMSA, RIP, smiFISH, KD with functional readout), preprint, single lab","pmids":[],"is_preprint":true},{"year":2025,"finding":"RBMX and RBMXL1 share protein and RNA partners and act redundantly in brain development; RBMXL1 buffers the impact of RBMX deficiency in mice, explaining the discrepancy between severe human cortical phenotypes and mild mouse phenotypes upon Rbmx loss.","method":"Mouse Rbmx knockout model, human genetic analysis, protein/RNA partner co-immunoprecipitation comparing RBMX and RBMXL1, cellular rescue experiments","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mouse model with mechanistic follow-up, Co-IP for shared partners, preprint not yet peer-reviewed","pmids":[],"is_preprint":true}],"current_model":"RBMX is a nuclear RNA-binding protein (hnRNP G) that regulates alternative pre-mRNA splicing co-transcriptionally by binding m6A-modified nascent RNA and the phosphorylated CTD of RNAPII via its RGG motifs, interacting directly with splicing factors (Htra2-beta1, SRSF1, U2AF65, SRp75) and their target pre-mRNAs to control exon inclusion or skipping; it also maintains genome integrity by accumulating at DNA double-strand breaks in a PARP1-dependent manner to facilitate BRCA2 expression and homologous recombination, by binding ssDNA and recruiting TopBP1 to activate ATR on repetitive DNAs, and by associating with cohesin subunits and inhibiting Wapl to maintain centromeric sister chromatid cohesion; additional roles include regulating TERRA levels through the nuclear exosome (via ZCCHC8 interaction), controlling transcription of the CBX5/HP1α locus in myeloid leukemia, and being post-translationally regulated by PRMT5-mediated methylation of its RGG/RG motif and by (de)SUMOylation."},"narrative":{"mechanistic_narrative":"RBMX (hnRNP G) is a nuclear RNA-binding protein that couples co-transcriptional pre-mRNA splicing regulation to genome maintenance [PMID:31445886, PMID:22344029]. It acts as an m6A reader that engages the phosphorylated CTD of RNA Polymerase II through RGG motifs in its low-complexity region, co-transcriptionally associating with RNAPII and nascent pre-mRNA so that m6A near splice sites tunes RBMX binding and exon inclusion transcriptome-wide [PMID:31445886]; functionally distinct domains support this, including an N-terminal RRM, a central nascent-transcript targeting domain that recruits RBMX to active transcription units, and a C-terminal auxiliary RNA-binding domain [PMID:21327109]. RBMX directs specific splicing outcomes largely through direct protein-protein contacts with splicing factors rather than by RNA binding alone: it promotes SMN2 exon 7 inclusion via Htra2-beta1 [PMID:12165565], cooperates with SRSF1 (in a manner controlled by PRMT5 methylation of its RGG/RG motif) to govern MDM4 exon 6 inclusion and downstream p53 signaling [PMID:34260915], partners with U2AF65 to control HPV16 transcript splicing [PMID:35357488], and antagonizes hnRNP A1 to shift PKM splicing toward PKM1 and restrain glycolysis [PMID:33564070]. In parallel, RBMX safeguards genome integrity: it accumulates at DNA double-strand breaks in a PARP1-dependent manner to promote BRCA2 expression and homologous recombination [PMID:22344029], binds ssDNA at sites adjacent to RPA to recruit TopBP1 and activate ATR on repetitive DNA during replication stress [PMID:32494026], and maintains centromeric sister chromatid cohesion by associating with cohesin subunits Scc1/Smc3 and acting as a Wapl inhibitor [PMID:22832223], with satellite I noncoding RNA stabilizing RBMX within a centromeric ncRNP complex [PMID:29383807]. RBMX also regulates RNA metabolism beyond splicing, promoting TERRA degradation by bridging it to the nuclear exosome via ZCCHC8 and thereby limiting telomeric R-loops [PMID:37756323], and controlling nascent transcription of the CBX5/HP1α locus to support leukemic cell survival [PMID:34458856]. Its activity is modulated post-translationally by PRMT5-mediated arginine methylation [PMID:34260915] and by (de)SUMOylation [PMID:35357488]. RBMX and its retrogene RBMXL1 share partners and act redundantly, with RBMXL1 buffering RBMX loss in brain development.","teleology":[{"year":2002,"claim":"Established that RBMX achieves splice-site specificity through protein-protein interaction rather than nonspecific RNA binding, defining its mode of action as a splicing regulator.","evidence":"in vivo splicing assays with hnRNP-G deletion mutants and Htra2-beta1 interaction analysis on SMN2 exon 7","pmids":["12165565"],"confidence":"High","gaps":["Did not define the RNA elements or genome-wide targets","Mechanism of co-transcriptional recruitment unaddressed"]},{"year":2006,"claim":"Showed RBMX can act at the DNA/promoter level, regulating SREBP-1c transcription in response to dietary fructose, broadening its role beyond RNA processing.","evidence":"MALDI-TOF identification, EMSA with anti-RBMX antibody, and SREBP-1c promoter gain/loss-of-function in hepatoma cells","pmids":["17188681"],"confidence":"Medium","gaps":["Direct DNA binding versus complex recruitment not resolved","No structural basis for promoter recognition"]},{"year":2009,"claim":"Identified SAFB1 as an RBMX partner required for RBMX-driven Srebp-1c promoter activity, providing a protein-complex mechanism for the transcriptional role.","evidence":"yeast two-hybrid, Co-IP, ChIP, and promoter activity assays","pmids":["19403048"],"confidence":"Medium","gaps":["Generality of SAFB1 dependence at other loci unknown","Interplay with RBMX RNA-binding function unaddressed"]},{"year":2010,"claim":"Resolved RBMX into functionally distinct domains, separating RNA-sequence recognition from recruitment to active transcription units.","evidence":"domain deletion analysis with injection into Xenopus oocytes and RNA-binding assays","pmids":["21327109"],"confidence":"Medium","gaps":["Structural model of the NTD lacking","How