{"gene":"RBM10","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2013,"finding":"RBM10 binds pre-mRNA at sites in the vicinity of splice sites (identified by PAR-CLIP) and promotes exon skipping; loss-of-function and gain-of-function experiments in human cell lines, combined with minigene assays, established RBM10 as a regulator of alternative splicing, and splicing defects were confirmed in a patient carrying an RBM10 mutation.","method":"PAR-CLIP binding-site mapping, loss-of-function/gain-of-function experiments, minigene splicing assays, patient-derived cell analysis","journal":"EMBO Molecular Medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (PAR-CLIP, functional KD/OE, minigene assays) in a single rigorous study, with patient validation","pmids":["24000153"],"is_preprint":false},{"year":2014,"finding":"RBM10 promotes exon skipping of Fas pre-mRNA and selection of an internal 5′-splice site in Bcl-x pre-mRNA, regulating alternative splicing of apoptosis-related genes; a consensus RBM10-binding sequence at 5′-splice sites of target exons was proposed.","method":"Minigene splicing assays, RBM10 knockdown/overexpression in human cell lines, RT-PCR","journal":"FEBS Letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional KD/OE with defined splicing readout, single lab, two orthogonal methods","pmids":["24530524"],"is_preprint":false},{"year":2016,"finding":"RBM10 inhibits cell proliferation by promoting exon 9 skipping of NUMB pre-mRNA, generating a negative regulator of Notch signaling. The cancer-associated V354E mutation in the RRM2 domain disrupts this splicing activity without abolishing RRM2 binding to NUMB RNA regulatory sequences, and other lung adenocarcinoma mutations also compromise NUMB exon 9 regulation.","method":"Xenograft tumor growth assay (KD/OE), minigene splicing assays, RNA-binding assay, structural modeling, mutation analysis","journal":"RNA Biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (functional xenograft, minigene, RNA binding, mutagenesis) establishing mechanism, single lab","pmids":["26853560"],"is_preprint":false},{"year":2017,"finding":"RBM10 negatively autoregulates its own mRNA and protein expression and cross-regulates its paralog RBM5 by promoting alternative splicing-coupled nonsense-mediated mRNA decay (AS-NMD); skipping of exon 6 or 12 in RBM10 and exon 6 or 16 in RBM5 triggers NMD. LUAD-associated splice-site mutations abolishing exon inclusion correlated with reduced RBM10 RNA expression.","method":"Computational analysis, RT-PCR/qPCR, minigene assays, NMD inhibition experiments, patient mutation analysis","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (computational + minigene + NMD inhibitor + patient data) establishing autoregulatory mechanism","pmids":["28586478"],"is_preprint":false},{"year":2017,"finding":"An RRM1-ZnF module of RBM10 recognizes a GGA-centered exonic motif to promote exon skipping, while the RRM2 domain recognizes a C-rich intronic 3′ sequence of NUMB exon 9. A polypeptide containing RRM1, ZnF1, and RRM2 in tandem recognizes a Fas exon 6 RNA sequence with ~20 nM affinity, explaining high-fidelity RNA recognition by cooperativity of domains.","method":"In vitro RNA-binding assays, NMR structure determination (RRM1, ZnF1, RRM2), domain deletion/combination experiments, splicing reporter assays","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure + in vitro binding assays + mutagenesis/domain dissection, multiple orthogonal methods","pmids":["28379442"],"is_preprint":false},{"year":2015,"finding":"NMR structure determination revealed that the RBM10 OCRE sequence motif forms a 55-residue globular domain with an antiparallel arrangement of six β-strands containing Tyr triplets; this domain is distinct from RNA recognition motifs and is proposed to mediate spliceosome protein–protein interactions.","method":"NMR structure determination","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Moderate — atomic-resolution NMR structure of the OCRE domain, single study with rigorous structural method","pmids":["26712279"],"is_preprint":false},{"year":2018,"finding":"RBM10 cooperatively binds RNA through three domains (RRM1, ZnF1, RRM2): the combination recognizes a specific Fas exon 6 mRNA sequence with 20 nM affinity, whereas individual domains bind with micromolar affinity. NMR structures of RRM1, ZnF1, and the V354del isoform of RRM2 confirmed canonical RNA recognition elements.","method":"NMR structure determination, in vitro RNA-binding affinity measurements with domain combinations","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structures + quantitative binding assays, single study, multiple orthogonal methods","pmids":["29450990"],"is_preprint":false},{"year":2018,"finding":"RBM10 performs a splicing-independent function in the heart: it associates with the non-canonical poly(A) polymerase Star-PAP (TUT1) via its RRM2 domain binding to the Star-PAP catalytic domain, binds pre-mRNA 3′ UTRs, assembles the Star-PAP complex, and guides it to mRNAs encoding anti-hypertrophy regulators to control their 3′-end processing. RBM10 is downregulated during cardiac hypertrophy and heart failure; re-expression rescues cardiomyocyte hypertrophy.","method":"Co-IP, domain mapping (RRM2 binding to Star-PAP catalytic domain), 3′-end processing assays, RBM10 KD/OE in rat cardiomyoblasts (H9c2), cardiac hypertrophy model in Wistar rats","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain-level mapping, in vitro and in vivo functional assays, multiple orthogonal methods","pmids":["30257214"],"is_preprint":false},{"year":2016,"finding":"RBM10 iCLIP profiling in mouse embryonic mandibular cells showed preferential binding to intronic pre-mRNA regions consistent with a splicing role; RBM10 also binds spliceosomal snRNAs U2 and U12. RNA-seq of RBM10 KO mouse mandibular and ES cells revealed widespread alternative splicing changes in bound transcripts, and depletion of RBM10 in mouse ES cells caused proliferation defects and altered differentiation potential.","method":"iCLIP, RNA-seq (KO cells), CRISPR/Cas9 KO, proliferation assays, differentiation assays","journal":"RNA Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — iCLIP + KO RNA-seq + functional phenotypes, multiple orthogonal methods in relevant developmental model","pmids":["27763814"],"is_preprint":false},{"year":2024,"finding":"RBM10 and its paralog RBM5 are subunits of the U2 snRNP, associating with precatalytic A/B-like spliceosomes at intronic branch sites genome-wide. A conserved peptide containing a zinc finger motif (separate from known functional domains) mediates the U2 snRNP interaction. Deletion of this peptide disrupts U2 association and renders RBM10 inactive for repression of many alternative exons.","method":"Biochemical isolation of chromatin-associated spliceosomal RNP complexes, MS proteomics, branch-site sequencing, domain deletion mutagenesis, splicing reporter