recruitment integrates with splice-site selection unclear"]},{"year":2011,"claim":"Extended the splicing-factor interaction model by showing RBMX represses tau exon 10 through a complex with SRp75, relevant to FTDP-17.","evidence":"co-transfection splicing assays, Co-IP, and RNAi","pmids":["21723381"],"confidence":"Medium","gaps":["Direct RNA contacts on the tau intron not mapped","Single-cell-system validation only"]},{"year":2012,"claim":"Revealed an unanticipated genome-maintenance role: RBMX accumulates at DSBs in a PARP1-dependent manner and promotes HR via BRCA2 expression.","evidence":"genome-wide siRNA screen, lesion localization imaging, and HR assays with domain analysis","pmids":["22344029"],"confidence":"High","gaps":["Whether BRCA2 regulation is transcriptional or splicing-based not fully resolved","RNA-binding requirement at lesions unclear"]},{"year":2012,"claim":"Defined RBMX as a centromeric cohesion factor, linking it to faithful chromosome segregation through Wapl inhibition.","evidence":"RNAi depletion, reciprocal Co-IP with Scc1/Smc3 and Wapl, chromosome morphology, and Wapl epistasis","pmids":["22832223"],"confidence":"High","gaps":["Direct biochemical basis of Wapl inhibition unknown","Whether RNA binding contributes to cohesion not tested"]},{"year":2018,"claim":"Connected RBMX cohesion function to a noncoding RNP, showing satellite I RNA stabilizes RBMX and Sororin in an M-phase centromere complex.","evidence":"LC/MS purification of satellite I ncRNP, RNAi, cell-cycle synchronization, and immunofluorescence","pmids":["29383807"],"confidence":"Medium","gaps":["Stoichiometry and architecture of the ncRNP undefined","Single-lab; limited orthogonal validation"]},{"year":2019,"claim":"Unified RBMX splicing activity under a co-transcriptional, m6A-reader framework, mechanistically linking RNA modification, RNAPII CTD binding, and exon inclusion genome-wide.","evidence":"in vitro CTD binding, CLIP-seq, ChIP-seq, RGG-motif mutagenesis, and transcriptome-wide splicing analysis","pmids":["31445886"],"confidence":"High","gaps":["Direct m6A-binding affinity/structural basis not defined","How m6A reading is integrated with specific splicing-factor partners unresolved"]},{"year":2019,"claim":"Clarified that RBMX binding to the lncRNA NORAD is dispensable for NORAD-mediated genomic stability, refining which RBMX RNA interactions are functionally relevant.","evidence":"RNA FISH, cellular fractionation, and genetic rescue with PUM- and RBMX-binding-mutant NORAD","pmids":["31343408"],"confidence":"High","gaps":["Does not exclude RBMX-NORAD roles in other contexts","No direct test of RBMX binding kinetics on NORAD"]},{"year":2020,"claim":"Defined a distinct ATR-activating pathway in which ssDNA-bound RBMX recruits TopBP1 on repetitive DNA, independent of the canonical ssDNA-dsDNA junction/9-1-1 route.","evidence":"super-resolution STORM, ChIP-seq, in vitro ssDNA binding, RNAi, and replication-stress/SCE assays","pmids":["32494026"],"confidence":"High","gaps":["How RBMX selects repetitive loci versus general ssDNA unclear","Relationship to RBMX splicing function unaddressed"]},{"year":2021,"claim":"Established PRMT5 methylation of the RBMX RGG/RG motif as a switch controlling RBMX/SRSF1 complex assembly and MDM4 splicing, tying RBMX to p53 regulation and Shashi-XLID.","evidence":"PRMT5 methylation assay, RBMX/SRSF1 Co-IP, SRSF1-MDM4 RIP, minigene splicing, and CRISPR isogenic hiPSCs with transcriptomics","pmids":["34260915"],"confidence":"High","gaps":["Other methylation-dependent splicing targets not mapped","Stoichiometry of higher-order RBMX/SRSF1 assemblies undefined"]},{"year":2021,"claim":"Showed RBMX (with RBMXL1) controls nascent CBX5/HP1α transcription to support leukemic cell growth, identifying a transcription-level effector relevant to myeloid malignancy.","evidence":"RIP, chromatin accessibility, nascent transcription analysis, and CBX5 rescue in murine/human AML cells","pmids":["34458856"],"confidence":"High","gaps":["Mechanism by which RBMX engages the CBX5 locus unclear","Direct DNA versus nascent-RNA contact not distinguished"]},{"year":2021,"claim":"Demonstrated RBMX competitively antagonizes hnRNP A1 at PKM exon 9 to favor PKM1, linking RBMX splicing control to metabolic and tumor-suppressive output.","evidence":"RBMX/hnRNP A1 Co-IP, PKM splicing analysis, and RNAi/overexpression with in vitro and in vivo assays","pmids":["33564070"],"confidence":"Medium","gaps":["Direct RNA-binding competition not biochemically reconstituted","Single cancer context"]},{"year":2022,"claim":"Mapped a splicing-enhancing region of RBMX acting via U2AF65 on HPV16 pre-mRNA and showed SUMOylation status, modulated by DDR, tunes these interactions.","evidence":"splicing-enhancer mutagenesis, RNA binding, U2AF65 Co-IP, domain deletion, and sumoylation assays in keratinocytes","pmids":["35357488"],"confidence":"Medium","gaps":["SUMO sites on RBMX not pinpointed","Generality beyond viral transcripts untested"]},{"year":2023,"claim":"Identified RBMX as a factor that delivers TERRA to the nuclear exosome via ZCCHC8, controlling telomeric R-loop levels and telomere stability.","evidence":"RIP, RBMX/ZCCHC8 Co-IP, TERRA level and R-loop measurement, and replication-stress assays","pmids":["37756323"],"confidence":"Medium","gaps":["Direct handoff mechanism to exosome not reconstituted","Single-lab functional readouts"]},{"year":2024,"claim":"Linked RBMX SUMOylation status to exosomal miRNA loading in diabetic kidney disease, extending RBMX RNA-binding roles to extracellular vesicle cargo.","evidence":"Co-IP, SUMOylation assays, RIP, confocal microscopy, and AAV-mediated Rbmx overexpression in mice","pmids":["39341454"],"confidence":"Low","gaps":["Complex multi-step mechanism with limited orthogonal validation","Direct RBMX-miRNA binding specificity not established","Disease-context specificity