assays","journal":"Molecular Cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — biochemical reconstitution-level isolation + MS + mutagenesis + transcriptome-wide branch-site mapping in a rigorous single study","pmids":["38537639"],"is_preprint":false},{"year":2017,"finding":"Rbm10 controls appropriate splicing of Dnmt3b: Rbm10 deficiency decreases the non-enzymatic isoform Dnmt3b3 and increases the enzymatically active isoform Dnmt3b2. Both isoforms associate with NF-κB, and elevated Dnmt3b2 increases DNA methylation at NF-κB-responsive promoters, suppressing NF-κB-mediated transcription and inflammation in vivo and in vitro.","method":"RT-PCR (splicing isoform analysis), ChIP, promoter methylation assay, NF-κB reporter assay, RBM10 KO mice, in vitro Dnmt3b isoform overexpression","journal":"International Immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (splicing, ChIP, methylation, NF-κB reporter, in vivo KO), mechanism established","pmids":["29309623"],"is_preprint":false},{"year":2020,"finding":"Dengue virus NS5 polymerase interacts with RBM10 and triggers its proteasome-mediated degradation. RBM10 is responsible for exon 4 skipping in SAT1 pre-mRNA; its depletion during infection causes exon 4 inclusion generating an NMD-susceptible isoform, reducing SAT1 protein and limiting antiviral defense. RBM10 also interacts with viral RNA and RIG-I and promotes RIG-I ubiquitination (activating it), contributing to innate immune signaling.","method":"Co-IP (NS5-RBM10 interaction), proteasome inhibitor rescue, RBM10 KD/OE in infected cells, RT-PCR splicing assay, viral replication assays, RIG-I ubiquitination assay","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, proteasome inhibition, KD/OE, splicing, ubiquitination) in a single study establishing mechanism","pmids":["32432721"],"is_preprint":false},{"year":2013,"finding":"S1-1/RBM10 contains multiple nuclear localization sequences (NLSs): a classical bipartite NLS (NLS1, aa 743–759), an NLS in the RRM1 region (NLS2, aa 60–136), and a novel NLS within the OCRE octamer-repeat region (NLS3, aa 481–540). These three NLSs act cooperatively; removal of all three renders the protein completely cytoplasmic. Nuclear localization is regulated in a cell-type-specific manner.","method":"Deletion and substitution mutagenesis, EGFP/FLAG fusion reporter assays, subcellular localization imaging","journal":"Biology of the Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic mutagenesis with reporter assays, single lab, two orthogonal methods (deletion mutagenesis + reporter imaging)","pmids":["23294349"],"is_preprint":false},{"year":2016,"finding":"Src family tyrosine kinase Fyn induces translocation of RBM10 from the nucleus to cell peripheries in a kinase activity-dependent manner. At the cell periphery, RBM10 colocalizes with the Rac-specific GAP FilGAP and is required for peripheral FilGAP localization. RBM10 depletion abolishes FilGAP-mediated suppression of cell spreading and ruffle formation, suggesting RBM10 stimulates FilGAP RacGAP activity in a Src-regulated manner.","method":"Co-IP (RBM10-FilGAP interaction), siRNA knockdown, immunofluorescence localization, cell spreading assay, membrane ruffle assay, kinase-dead Fyn mutant","journal":"PLoS One","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + localization + functional KD assays, single lab, multiple orthogonal methods","pmids":["26751795"],"is_preprint":false},{"year":2019,"finding":"RBM10 suppresses lung adenocarcinoma cell proliferation via a RAP1/AKT/CREB signaling pathway: RBM10 overexpression decreases RAP1 activation; EPAC stimulation/inhibition abolishes the effects of RBM10 KD/OE; and RBM10 reduces CREB phosphorylation through AKT, independently of MAPK/ERK and P38/MAPK pathways.","method":"cDNA microarray, RBM10 OE/KD, EPAC pharmacological modulation, Western blot (pCREB, pAKT), in vitro and in vivo proliferation assays","journal":"Journal of Cellular and Molecular Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis + multiple signaling pathway readouts, single lab","pmids":["30955253"],"is_preprint":false},{"year":2022,"finding":"RBM10 modulates alternative splicing of Bcl-x to regulate the ratio of proapoptotic Bcl-xS to antiapoptotic Bcl-xL isoforms. RBM10 deficiency decreases this ratio, diminishing EGFR inhibitor-mediated apoptosis. Coinhibition of Bcl-xL and mutant EGFR overcomes RBM10-deficiency-induced resistance.","method":"Patient-derived EGFR-mutant tumor models (in vitro and in vivo), RT-PCR (Bcl-x isoform ratio), apoptosis assays, genetic RBM10 inactivation, pharmacological Bcl-xL inhibition","journal":"Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — patient-derived models + splicing assay + apoptosis assay + pharmacological rescue, multiple orthogonal methods","pmids":["35579943"],"is_preprint":false},{"year":2021,"finding":"RBM10 overexpression in HepG2 cells causes M-phase growth arrest with monopolar spindle due to impaired centriole duplication. Nuclear RBM10 sequesters centriole duplication regulators PLK4, STIL, and SAS6 into large nuclear domains, depleting them from centrioles. This requires nuclear localization (cytoplasmic NES-forced RBM10 does not cause arrest). RBM10 depletion increases cytoplasmic PLK4 and supernumerary centrioles in HepG2 but not A549 cells, indicating cell-type specificity.","method":"HepG2 RBM10 KO cell lines, doxycycline-inducible re-expression, flow cytometry (M-phase arrest), immunofluorescence (centriole markers), NES mutant forcing cytoplasmic localization, siRNA KD","journal":"Genes to Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO + inducible re-expression + localization mutant + imaging, single lab, multiple methods","pmids":["31820547"],"is_preprint":false},{"year":2021,"finding":"RBM10 nuclear localization is regulated by sequestration in S1-1 nuclear bodies (NBs). Two NB-targeting sequences (NBTSs) are identified: one in the KEKE motif region and one in the C2H2 zinc finger (ZnF). These NBTSs act synergistically; the C2H2 ZnF is also essential for alternative splicing regulation. NB-localization of RBM10 increases when cellular transcription decreases, suggesting NBs sequester RBM10 to control its splicing activity.","method":"Deletion mutagenesis, reporter constructs, immunofluorescence, transcription inhibition experiments","journal":"International Journal of Molecular Sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — systematic mutagenesis with imaging and functional splicing readouts, single lab","pmids":["34638866"],"is_preprint":false},{"year":2017,"finding":"RBM10 knockdown alters splicing of SMN2 pre-mRNA in multiple cancer and normal cell lines, resulting in preferential expression of the full-length exon-7-retaining SMN2 transcript and increased full-length SMN protein. Re-expression of RBM10 in a stable KD line reverted this effect, confirming specificity.","method":"siRNA KD, RT-PCR splicing array platform, Western blot, re-expression rescue, primary SMA patient fibroblasts","journal":"BMC Molecular Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD + rescue re-expression + multiple cell lines + protein-level validation, single lab","pmids":["28728573"],"is_preprint":false},{"year":2017,"finding":"RBM5 post-transcriptionally regulates RBM10 expression via direct interaction with specific RBM10 splice variants, as demonstrated by RIP-Seq and Western blotting in an RBM5-null SCLC cell line. In this context, RBM10 promotes (rather than suppresses) cell proliferation and other transformation-associated processes.","method":"RNA immunoprecipitation sequencing (RIP-Seq), Western blotting, transcriptome analysis, functional cell proliferation assays","journal":"PLoS One","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP-Seq + Western blot + functional assays, single lab","pmids":["28662214"],"is_preprint":false},{"year":2021,"finding":"In fission yeast, Rbm10 (ortholog of human RBM10) associates with the histone deacetylase Clr6 complex and chromatin remodelers important for heterochromatin silencing. Deletion of Rbm10 causes severe heterochromatin defects and significant reduction of Clr6 at heterochromatin, without major effects on genome-wide splicing, revealing a splicing-independent role in heterochromatin assembly.","method":"Proteomics (Rbm10 interactome), ChIP-seq (Clr6 localization), deep RNA-seq, genetic deletion, silencing reporter assays","journal":"Epigenetics & Chromatin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomic interaction + ChIP + functional heterochromatin assays, single lab, fission yeast ortholog","pmids":["33468217"],"is_preprint":false},{"year":2024,"finding":"RBM10 has a splicing-independent role in DNA replication fork stability: it associates with active DNA replication forks via interaction with DNA Primase Subunit 1 (PRIM1), recruits HDAC1 to facilitate H4K16 deacetylation, and maintains R-loop homeostasis. WEE1 inhibition is synthetically lethal with RBM10 deficiency (identified by CRISPR-Cas9 SL screen), and this lethality is mechanistically linked to replication stress.","method":"CRISPR-Cas9 synthetic lethality screen, DNA fiber assay (replication fork), iPOND/replication fork proteomics, HDAC1 recruitment assay, H4K16 acetylation ChIP, R-loop quantification, in vitro and in vivo WEE1 inhibitor treatment","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — CRISPR SL screen + DNA fiber assay + ChIP + in vivo validation, multiple orthogonal methods establishing novel mechanism","pmids":["39080280"],"is_preprint":false},{"year":2024,"finding":"RBM10 promotes exon 18 skipping of ASPM pre-mRNA by interacting with SRSF2. The C761Y mutation in the RBM10 C2H2-type zinc finger domain impairs its interaction with SRSF2, causing loss of ASPM exon 18 skipping, generating the ASPM203 isoform which stabilizes DVL2 and enhances β-catenin/Wnt signaling to promote cholangiocarcinoma progression.","method":"RNA-seq (alternative splicing), minigene reporter assays, Co-IP (RBM10-SRSF2 interaction with WT vs C761Y), Western blot, functional tumor assays","journal":"Journal of Experimental & Clinical Cancer Research","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP showing interaction disrupted by mutation + minigene + functional assays + downstream pathway validation, multiple orthogonal methods","pmids":["38576051"],"is_preprint":false},{"year":2021,"finding":"RBM10 binds MALAT1 lncRNA (highest binding peak among ncRNAs by CLIP-Seq), and RBM10 inhibits invasion/migration of NSCLC by recruiting METTL3 to suppress m6A methylation of MALAT1, thereby affecting PI3K/AKT/mTOR pathway phosphorylation.","method":"CLIP-Seq, RIP assay (RBM10-MALAT1), MeRIP-qPCR (m6A methylation), Co-IP (RBM10-METTL3), transwell invasion/migration assays, Western blot","journal":"Life Sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — CLIP-Seq + RIP + MeRIP + Co-IP + functional assays, single lab","pmids":["36608868"],"is_preprint":false},{"year":2021,"finding":"Star-PAP global mRNA association depends on RBM10: knockdown of RBM10 causes global loss of Star-PAP binding to target mRNAs and compromises 3′-end processing of Star-PAP target mRNAs while also regulating stability/turnover of another set of mRNAs.","method":"HITS-CLIP (Star-PAP binding landscape), RBM10 KD, 3′-end processing assays, mRNA stability assays","journal":"International Journal of Molecular Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — HITS-CLIP + KD + 3′-processing assays, single lab, multiple methods","pmids":["34576144"],"is_preprint":false},{"year":2024,"finding":"cSrc kinase phosphorylates RBM10 at three tyrosine residues (Y81, Y500, Y971). This phosphorylation is induced during cardiac hypertrophy, promotes nuclear localization of RBM10 and its interaction with Star-PAP, and is required for anti-hypertrophy gene expression and 3′-end mRNA formation. Inhibition of cSrc or phospho-deficient RBM10 mutations prevent reversal of cardiac hypertrophy even when RBM10 levels are restored.","method":"In vitro kinase assay (cSrc phosphorylating RBM10), phospho-deficient mutants (Y→F), cSrc inhibitor treatment, isoproterenol-induced rat heart hypertrophy model, Co-IP (phospho-RBM10–Star-PAP), nuclear localization assay","journal":"Life Sciences","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assay + phospho-deficient mutagenesis + in vivo animal model + Co-IP, multiple orthogonal methods","pmids":["38309577"],"is_preprint":false},{"year":2023,"finding":"RBM10 promotes exclusion of hTERT exons 7 and 8 to generate the non-functional hTERT-s isoform in pancreatic cancer, suppressing telomerase activity and telomere maintenance. This was confirmed by RNA-IP and RNA pulldown assays. RBM10 gain or loss significantly changed pancreatic cancer cell proliferation in vitro and in xenografts.","method":"RNA-IP, RNA pulldown, minigene/splicing assays, RBM10 OE/KD, telomerase activity assay, xenograft tumor growth","journal":"American Journal of Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-IP + pulldown + functional assays, single lab","pmids":["33520366"],"is_preprint":false},{"year":2020,"finding":"miR-335 directly targets the 3′UTR of RBM10 mRNA (confirmed by luciferase reporter assay), downregulating RBM10 protein post-transcriptionally. This reduces RBM10-mediated exon skipping in NUMB pre-mRNA, increasing the Numb long isoform (Numb-L), which promotes endometrial cancer tumor growth in xenograft models.","method":"Luciferase reporter assay (miR-335 targeting RBM10 3′UTR), Western blot, xenograft mouse model, RT-PCR (NUMB splicing)","journal":"Kaohsiung Journal of Medical Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter + in vivo xenograft + splicing assay, single lab","pmids":["31894898"],"is_preprint":false},{"year":2022,"finding":"RBM10 interacts directly with NPTX1 mRNA (demonstrated by RIP assay) and regulates NPTX1 mRNA stability, as confirmed by actinomycin