unclear"]},{"year":2024,"claim":"Showed the SOCS5 SH2 domain directly binds the RBMX RRM and co-activates the SREBP1 promoter to drive lipogenesis, providing a partner-based mechanism for RBMX transcriptional activity.","evidence":"Co-IP, GST-pulldown, SREBP1 promoter assay, and SH2/RRM domain mutation analysis","pmids":["38429411"],"confidence":"Medium","gaps":["Relationship to SAFB1-dependent SREBP regulation unresolved","Single-lab functional context"]},{"year":2025,"claim":"Identified phosphorylation of RBMX at S189 as a regulatable mark influencing PLA2G7 alternative splicing and inflammatory output.","evidence":"multi-omics with site-specific dephosphorylation of RBMX S189 by mycobacterial PstP","pmids":["41675711"],"confidence":"Medium","gaps":["Direct functional validation of S189 in splicing limited","Host kinase for S189 in normal physiology unknown"]},{"year":2025,"claim":"Demonstrated allele-specific RBMX binding to the DDIT4 3'UTR controlling DDIT4 protein levels and mTORC1 repression, implicating RBMX in 3'UTR-dependent translational/expression control.","evidence":"RNA-EMSA, RIP, smiFISH, RBMX depletion, CRISPR allele editing, and polysome profiling (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint; not peer-reviewed","Mechanism (stability vs translation) of allele-specific effect not fully resolved"]},{"year":2025,"claim":"Established functional redundancy between RBMX and its retrogene RBMXL1, explaining species-dependent phenotype severity through shared partners.","evidence":"Rbmx knockout mouse, human genetics, and Co-IP comparing RBMX/RBMXL1 partners with rescue (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint; not peer-reviewed","Extent of non-redundant RBMX functions undefined"]},{"year":null,"claim":"How RBMX integrates its parallel roles in co-transcriptional splicing, DNA-damage/replication-stress signaling, and centromeric cohesion into a unified molecular logic, and how its PTM repertoire (methylation, SUMOylation, phosphorylation) coordinates switching among them, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated structural model of domain usage across functions","Cross-talk between splicing and genome-maintenance activities untested","PTM hierarchy and timing not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[1,2,9,14,16,22]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[4,11]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[6,11,12,20]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,5,14]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,17,18]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,3,4]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,2,5,16]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0,4]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,8]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[6,11,12]}],"complexes":["RBMX/SRSF1 splicing complex","centromere satellite I ncRNP","cohesin (Scc1/Smc3/Wapl-associated)"],"partners":["SRSF1","U2AF65","HNRNPA1","HTRA2-BETA1","ZCCHC8","TOPBP1","SAFB1","SOCS5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P38159","full_name":"RNA-binding motif protein, X chromosome","aliases":["Glycoprotein p43","Heterogeneous nuclear ribonucleoprotein G","hnRNP G"],"length_aa":391,"mass_kda":42.3,"function":"RNA-binding protein that plays several role in the regulation of pre- and post-transcriptional processes. 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Also plays a role in the cytoplasmic TNFR1 trafficking pathways; promotes both the IL-1-beta-mediated inducible proteolytic cleavage of TNFR1 ectodomains and the release of TNFR1 exosome-like vesicles to the extracellular compartment","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P38159/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/RBMX","classification":"Common 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\"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide screen with mechanistic follow-up (PARP1 dependence, BRCA2 expression link, domain analysis), multiple orthogonal methods in a rigorous study\",\n      \"pmids\": [\"22344029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"hnRNPG (RBMX) acts as an m6A reader protein that directly binds the phosphorylated C-terminal domain (CTD) of RNA Polymerase II via its RGG motifs in the low-complexity region, co-transcriptionally associates with RNAPII and nascent pre-mRNA, and regulates alternative splicing transcriptome-wide; m6A near splice sites modulates hnRNPG binding, which in turn influences RNAPII occupancy patterns and promotes exon inclusion.\",\n      \"method\": \"RNA binding assays, CLIP-seq, ChIP-seq, in vitro CTD binding assays, domain mutant analysis, transcriptome-wide splicing analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (in vitro binding, CLIP-seq, ChIP-seq, mutagenesis) in a single rigorous study establishing the mechanism\",\n      \"pmids\": [\"31445886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"hnRNP-G (RBMX) promotes inclusion of SMN2 exon 7 via a direct protein-protein interaction with the SR-like splicing factor Htra2-beta1, not through non-specific RNA binding; deletion mutant analysis showed the specific protein-protein interaction mediates exon 7 inclusion.\",\n      \"method\": \"In vivo splicing assays, deletion mutagenesis of hnRNP-G, protein-protein interaction assays with Htra2-beta1\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vivo splicing assay with deletion mutants and direct protein-protein interaction validation, multiple orthogonal approaches\",\n      \"pmids\": [\"12165565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RBMX maintains centromeric sister chromatid cohesion by associating with cohesin subunits Scc1 and Smc3, and with the cohesion regulator Wapl; RBMX depletion causes premature cohesin loss from centromeres before anaphase with delocalization of the shugoshin complex. RBMX is required for cohesion only in the presence of Wapl, suggesting RBMX acts as a Wapl inhibitor.\",\n      \"method\": \"RNAi depletion, co-immunoprecipitation with cohesin subunits, chromosome morphology analysis, epistasis with Wapl\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, epistasis with Wapl, defined cellular phenotype (premature chromatid separation), multiple orthogonal methods\",\n      \"pmids\": [\"22832223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RBMX is an ssDNA-binding protein that, in response to replication stress, binds to ssDNA at adjacent but non-overlapping sites from RPA and recruits TopBP1, thereby activating ATR on repetitive DNA regions; this ssDNA-RBMX-TopBP1 pathway is independent of ssDNA-dsDNA junctions and the 9-1-1 complex.\",\n      \"method\": \"Super-resolution STORM imaging, ChIP-seq, RNAi depletion, in vitro ssDNA binding, replication stress assays, micronuclei and SCE measurement\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods including super-resolution imaging, ChIP-seq, and in vitro binding with functional validation of a novel pathway\",\n      \"pmids\": [\"32494026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RBMX RGG/RG motif is methylated by PRMT5, which regulates assembly of RBMX with the SRSF1 splicing factor into higher-order complexes; depletion of RBMX or disruption of the RBMX/SRSF1 complex reduces SRSF1 binding to MDM4 pre-mRNA, leading to MDM4 exon 6 exclusion, lower MDM4 protein, and aberrant p53 pathway activation.\",\n      \"method\": \"PRMT5 methylation assay of RBMX RGG motif, co-immunoprecipitation of RBMX/SRSF1 complex, RIP for SRSF1-MDM4 pre-mRNA, splicing minigene/endogenous analysis, CRISPR-Cas9 isogenic Shashi-XLID hiPSCs, transcriptomic analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — PTM identified (PRMT5 methylates RBMX RGG motif), protein complex validated, splicing mechanism established with isogenic disease model and transcriptomics\",\n      \"pmids\": [\"34260915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RBMX and its retrogene RBMXL1 directly bind mRNAs and control nascent transcription of the CBX5 (HP1α) locus; forced CBX5 expression rescues cell growth and apoptosis defects caused by RBMX/L1 loss in myeloid leukemia cells.\",\n      \"method\": \"RIP for mRNA binding, chromatin accessibility assays, nascent RNA transcription analysis, rescue experiment with forced CBX5 expression, KD in murine and human AML cells\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RIP, chromatin assays, nascent transcription, genetic rescue) in a focused mechanistic study\",\n      \"pmids\": [\"34458856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RBMX binds hnRNP A1 and competitively inhibits the combination of the RGG motif in hnRNP A1 with sequences flanking PKM exon 9, resulting in reduced PKM2 and elevated PKM1 levels, thereby attenuating glycolysis and tumor progression in bladder cancer.\",\n      \"method\": \"Co-immunoprecipitation of RBMX and hnRNP A1, PKM splicing analysis, RNAi and overexpression with functional assays in vitro and in vivo\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and splicing assays with functional rescue, single lab, multiple methods\",\n      \"pmids\": [\"33564070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RBMX associates with satellite I noncoding RNA specifically during M phase and is a component of the centromere ncRNP complex; knockdown of RBMX or satellite I RNA causes premature sister chromatid separation, and satellite I RNA stabilizes RBMX and Sororin levels in the ncRNP complex.\",\n      \"method\": \"Purification of satellite I ncRNP complex by LC/MS, RNAi knockdown, cell cycle synchronization, immunofluorescence\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-based complex purification, RNAi phenotype, but single lab with limited orthogonal validation of mechanism\",\n      \"pmids\": [\"29383807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"hnRNP G (RBMX) contains at least three functionally distinct domains: an N-terminal RRM, a centrally positioned Nascent Transcripts Targeting Domain (NTD, residues 186–236) required for recruitment to active transcription units independently of RNA sequence specificity, and a C-terminal auxiliary RNA-binding domain (RBD, 58 residues) that recognizes an RNA hairpin motif.\",\n      \"method\": \"Deletion analysis in Xenopus oocytes, injection of domain mutants, RNA binding assays with characterized RNA probe\",\n      \"journal\": \"Nucleus\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain deletion analysis with functional readout in an amphibian oocyte system, single lab, two orthogonal approaches\",\n      \"pmids\": [\"21327109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"hnRNPG (RBMX) inhibits splicing of tau exon 10 and interacts with SRp75 and hnRNPE2; SRp75 binds the proximal downstream intron of tau exon 10 at the FTDP-17 hotspot region, and hnRNPG forms a complex with SRp75 to regulate exon 10 splicing.\",\n      \"method\": \"Co-transfection splicing assays, co-immunoprecipitation, RNAi\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP and splicing assays with RNAi, single lab, multiple methods\",\n      \"pmids\": [\"21723381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RBMX acts as a transcriptional regulator of the SREBP-1c gene promoter in mouse liver in response to high-fructose diet, as demonstrated by EMSA (anti-RBMX antibody displaces fructose-induced bands) and by the fact that overexpression or suppression of RBMX regulates SREBP-1c promoter activity in rat hepatoma cells.