D mRNA decay experiments in pancreatic cancer cells.","method":"RIP assay, actinomycin D mRNA stability assay, RT-qPCR, Western blot","journal":"Oncology Letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single RIP assay + mRNA stability experiment, single lab, limited mechanistic detail","pmids":["35836482"],"is_preprint":false},{"year":2025,"finding":"RBM10 loss in thyroid cancer causes exon inclusion events in cytoskeletal and ECM transcripts (vinculin VCL, tenascin C TNC, CD44), leading to RAC1 activation and increased cell velocity and invasiveness. Knockdown of the specific exon inclusion isoforms of VCL (reduced velocity), TNC, or CD44 (reduced invasiveness) reverses these phenotypes. In a mouse HrasG12V/Rbm10KO thyrocyte model, metastases develop and are reversed by RBM10 re-expression or combined knockdown of the three inclusion isoforms.","method":"RNA-seq (exon inclusion analysis), isoform-specific siRNA KD, RAC1-GTP pulldown assay, cell velocity assay, invasion assay, mouse genetic model (Rbm10KO), RBM10 re-expression rescue","journal":"Journal of Experimental Medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RNA-seq, isoform-specific KD, RAC1 activity, mouse model, rescue) establishing splicing-to-metastasis mechanism","pmids":["39992626"],"is_preprint":false},{"year":2025,"finding":"RBM10 interacts with RORB transcription factor in liquid condensates in neuroblastoma cells, repressing RORB transactivation. A small peptide blocking the RBM10-RORB interaction suppresses lysosomal biogenesis, tumorigenesis, and aggressiveness by derepressing NR1D1/RIOK3-mediated suppression of NF-κB activity.","method":"Co-IP, immunofluorescence, liquid condensate assays, small-peptide inhibitor, functional tumor assays","journal":"Advanced Science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP + peptide inhibitor + functional assays, single lab, limited mechanistic depth in abstract","pmids":["40899609"],"is_preprint":false},{"year":2024,"finding":"RBM10 forms a trimeric complex with YBX1 and phosphatase PPM1B; PPM1B dephosphorylates YBX1 within this complex. RBM10 knockdown attenuates the YBX1-PPM1B association, leading to elevated YBX1 phosphorylation and nuclear translocation, promoting breast cancer proliferation and migration. PPM1B overexpression reverses the tumorigenic effects of RBM10 depletion.","method":"Co-IP (triple complex), Western blot (YBX1 phosphorylation, nuclear fractionation), RBM10 KD, PPM1B OE rescue, xenograft assay","journal":"Experimental Cell Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + genetic rescue + in vivo validation, single lab, multiple methods","pmids":["38246397"],"is_preprint":false},{"year":2025,"finding":"HIV-1 Vpu interacts with RBM10 (identified by APEX2-proximity labeling + IP-MS) and promotes its degradation through the ubiquitin-proteasome pathway. RBM10 inhibits HIV-1 replication by binding to viral RNA and reducing incompletely spliced HIV-1 transcripts, and promotes transcription of antiviral genes.","method":"APEX2-proximity labeling + mass spectrometry, IP-MS, Co-IP, proteasome inhibitor rescue, RNA-IP (RBM10-viral RNA), viral replication assays","journal":"mSystems","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple interaction methods (APEX2-MS, IP-MS, Co-IP) + functional assays, single lab","pmids":["40742131"],"is_preprint":false},{"year":2026,"finding":"RBM10 directly binds intronic flanking sequences of circHIPK3 and circSMARCA5 pre-mRNAs (PAR-CLIP + RNA pulldown). Binding to the 3′ flanking region more efficiently promotes exon skipping and circularization than 5′ binding. RBM10 loss impairs formation of these circRNAs; RBM10 point mutants with defective exon skipping also fail to regulate circRNA production. Modulation of circHIPK3 and circSMARCA5 phenocopies RBM10 restoration in mutant LUAD cells. RBM10 interacts with SF3B1 as an upstream event governing circHIPK3 biogenesis.","method":"PAR-CLIP, RNA pulldown, splicing reporter assay, RBM10 point mutants, functional tumor assays, Co-IP (RBM10-SF3B1), subcellular fractionation","journal":"Biomarker Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PAR-CLIP + pulldown + reporter assay + mutagenesis + functional rescue, single lab","pmids":["41673707"],"is_preprint":false},{"year":1996,"finding":"DXS8237E (the gene later identified as RBM10) was isolated from human fetal brain cDNA, maps within 20 kb upstream of UBE1 at Xp11.23, and is subject to X inactivation (unlike its neighbor UBE1 which escapes X inactivation), as demonstrated in somatic cell hybrids containing an inactive human X chromosome.","method":"cDNA cloning, somatic cell hybrid analysis, Northern blot (expression), X-inactivation assay","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct X-inactivation assay in somatic cell hybrids, single study, genomic localization experiment","pmids":["8808293"],"is_preprint":false}],"current_model":"RBM10 is a nuclear RNA-binding protein that functions primarily as an alternative splicing regulator by binding pre-mRNA at intronic and exonic sites (via cooperative action of RRM1, ZnF1, and RRM2 domains, with an additional U2 snRNP-interaction domain containing a zinc finger motif), promoting exon skipping of target genes including NUMB (suppressing Notch signaling), Fas, Bcl-x, Dnmt3b, hTERT, and cytoskeletal/ECM transcripts; it also performs splicing-independent functions including 3′-end mRNA processing in the heart by associating with the poly(A) polymerase Star-PAP (regulated by cSrc-mediated phosphorylation at Y81/Y500/Y971), regulation of DNA replication fork stability via HDAC1 recruitment and H4K16 deacetylation, interaction with FilGAP to modulate Rac-mediated cytoskeletal dynamics, and antiviral roles through RIG-I ubiquitination and viral RNA binding; it autoregulates its own expression and cross-regulates RBM5 through AS-coupled nonsense-mediated decay, and its nuclear localization is controlled by multiple cooperative NLS sequences and regulated sequestration into nuclear bodies."