\",\n      \"method\": \"MALDI-TOF mass spectrometry identification, EMSA with anti-RBMX antibody, overexpression and siRNA suppression with SREBP-1c promoter assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — EMSA and functional promoter assays with gain/loss of function, single lab\",\n      \"pmids\": [\"17188681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RBMX interacts with SAFB1 (scaffold attachment factor B1), and both proteins bind the upstream region of the Srebp-1c gene; SAFB1 is required for RBMX-induced Srebp-1c promoter activity, and the effect of SAFB1 overexpression on the Srebp-1c promoter is only observed in the presence of RBMX.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, chromatin immunoprecipitation (ChIP), RNAi, promoter activity assay\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — yeast two-hybrid confirmed by Co-IP and ChIP, multiple methods, single lab\",\n      \"pmids\": [\"19403048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"RBMX associates with ARTS-1 (aminopeptidase regulator of TNFR1 shedding) by co-immunoprecipitation, and RNAi knockdown of RBMX reduces both constitutive release of TNFR1 exosome-like vesicles and IL-1β-mediated inducible proteolytic cleavage of TNFR1 ectodomains; conversely, RBMX overexpression increases both forms of TNFR1 release.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, RBMX overexpression, TNFR1 release assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP with reciprocal gain/loss of function, single lab, multiple approaches\",\n      \"pmids\": [\"18445477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"hnRNP G (RBMX) binds a purine-rich splicing enhancer sequence in HPV16 pre-mRNA and promotes splicing to splice site SA2709, enhancing E2 mRNA production; the splicing-enhancing function maps to amino acids 236–286 and involves interaction with splicing factor U2AF65. Additionally, DDR reduces sumoylation of hnRNP G and this enhances hnRNP G interactions with HPV16 E2 mRNAs and U2AF65. hnRNP G also promotes intron retention in the HPV16 E6 coding region to inhibit spliced E7 oncogene mRNA production.\",\n      \"method\": \"Mutational analysis of splicing enhancer, RNA binding assays, co-immunoprecipitation with U2AF65, domain deletion mapping, sumoylation assay, keratinocyte differentiation and DDR treatments\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping, Co-IP, mutation of splicing enhancer and functional readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35357488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NORAD localizes predominantly to the cytoplasm (not nucleus) with or without DNA damage, and genetic rescue experiments showed PUM binding (not RBMX binding) is required for NORAD-mediated maintenance of genomic stability; RBMX binding to NORAD is dispensable for this function.\",\n      \"method\": \"RNA FISH, cellular fractionation, genetic rescue experiments with PUM-binding mutant and RBMX-binding mutant NORAD\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (FISH, fractionation, genetic rescue) consistently showing RBMX binding to NORAD is NOT required for genome stability; replicated across approaches\",\n      \"pmids\": [\"31343408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RBMX binds TERRA (telomeric repeat-containing RNA) and simultaneously binds the nuclear exosome targeting protein ZCCHC8; RBMX depletion elevates TERRA levels, enhances telomere R-loop formation, and slows TERRA degradation, indicating RBMX promotes TERRA degradation by facilitating its transport to the nuclear exosome.\",\n      \"method\": \"RNA immunoprecipitation, co-immunoprecipitation of RBMX and ZCCHC8, RBMX depletion with TERRA level measurement, R-loop analysis, replication stress assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — RIP and Co-IP with functional readouts, single lab, multiple methods\",\n      \"pmids\": [\"37756323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RBMX interacts with Borna disease virus (BDV) nucleoprotein in the nucleus; knockdown of RBMX disrupts formation of viral nuclear inclusion bodies (vSPOTs) and reduces BDV transcription and replication.\",\n      \"method\": \"Co-immunoprecipitation of RBMX with BDV nucleoprotein, RNAi knockdown, fluorescence imaging of vSPOTs, BDV transcription/replication assay\",\n      \"journal\": \"The Journal of general virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and functional knockdown with defined phenotypic readout, single lab\",\n      \"pmids\": [\"26333388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RBMX (hnRNP-G) forms a complex with ZAP3, PP1, SAM68, CIA, and NF110/45 in the nucleus; the interaction of hnRNP-G with ZAP3 and SAM68 is lost upon digestion of endogenous nucleic acid, indicating these interactions are nucleic acid-dependent.\",\n      \"method\": \"Proteomic analysis (mass spectrometry) of ZAP3 complex, nucleic acid digestion experiment to test interaction dependency\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — MS-based interactome from ZAP3 pulldown, single method, RBMX not the primary focus\",\n      \"pmids\": [\"17890166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DeSUMOylation of RBMX in diabetic kidney disease alters exosomal miRNA content; RBMX binds miR-26a, miR-23c, and miR-874 within exosomes, and these miRNAs protect against mitochondrial damage by targeting CERS6 mRNA.\",\n      \"method\": \"Co-immunoprecipitation, SUMOylation assays, RNA immunoprecipitation, confocal microscopy, AAV-mediated Rbmx overexpression in mice\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — multiple assays but complex multi-step mechanism, single lab, limited orthogonal validation\",\n      \"pmids\": [\"39341454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The SOCS5 SH2 domain (with critical residues Y413 and D443) directly binds the RBMX RRM domain; SOCS5-RBMX co-stimulate the SREBP1 promoter to induce de novo lipogenesis, and SH2 domain mutations reverse this effect.\",\n      \"method\": \"Co-immunoprecipitation, GST-pulldown, SREBP1 promoter assay, domain mutation analysis\",\n      \"journal\": \"NPJ precision oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal Co-IP and GST-pulldown with domain mapping and promoter functional assay, single lab\",\n      \"pmids\": [\"38429411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Mycobacterial phosphatase PstP dephosphorylates RBMX at serine 189 (S189), which influences the alternative splicing of PLA2G7, resulting in increased levels of a PLA2G7 transcript containing exon 9 that potentiates inflammatory responses.\",\n      \"method\": \"Multi-omics (proteomics, phosphoproteomics, transcriptomics, interactomics), site-specific dephosphorylation analysis of RBMX S189 by PstP\",\n      \"journal\": \"iMetaOmics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multi-omics identification with phosphosite specificity, but limited direct functional validation of RBMX S189 in splicing, single study\",\n      \"pmids\": [\"41675711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBMX influences allele-dependent differences in DDIT4 protein expression at a 3'UTR SNP (rs1053639); RBMX binds DDIT4 3'UTR in an allele-specific manner (RNA-EMSA, RIP, smiFISH), and RBMX depletion reduces DDIT4 protein in TT clones to AA levels, modulating mTORC1 repression under ER stress.\",\n      \"method\": \"RNA-EMSA, RIP, smiFISH, RBMX depletion, CRISPR genome editing for allele comparison, polysome profiling\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (EMSA, RIP, smiFISH, KD with functional readout), preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBMX and RBMXL1 share protein and RNA partners and act redundantly in brain development; RBMXL1 buffers the impact of RBMX deficiency in mice, explaining the discrepancy between severe human cortical phenotypes and mild mouse phenotypes upon Rbmx loss.\",\n      \"method\": \"Mouse Rbmx knockout model, human genetic analysis, protein/RNA partner co-immunoprecipitation comparing RBMX and RBMXL1, cellular rescue experiments\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mouse model with mechanistic follow-up, Co-IP for shared partners, preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"RBMX is a nuclear RNA-binding protein (hnRNP G) that regulates alternative pre-mRNA splicing co-transcriptionally by binding m6A-modified nascent RNA and the phosphorylated CTD of RNAPII via its RGG motifs, interacting directly with splicing factors (Htra2-beta1, SRSF1, U2AF65, SRp75) and their target pre-mRNAs to control exon inclusion or skipping; it also maintains genome integrity by accumulating at DNA double-strand breaks in a PARP1-dependent manner to facilitate BRCA2 expression and homologous recombination, by binding ssDNA and recruiting TopBP1 to activate ATR on repetitive DNAs, and by associating with cohesin subunits and inhibiting Wapl to maintain centromeric sister chromatid cohesion; additional roles include regulating TERRA levels through the nuclear exosome (via ZCCHC8 interaction), controlling transcription of the CBX5/HP1α locus in myeloid leukemia, and being post-translationally regulated by PRMT5-mediated methylation of its RGG/RG motif and by (de)SUMOylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RBMX (hnRNP G) is a nuclear RNA-binding protein that couples co-transcriptional pre-mRNA splicing regulation to genome maintenance [#1, #0]. It acts as an m6A reader that engages the phosphorylated CTD of RNA Polymerase II through RGG motifs in its low-complexity region, co-transcriptionally associating with RNAPII and nascent pre-mRNA so that m6A near splice sites tunes RBMX binding and exon inclusion transcriptome-wide [#1]; functionally distinct domains support this, including an N-terminal RRM, a central nascent-transcript targeting domain that recruits RBMX to active transcription units, and a C-terminal auxiliary RNA-binding domain [#9]. RBMX directs specific splicing outcomes largely through direct protein-protein contacts with splicing factors rather than by RNA binding alone: it promotes SMN2 exon 7 inclusion via Htra2-beta1 [#2], cooperates with SRSF1 (in a manner controlled by PRMT5 methylation of its RGG/RG motif) to govern MDM4 exon 6 inclusion and downstream p53 signaling [#5], partners with U2AF65 to control HPV16 transcript splicing [#14], and antagonizes hnRNP A1 to shift PKM splicing toward PKM1 and restrain glycolysis [#7]. In parallel, RBMX safeguards genome integrity: it accumulates at DNA double-strand breaks in a PARP1-dependent manner to promote BRCA2 expression and homologous recombination [#0], binds ssDNA at sites adjacent to RPA to recruit TopBP1 and activate ATR on repetitive DNA during replication stress [#4], and maintains centromeric sister chromatid cohesion by associating with cohesin subunits Scc1/Smc3 and acting as a Wapl inhibitor [#3], with satellite I noncoding RNA stabilizing RBMX within a centromeric ncRNP complex [#8]. RBMX also regulates RNA metabolism beyond splicing, promoting TERRA degradation by bridging it to the nuclear exosome via ZCCHC8 and thereby limiting telomeric R-loops [#16], and controlling nascent transcription of the CBX5/HP1\\u03b1 locus to support leukemic cell survival [#6]. Its activity is modulated post-translationally by PRMT5-mediated arginine methylation [#5] and by (de)SUMOylation [#14]. RBMX and its retrogene RBMXL1 share partners and act redundantly, with RBMXL1 buffering RBMX loss in brain development [#23].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established that RBMX achieves splice-site specificity through protein-protein interaction rather than nonspecific RNA binding, defining its mode of action as a splicing regulator.