},"narrative":{"mechanistic_narrative":"RBM10 is a nuclear RNA-binding protein that functions principally as an alternative splicing regulator, binding pre-mRNA near splice sites to promote exon skipping across a large set of target transcripts [PMID:24000153, PMID:27763814]. It is a subunit of the U2 snRNP, associating with precatalytic A/B-like spliceosomes at intronic branch sites genome-wide through a conserved zinc-finger-containing peptide whose deletion abolishes U2 association and splicing repression activity [PMID:38537639]. High-fidelity target recognition arises from cooperative RNA binding by tandem RRM1, ZnF1, and RRM2 domains: the RRM1-ZnF module reads a GGA-centered exonic motif while RRM2 recognizes C-rich intronic sequence, and the combined module binds target RNA with nanomolar affinity versus micromolar affinity for isolated domains [PMID:28379442, PMID:29450990]; an additional OCRE domain forms a distinct β-stranded fold implicated in spliceosomal protein interactions [PMID:26712279]. Through these activities RBM10 controls splicing of genes governing proliferation, apoptosis, and differentiation, including exon 9 skipping of NUMB to suppress Notch-driven proliferation [PMID:26853560], Fas and Bcl-x splicing to set apoptotic isoform balance [PMID:24530524, PMID:35579943], Dnmt3b isoform choice to modulate NF-κB-responsive DNA methylation [PMID:29309623], and hTERT exon exclusion to limit telomerase activity [PMID:33520366]. RBM10 also negatively autoregulates its own expression and cross-regulates its paralog RBM5 via alternative-splicing-coupled nonsense-mediated decay [PMID:28586478]. Beyond canonical splicing, RBM10 performs splicing-independent roles: it assembles the non-canonical poly(A) polymerase Star-PAP complex via RRM2 binding to direct 3'-end mRNA processing of anti-hypertrophy transcripts in the heart, an activity gated by cSrc phosphorylation at Y81/Y500/Y971 [PMID:30257214, PMID:34576144, PMID:38309577]; it stabilizes DNA replication forks by associating with PRIM1 and recruiting HDAC1 for H4K16 deacetylation, with RBM10 deficiency being synthetically lethal with WEE1 inhibition [PMID:39080280]; and it acts in antiviral defense by binding viral RNA and being targeted for proteasomal degradation by dengue NS5 and HIV-1 Vpu [PMID:32432721, PMID:40742131]. Loss-of-function mutations in RBM10, including LUAD-associated splice-site and RRM2 mutations and a cholangiocarcinoma C2H2 zinc-finger C761Y mutation that disrupts SRSF2 interaction, impair its splicing activity and promote tumorigenesis [PMID:26853560, PMID:28586478, PMID:38576051], and RBM10 splicing defects were confirmed in a patient carrying an RBM10 mutation [PMID:24000153].","teleology":[{"year":1996,"claim":"Before functional characterization, the gene's chromosomal identity was established, placing DXS8237E/RBM10 at Xp11.23 and showing it is subject to X inactivation.","evidence":"cDNA cloning and X-inactivation assay in somatic cell hybrids carrying an inactive X chromosome","pmids":["8808293"],"confidence":"Medium","gaps":["No protein function assigned at this stage","No RNA-binding or splicing activity tested"]},{"year":2013,"claim":"The core function was defined: RBM10 binds pre-mRNA near splice sites and acts as an alternative-splicing regulator promoting exon skipping, with disease relevance shown through patient-derived splicing defects.","evidence":"PAR-CLIP binding-site mapping, KD/OE and minigene assays in human cells, plus patient cell analysis","pmids":["24000153"],"confidence":"High","gaps":["Domain basis of RNA recognition not yet resolved","Spliceosomal context of action unknown"]},{"year":2013,"claim":"Nuclear access of RBM10 was shown to require three cooperative NLSs, establishing that its function depends on regulated nuclear import.","evidence":"Deletion/substitution mutagenesis and EGFP/FLAG reporter localization imaging","pmids":["23294349"],"confidence":"Medium","gaps":["Import receptors not identified","Mechanism of cell-type-specific regulation unresolved"]},{"year":2014,"claim":"RBM10 was linked to apoptotic isoform control by directing Fas exon skipping and Bcl-x 5'-splice-site selection, with a proposed consensus binding motif.","evidence":"Minigene assays, KD/OE, and RT-PCR in human cell lines","pmids":["24530524"],"confidence":"Medium","gaps":["Direct binding to these targets not structurally validated here","Physiological apoptotic consequence not tested in vivo"]},{"year":2015,"claim":"The OCRE motif was shown to fold into a discrete β-stranded globular domain distinct from RRMs, implicating it in spliceosomal protein-protein interactions rather than RNA binding.","evidence":"NMR structure determination of the OCRE domain","pmids":["26712279"],"confidence":"High","gaps":["Specific protein partners of OCRE not identified","Functional requirement for splicing not tested"]},{"year":2016,"claim":"RBM10 was connected to growth control via NUMB exon 9 skipping to suppress Notch signaling, and cancer mutations were shown to uncouple RNA binding from splicing activity.","evidence":"Xenograft assays, minigene and RNA-binding assays, structural modeling, mutation analysis (including V354E)","pmids":["26853560"],"confidence":"High","gaps":["Mechanism by which V354E disrupts splicing without abolishing binding unresolved","Generality across other targets not addressed"]},{"year":2016,"claim":"Transcriptome-wide binding and KO analysis in a developmental model confirmed preferential intronic binding and a requirement for RBM10 in proliferation and differentiation, while binding to U2/U12 snRNAs hinted at a spliceosomal association.","evidence":"iCLIP, KO RNA-seq, CRISPR/Cas9 KO, proliferation and differentiation assays in mouse cells","pmids":["27763814"],"confidence":"High","gaps":["Direct snRNP incorporation not yet demonstrated biochemically","Developmental phenotype mechanism not dissected"]},{"year":2016,"claim":"A cytoplasmic, splicing-independent role was uncovered: Fyn-driven RBM10 translocation to the cell periphery supports FilGAP RacGAP activity controlling cell spreading and ruffling.","evidence":"Co-IP, siRNA KD, immunofluorescence, cell spreading/ruffle assays, kinase-dead Fyn mutant","pmids":["26751795"],"confidence":"Medium","gaps":["Single-lab Co-IP without reciprocal structural mapping","Physiological significance of cytoplasmic pool unclear"]},{"year":2017,"claim":"RBM10 was shown to autoregulate its own expression and cross-regulate RBM5 through AS-coupled NMD, defining a feedback architecture relevant to LUAD mutations.","evidence":"Computational analysis, RT-PCR/qPCR, minigene assays, NMD inhibition, patient mutation analysis","pmids":["28586478"],"confidence":"High","gaps":["Quantitative contribution of feedback to homeostasis unresolved","Trigger for differential exon choice unknown"]},{"year":2017,"claim":"The structural logic of target recognition was established: RRM1-ZnF reads an exonic GGA motif and RRM2 reads C-rich intronic sequence, with domain cooperativity giving high-affinity, high-fidelity binding.","evidence":"NMR structures of RRM1/ZnF1/RRM2, in vitro binding, domain dissection, splicing reporters","pmids":["28379442"],"confidence":"High","gaps":["How motif engagement translates to spliceosome modulation not fully defined","OCRE contribution not integrated"]},{"year":2017,"claim":"RBM10 was tied to epigenetic and inflammatory output through Dnmt3b isoform control, linking splicing to NF-κB-responsive promoter methylation.","evidence":"Splicing RT-PCR, ChIP, methylation assay, NF-κB reporter, RBM10 KO mice","pmids":["29309623"],"confidence":"High","gaps":["Direct binding to Dnmt3b pre-mRNA not mapped","Breadth of methylation changes not genome-wide"]},{"year":2017,"claim":"RBM10 was shown to influence SMN2 exon 7 inclusion, raising potential relevance to spinal muscular atrophy splicing, with rescue confirming specificity.","evidence":"siRNA KD, splicing array RT-PCR, Western blot, re-expression rescue, SMA patient fibroblasts","pmids":["28728573"],"confidence":"Medium","gaps":["Direct binding to SMN2 not demonstrated","Single-lab observation"]},{"year":2017,"claim":"Context-dependent regulation was revealed: in an RBM5-null SCLC background, RBM5 post-transcriptionally regulates specific RBM10 splice variants and RBM10 promotes rather than suppresses proliferation.","evidence":"RIP-Seq, Western blotting, transcriptome and proliferation assays","pmids":["28662214"],"confidence":"Medium","gaps":["Mechanism of context-dependent reversal of growth effect unclear","Single cell-line context"]},{"year":2018,"claim":"Cooperative tri-domain RNA recognition was quantitatively confirmed, showing nanomolar Fas-exon-6 binding by RRM1-ZnF1-RRM2 versus micromolar by single domains, and structural integrity of the V354del RRM2.","evidence":"NMR structures and quantitative in vitro binding affinity measurements","pmids":["29450990"],"confidence":"High","gaps":["Structure of the full tri-domain-RNA complex not solved","Dynamics of cooperative assembly not resolved"]},{"year":2018,"claim":"A major splicing-independent function was defined in the heart: RBM10 assembles and directs the Star-PAP 3'-end processing complex toward anti-hypertrophy transcripts, with loss promoting hypertrophy.","evidence":"Reciprocal Co-IP, RRM2 domain mapping, 3'-end processing assays, H9c2 KD/OE, rat cardiac hypertrophy model","pmids":["30257214"],"confidence":"High","gaps":["Full set of Star-PAP target mRNAs not enumerated here","Relationship between splicing and 3'-processing roles unresolved"]},{"year":2019,"claim":"A signaling axis was proposed for tumor suppression: RBM10 dampens RAP1/AKT/CREB signaling to limit LUAD proliferation, independent of MAPK pathways.","evidence":"Microarray, OE/KD, EPAC pharmacological epistasis, Western blot, in vitro/in vivo proliferation","pmids":["30955253"],"confidence":"Medium","gaps":["Whether the effect is splicing-mediated not established","Direct molecular link between RBM10 and RAP1 unknown"]},{"year":2020,"claim":"RBM10 was assigned antiviral function: dengue NS5 degrades it, and RBM10 controls SAT1 splicing while binding viral RNA and promoting activating RIG-I ubiquitination.","evidence":"Co-IP, proteasome inhibitor rescue, KD/OE in infected cells, splicing RT-PCR, RIG-I ubiquitination assay","pmids":["32432721"],"confidence":"High","gaps":["Mechanism of RIG-I ubiquitin transfer not defined","Direct E3 ligase activity of RBM10 not demonstrated"]},{"year":2020,"claim":"Upstream control of RBM10 levels was shown through miR-335 targeting its 3'UTR, linking RBM10 downregulation to NUMB-L accumulation and tumor growth.","evidence":"Luciferase reporter, Western blot, xenograft, NUMB splicing RT-PCR","pmids":["31894898"],"confidence":"Medium","gaps":["Other regulatory inputs to RBM10 not surveyed","Single-context observation"]},{"year":2021,"claim":"Sequestration of RBM10 into S1-1 nuclear bodies was shown to regulate its splicing activity, with two NBTSs and a requirement of the C2H2 ZnF for both NB targeting and splicing.","evidence":"Deletion mutagenesis, reporter constructs, immunofluorescence, transcription inhibition","pmids":["34638866"],"confidence":"Medium","gaps":["Physiological signals controlling NB sequestration unknown","Composition of S1-1 NBs not defined"]},{"year":2021,"claim":"A nuclear, splicing-independent role in centriole control was revealed: nuclear RBM10 sequesters PLK4/STIL/SAS6 to restrain centriole duplication in a cell-type-specific manner.","evidence":"HepG2 KO and inducible re-expression, flow cytometry, centriole-marker imaging, NES mutant","pmids":["31820547"],"confidence":"Medium","gaps":["Direct binding to centriole regulators not shown","Basis of HepG2-versus-A549 specificity unknown"]},{"year":2021,"claim":"RBM10's contribution to 3'-end processing was generalized: it is globally required for Star-PAP mRNA association and target 3'-end processing.","evidence":"HITS-CLIP of Star-PAP, RBM10 KD, 3'-end processing and stability assays","pmids":["34576144"],"confidence":"Medium","gaps":["Single-lab dataset","Overlap with splicing targets not resolved"]},{"year":2021,"claim":"An m6A regulatory role was reported: RBM10 binds MALAT1 and recruits METTL3 to alter MALAT1 m6A and PI3K/AKT/mTOR signaling, suppressing NSCLC invasion.","evidence":"CLIP-Seq, RIP, MeRIP-qPCR, Co-IP with METTL3, transwell assays","pmids":["36608868"],"confidence":"Medium","gaps":["Mechanistic link between m6A change and signaling not fully established","Single-lab study"]},{"year":2021,"claim":"A splicing-independent heterochromatin function emerged from the fission yeast ortholog, which associates with the Clr6 HDAC complex and is required for heterochromatin silencing.","evidence":"Proteomics, Clr6 ChIP-seq, deep RNA-seq, genetic deletion, silencing reporters","pmids":["33468217"],"confidence":"Medium","gaps":["Conservation of this role in human RBM10 not demonstrated","Direct Clr6/HDAC binding interface not mapped"]},{"year":2022,"claim":"RBM10's Bcl-x splicing role was tied to therapy response: deficiency lowers the Bcl-xS/Bcl-xL ratio, conferring EGFR-inhibitor resistance reversible by Bcl-xL co-inhibition.","evidence":"Patient-derived EGFR-mutant models, Bcl-x isoform RT-PCR, apoptosis assays, genetic inactivation, pharmacological rescue","pmids":["35579943"],"confidence":"High","gaps":["Direct RBM10 binding to Bcl-x not re-mapped here","Generalizability across EGFR genotypes not fully tested"]},{"year":2022,"claim":"RBM10 was shown to regulate NPTX1 mRNA stability, extending its post-transcriptional repertoire beyond splicing.","evidence":"RIP assay and actinomycin D mRNA decay experiments in pancreatic cancer cells","pmids":["35836482"],"confidence":"Low","gaps":["Single RIP plus stability experiment without reciprocal validation","Mechanism of stability control undefined"]},{"year":2023,"claim":"RBM10 was shown to suppress telomerase by excluding hTERT exons 7/8 to produce the inactive hTERT-s isoform, affecting pancreatic cancer growth.","evidence":"RNA-IP, RNA pulldown, minigene/splicing assays, OE/KD, telomerase assay, xenograft","pmids":["33520366"],"confidence":"Medium","gaps":["Binding-site mapping limited","Single-lab study"]},{"year":2024,"claim":"The biochemical basis of RBM10's spliceosomal action was established: it (with RBM5) is a U2 snRNP subunit binding precatalytic spliceosomes at branch sites via a conserved zinc-finger peptide required for exon repression.","evidence":"Chromatin-associated RNP isolation, MS proteomics, branch-site sequencing, domain deletion, splicing reporters","pmids":["38537639"],"confidence":"High","gaps":["Structural detail of the RBM10-U2 contact not solved","How U2 association drives exon skipping mechanistically unresolved"]},{"year":2024,"claim":"The cardiac Star-PAP function