\",\n      \"evidence\": \"in vivo splicing assays with hnRNP-G deletion mutants and Htra2-beta1 interaction analysis on SMN2 exon 7\",\n      \"pmids\": [\"12165565\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the RNA elements or genome-wide targets\", \"Mechanism of co-transcriptional recruitment unaddressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed RBMX can act at the DNA/promoter level, regulating SREBP-1c transcription in response to dietary fructose, broadening its role beyond RNA processing.\",\n      \"evidence\": \"MALDI-TOF identification, EMSA with anti-RBMX antibody, and SREBP-1c promoter gain/loss-of-function in hepatoma cells\",\n      \"pmids\": [\"17188681\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DNA binding versus complex recruitment not resolved\", \"No structural basis for promoter recognition\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified SAFB1 as an RBMX partner required for RBMX-driven Srebp-1c promoter activity, providing a protein-complex mechanism for the transcriptional role.\",\n      \"evidence\": \"yeast two-hybrid, Co-IP, ChIP, and promoter activity assays\",\n      \"pmids\": [\"19403048\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of SAFB1 dependence at other loci unknown\", \"Interplay with RBMX RNA-binding function unaddressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved RBMX into functionally distinct domains, separating RNA-sequence recognition from recruitment to active transcription units.\",\n      \"evidence\": \"domain deletion analysis with injection into Xenopus oocytes and RNA-binding assays\",\n      \"pmids\": [\"21327109\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural model of the NTD lacking\", \"How recruitment integrates with splice-site selection unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended the splicing-factor interaction model by showing RBMX represses tau exon 10 through a complex with SRp75, relevant to FTDP-17.\",\n      \"evidence\": \"co-transfection splicing assays, Co-IP, and RNAi\",\n      \"pmids\": [\"21723381\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RNA contacts on the tau intron not mapped\", \"Single-cell-system validation only\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed an unanticipated genome-maintenance role: RBMX accumulates at DSBs in a PARP1-dependent manner and promotes HR via BRCA2 expression.\",\n      \"evidence\": \"genome-wide siRNA screen, lesion localization imaging, and HR assays with domain analysis\",\n      \"pmids\": [\"22344029\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether BRCA2 regulation is transcriptional or splicing-based not fully resolved\", \"RNA-binding requirement at lesions unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined RBMX as a centromeric cohesion factor, linking it to faithful chromosome segregation through Wapl inhibition.\",\n      \"evidence\": \"RNAi depletion, reciprocal Co-IP with Scc1/Smc3 and Wapl, chromosome morphology, and Wapl epistasis\",\n      \"pmids\": [\"22832223\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical basis of Wapl inhibition unknown\", \"Whether RNA binding contributes to cohesion not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected RBMX cohesion function to a noncoding RNP, showing satellite I RNA stabilizes RBMX and Sororin in an M-phase centromere complex.\",\n      \"evidence\": \"LC/MS purification of satellite I ncRNP, RNAi, cell-cycle synchronization, and immunofluorescence\",\n      \"pmids\": [\"29383807\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and architecture of the ncRNP undefined\", \"Single-lab; limited orthogonal validation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Unified RBMX splicing activity under a co-transcriptional, m6A-reader framework, mechanistically linking RNA modification, RNAPII CTD binding, and exon inclusion genome-wide.\",\n      \"evidence\": \"in vitro CTD binding, CLIP-seq, ChIP-seq, RGG-motif mutagenesis, and transcriptome-wide splicing analysis\",\n      \"pmids\": [\"31445886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct m6A-binding affinity/structural basis not defined\", \"How m6A reading is integrated with specific splicing-factor partners unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Clarified that RBMX binding to the lncRNA NORAD is dispensable for NORAD-mediated genomic stability, refining which RBMX RNA interactions are functionally relevant.\",\n      \"evidence\": \"RNA FISH, cellular fractionation, and genetic rescue with PUM- and RBMX-binding-mutant NORAD\",\n      \"pmids\": [\"31343408\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not exclude RBMX-NORAD roles in other contexts\", \"No direct test of RBMX binding kinetics on NORAD\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a distinct ATR-activating pathway in which ssDNA-bound RBMX recruits TopBP1 on repetitive DNA, independent of the canonical ssDNA-dsDNA junction/9-1-1 route.\",\n      \"evidence\": \"super-resolution STORM, ChIP-seq, in vitro ssDNA binding, RNAi, and replication-stress/SCE assays\",\n      \"pmids\": [\"32494026\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RBMX selects repetitive loci versus general ssDNA unclear\", \"Relationship to RBMX splicing function unaddressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established PRMT5 methylation of the RBMX RGG/RG motif as a switch controlling RBMX/SRSF1 complex assembly and MDM4 splicing, tying RBMX to p53 regulation and Shashi-XLID.\",\n      \"evidence\": \"PRMT5 methylation assay, RBMX/SRSF1 Co-IP, SRSF1-MDM4 RIP, minigene splicing, and CRISPR isogenic hiPSCs with transcriptomics\",\n      \"pmids\": [\"34260915\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other methylation-dependent splicing targets not mapped\", \"Stoichiometry of higher-order RBMX/SRSF1 assemblies undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed RBMX (with RBMXL1) controls nascent CBX5/HP1\\u03b1 transcription to support leukemic cell growth, identifying a transcription-level effector relevant to myeloid malignancy.