was shown to be switched on by cSrc phosphorylation of RBM10 at Y81/Y500/Y971, which drives nuclear localization and Star-PAP binding needed to reverse hypertrophy.","evidence":"In vitro kinase assay, Y-to-F phospho-deficient mutants, cSrc inhibitor, isoproterenol rat heart model, Co-IP, localization assay","pmids":["38309577"],"confidence":"High","gaps":["Whether these sites affect splicing functions not tested","Upstream activator of cSrc in this context unclear"]},{"year":2024,"claim":"A splicing-independent role in replication fork stability was defined: RBM10 binds active forks via PRIM1, recruits HDAC1 for H4K16 deacetylation and R-loop control, and its loss is synthetically lethal with WEE1 inhibition.","evidence":"CRISPR-Cas9 synthetic lethality screen, DNA fiber assay, iPOND proteomics, HDAC1 recruitment, H4K16 ChIP, R-loop quantification, in vivo WEE1 inhibitor","pmids":["39080280"],"confidence":"High","gaps":["RNA-dependence of fork association not fully separated from protein interactions","Direct PRIM1 binding interface not mapped"]},{"year":2024,"claim":"A cholangiocarcinoma driver mechanism was defined: RBM10-SRSF2 cooperation promotes ASPM exon 18 skipping, and the C2H2 ZnF C761Y mutation disrupts SRSF2 binding to enhance Wnt/β-catenin signaling.","evidence":"RNA-seq, minigene reporters, Co-IP of WT vs C761Y with SRSF2, Western blot, tumor assays","pmids":["38576051"],"confidence":"High","gaps":["Generality of SRSF2 partnership across targets unknown","Structural basis of C761Y disruption unresolved"]},{"year":2024,"claim":"A non-RNA scaffolding role was reported: RBM10 nucleates a YBX1-PPM1B trimeric complex enabling PPM1B to dephosphorylate YBX1, restraining YBX1 nuclear translocation and breast cancer growth.","evidence":"Co-IP of triple complex, YBX1 phospho/fractionation Western blot, KD, PPM1B OE rescue, xenograft","pmids":["38246397"],"confidence":"Medium","gaps":["Direct binding interfaces not mapped","Single-lab study"]},{"year":2025,"claim":"RBM10 splicing of cytoskeletal/ECM transcripts was mechanistically tied to metastasis: loss causes VCL/TNC/CD44 exon inclusion that activates RAC1 and drives invasion, reversible by isoform knockdown or RBM10 re-expression.","evidence":"RNA-seq, isoform-specific siRNA, RAC1-GTP pulldown, velocity/invasion assays, Rbm10KO mouse model, rescue","pmids":["39992626"],"confidence":"High","gaps":["Direct binding to each target intron not mapped","How RAC1 is activated by the inclusion isoforms not defined"]},{"year":2025,"claim":"A condensate-based transcriptional repression role was reported: RBM10 interacts with RORB in liquid condensates to repress its transactivation and downstream lysosomal/NF-κB programs.","evidence":"Co-IP, immunofluorescence, condensate assays, peptide inhibitor, tumor assays in neuroblastoma","pmids":["40899609"],"confidence":"Low","gaps":["Limited mechanistic depth; not independently confirmed","Direct condensate composition and stoichiometry undefined"]},{"year":2025,"claim":"RBM10's antiviral role was extended to HIV-1: Vpu degrades RBM10, and RBM10 inhibits replication by binding viral RNA, reducing incompletely spliced transcripts and promoting antiviral gene transcription.","evidence":"APEX2-proximity labeling + IP-MS, Co-IP, proteasome inhibitor rescue, RNA-IP, viral replication assays","pmids":["40742131"],"confidence":"Medium","gaps":["Direct RBM10-Vpu interface not mapped","Mechanism of antiviral transcription promotion unclear"]},{"year":2026,"claim":"RBM10 was shown to drive circRNA biogenesis by binding intronic flanking sequences (preferentially 3') of circHIPK3/circSMARCA5 and acting with SF3B1, linking its exon-skipping activity to circularization in LUAD suppression.","evidence":"PAR-CLIP, RNA pulldown, splicing reporters, point mutants, Co-IP with SF3B1, fractionation, tumor assays","pmids":["41673707"],"confidence":"Medium","gaps":["Genome-wide scope of circRNA regulation unknown","Mechanistic relationship between exon skipping and back-splicing not fully resolved"]},{"year":null,"claim":"It remains unresolved how RBM10's many activities — canonical U2-coupled splicing, Star-PAP 3'-end processing, replication fork protection, circRNA biogenesis, and non-RNA scaffolding — are coordinated and partitioned within a single protein, and which are direct versus indirect.","evidence":"No single study integrates the splicing-dependent and splicing-independent functions or defines the regulatory logic switching between them","pmids":[],"confidence":"Low","gaps":["No unified structural/functional model across roles","Tissue- and context-specific deployment of each function undefined","Hierarchy between phosphorylation, NB sequestration, and partner choice unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,4,6,8,9,23,26,33]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,2,1,9,29]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[0,9,3]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7,24,31]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[12,16,17,25]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[9,17]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[21]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[13]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,3,4,9]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[9,10]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[21]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[11,32]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,3,22,29]}],"complexes":["U2 snRNP","Star-PAP (TUT1) 3'-end processing complex"],"partners":["RBM5","STAR-PAP/TUT1","SRSF2","SF3B1","HDAC1","PRIM1","FILGAP","YBX1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P98175","full_name":"RNA-binding protein 10","aliases":["G patch domain-containing protein 9","RNA-binding motif protein 10","RNA-binding protein S1-1","S1-1"],"length_aa":930,"mass_kda":103.5,"function":"Binds to ssRNA containing the consensus sequence 5'-AGGUAA-3' (PubMed:21256132). May be involved in post-transcriptional processing, most probably in mRNA splicing (PubMed:18315527). Binds to RNA homopolymers, with a preference for poly(G) and poly(U) and little for poly(A) (By similarity). May bind to specific miRNA hairpins (PubMed:28431233)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P98175/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RBM10","classification":"Not Classified","n_dependent_lines":589,"n_total_lines":1208,"dependency_fraction":0.48758278145695366},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000182872","cell_line_id":"CID001467","localizations":[{"compartment":"chromatin","grade":3}],"interactors":[{"gene":"COPZ1","stoichiometry":0.2},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"CCAR1","stoichiometry":0.2},{"gene":"SF3B1","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2},{"gene":"TOP1","stoichiometry":0.2},{"gene":"U2AF2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001467","total_profiled":1310},"omim":[{"mim_id":"612176","title":"MYB-LIKE, SWIRM, AND