\",\n      \"evidence\": \"RIP, chromatin accessibility, nascent transcription analysis, and CBX5 rescue in murine/human AML cells\",\n      \"pmids\": [\"34458856\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which RBMX engages the CBX5 locus unclear\", \"Direct DNA versus nascent-RNA contact not distinguished\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated RBMX competitively antagonizes hnRNP A1 at PKM exon 9 to favor PKM1, linking RBMX splicing control to metabolic and tumor-suppressive output.\",\n      \"evidence\": \"RBMX/hnRNP A1 Co-IP, PKM splicing analysis, and RNAi/overexpression with in vitro and in vivo assays\",\n      \"pmids\": [\"33564070\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RNA-binding competition not biochemically reconstituted\", \"Single cancer context\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapped a splicing-enhancing region of RBMX acting via U2AF65 on HPV16 pre-mRNA and showed SUMOylation status, modulated by DDR, tunes these interactions.\",\n      \"evidence\": \"splicing-enhancer mutagenesis, RNA binding, U2AF65 Co-IP, domain deletion, and sumoylation assays in keratinocytes\",\n      \"pmids\": [\"35357488\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SUMO sites on RBMX not pinpointed\", \"Generality beyond viral transcripts untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified RBMX as a factor that delivers TERRA to the nuclear exosome via ZCCHC8, controlling telomeric R-loop levels and telomere stability.\",\n      \"evidence\": \"RIP, RBMX/ZCCHC8 Co-IP, TERRA level and R-loop measurement, and replication-stress assays\",\n      \"pmids\": [\"37756323\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct handoff mechanism to exosome not reconstituted\", \"Single-lab functional readouts\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked RBMX SUMOylation status to exosomal miRNA loading in diabetic kidney disease, extending RBMX RNA-binding roles to extracellular vesicle cargo.\",\n      \"evidence\": \"Co-IP, SUMOylation assays, RIP, confocal microscopy, and AAV-mediated Rbmx overexpression in mice\",\n      \"pmids\": [\"39341454\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Complex multi-step mechanism with limited orthogonal validation\", \"Direct RBMX-miRNA binding specificity not established\", \"Disease-context specificity unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed the SOCS5 SH2 domain directly binds the RBMX RRM and co-activates the SREBP1 promoter to drive lipogenesis, providing a partner-based mechanism for RBMX transcriptional activity.\",\n      \"evidence\": \"Co-IP, GST-pulldown, SREBP1 promoter assay, and SH2/RRM domain mutation analysis\",\n      \"pmids\": [\"38429411\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship to SAFB1-dependent SREBP regulation unresolved\", \"Single-lab functional context\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified phosphorylation of RBMX at S189 as a regulatable mark influencing PLA2G7 alternative splicing and inflammatory output.\",\n      \"evidence\": \"multi-omics with site-specific dephosphorylation of RBMX S189 by mycobacterial PstP\",\n      \"pmids\": [\"41675711\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct functional validation of S189 in splicing limited\", \"Host kinase for S189 in normal physiology unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated allele-specific RBMX binding to the DDIT4 3'UTR controlling DDIT4 protein levels and mTORC1 repression, implicating RBMX in 3'UTR-dependent translational/expression control.\",\n      \"evidence\": \"RNA-EMSA, RIP, smiFISH, RBMX depletion, CRISPR allele editing, and polysome profiling (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint; not peer-reviewed\", \"Mechanism (stability vs translation) of allele-specific effect not fully resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established functional redundancy between RBMX and its retrogene RBMXL1, explaining species-dependent phenotype severity through shared partners.\",\n      \"evidence\": \"Rbmx knockout mouse, human genetics, and Co-IP comparing RBMX/RBMXL1 partners with rescue (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint; not peer-reviewed\", \"Extent of non-redundant RBMX functions undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RBMX integrates its parallel roles in co-transcriptional splicing, DNA-damage/replication-stress signaling, and centromeric cohesion into a unified molecular logic, and how its PTM repertoire (methylation, SUMOylation, phosphorylation) coordinates switching among them, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated structural model of domain usage across functions\", \"Cross-talk between splicing and genome-maintenance activities untested\", \"PTM hierarchy and timing not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [1, 2, 9, 14, 16, 22]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [4, 11]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [6, 11, 12, 20]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 5, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 17, 18]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 3, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 2, 5, 16]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 8]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [6, 11, 12]}\n    ],\n    \"complexes\": [\n      \"RBMX/SRSF1 splicing complex\",\n      \"centromere satellite I ncRNP\",\n      \"cohesin (Scc1/Smc3/Wapl-associated)\"\n    ],\n    \"partners\": [\n      \"SRSF1\",\n      \"U2AF65\",\n      \"HNRNPA1\",\n      \"Htra2-beta1\",\n      \"ZCCHC8\",\n      \"TopBP1\",\n      \"SAFB1\",\n      \"SOCS5\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}