MPN DOMAINS-CONTAINING PROTEIN 1; MYSM1","url":"https://www.omim.org/entry/612176"},{"mim_id":"311900","title":"TARP SYNDROME; TARPS","url":"https://www.omim.org/entry/311900"},{"mim_id":"300080","title":"RNA-BINDING MOTIF PROTEIN 10; RBM10","url":"https://www.omim.org/entry/300080"},{"mim_id":"211980","title":"LUNG CANCER","url":"https://www.omim.org/entry/211980"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nuclear speckles","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RBM10"},"hgnc":{"alias_symbol":["DXS8237E","KIAA0122","GPATC9","ZRANB5","GPATCH9","S1-1"],"prev_symbol":[]},"alphafold":{"accession":"P98175","domains":[{"cath_id":"3.30.70.330","chopping":"126-210","consensus_level":"high","plddt":86.4906,"start":126,"end":210},{"cath_id":"-","chopping":"213-241","consensus_level":"medium","plddt":81.4031,"start":213,"end":241},{"cath_id":"3.30.70.330","chopping":"304-385","consensus_level":"high","plddt":87.1044,"start":304,"end":385},{"cath_id":"2.20.25","chopping":"570-615","consensus_level":"high","plddt":89.1735,"start":570,"end":615},{"cath_id":"3.30.160","chopping":"752-813","consensus_level":"high","plddt":85.0063,"start":752,"end":813}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P98175","model_url":"https://alphafold.ebi.ac.uk/files/AF-P98175-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P98175-F1-predicted_aligned_error_v6.png","plddt_mean":59.97},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RBM10","jax_strain_url":"https://www.jax.org/strain/search?query=RBM10"},"sequence":{"accession":"P98175","fasta_url":"https://rest.uniprot.org/uniprotkb/P98175.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P98175/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P98175"}},"corpus_meta":[{"pmid":"20451169","id":"PMC_20451169","title":"Massively parallel sequencing of exons on the X chromosome identifies RBM10 as the gene that causes a syndromic form of cleft palate.","date":"2010","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20451169","citation_count":132,"is_preprint":false},{"pmid":"28296677","id":"PMC_28296677","title":"RBM10-TFE3 Renal Cell Carcinoma: A Potential Diagnostic Pitfall Due to Cryptic Intrachromosomal Xp11.2 Inversion Resulting in False-negative TFE3 FISH.","date":"2017","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/28296677","citation_count":108,"is_preprint":false},{"pmid":"28634282","id":"PMC_28634282","title":"Genomic Alterations in Fatal Forms of Non-Anaplastic Thyroid Cancer: Identification of MED12 and RBM10 as Novel Thyroid Cancer Genes Associated with Tumor Virulence.","date":"2017","source":"Clinical cancer research : an official journal of the American Association for Cancer 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Omics Analysis of the Role of RBM10 Gene Instability in Immune Regulation and Drug Sensitivity in Patients with Lung Adenocarcinoma (LUAD).","date":"2023","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/37509501","citation_count":77,"is_preprint":false},{"pmid":"16552754","id":"PMC_16552754","title":"Positive correlation between the expression of X-chromosome RBM genes (RBMX, RBM3, RBM10) and the proapoptotic Bax gene in human breast cancer.","date":"2006","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16552754","citation_count":72,"is_preprint":false},{"pmid":"24530524","id":"PMC_24530524","title":"RBM10 regulates alternative splicing.","date":"2014","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/24530524","citation_count":64,"is_preprint":false},{"pmid":"32432721","id":"PMC_32432721","title":"Dengue virus targets RBM10 deregulating host cell splicing and innate immune response.","date":"2020","source":"Nucleic acids 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patient carrying an RBM10 mutation.\",\n      \"method\": \"PAR-CLIP binding-site mapping, loss-of-function/gain-of-function experiments, minigene splicing assays, patient-derived cell analysis\",\n      \"journal\": \"EMBO Molecular Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (PAR-CLIP, functional KD/OE, minigene assays) in a single rigorous study, with patient validation\",\n      \"pmids\": [\"24000153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RBM10 promotes exon skipping of Fas pre-mRNA and selection of an internal 5′-splice site in Bcl-x pre-mRNA, regulating alternative splicing of apoptosis-related genes; a consensus RBM10-binding sequence at 5′-splice sites of target exons was proposed.\",\n      \"method\": \"Minigene splicing assays, RBM10 knockdown/overexpression in human cell lines, RT-PCR\",\n      \"journal\": \"FEBS Letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional KD/OE with defined splicing readout, single lab, two orthogonal methods\",\n      \"pmids\": [\"24530524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RBM10 inhibits cell proliferation by promoting exon 9 skipping of NUMB pre-mRNA, generating a negative regulator of Notch signaling. The cancer-associated V354E mutation in the RRM2 domain disrupts this splicing activity without abolishing RRM2 binding to NUMB RNA regulatory sequences, and other lung adenocarcinoma mutations also compromise NUMB exon 9 regulation.\",\n      \"method\": \"Xenograft tumor growth assay (KD/OE), minigene splicing assays, RNA-binding assay, structural modeling, mutation analysis\",\n      \"journal\": \"RNA Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (functional xenograft, minigene, RNA binding, mutagenesis) establishing mechanism, single lab\",\n      \"pmids\": [\"26853560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RBM10 negatively autoregulates its own mRNA and protein expression and cross-regulates its paralog RBM5 by promoting alternative splicing-coupled nonsense-mediated mRNA decay (AS-NMD); skipping of exon 6 or 12 in RBM10 and exon 6 or 16 in RBM5 triggers NMD. LUAD-associated splice-site mutations abolishing exon inclusion correlated with reduced RBM10 RNA expression.\",\n      \"method\": \"Computational analysis, RT-PCR/qPCR, minigene assays, NMD inhibition experiments, patient mutation analysis\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (computational + minigene + NMD inhibitor + patient data) establishing autoregulatory mechanism\",\n      \"pmids\": [\"28586478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"An RRM1-ZnF module of RBM10 recognizes a GGA-centered exonic motif to promote exon skipping, while the RRM2 domain recognizes a C-rich intronic 3′ sequence of NUMB exon 9. A polypeptide containing RRM1, ZnF1, and RRM2 in tandem recognizes a Fas exon 6 RNA sequence with ~20 nM affinity, explaining high-fidelity RNA recognition by cooperativity of domains.\",\n      \"method\": \"In vitro RNA-binding assays, NMR structure determination (RRM1, ZnF1, RRM2), domain deletion/combination experiments, splicing reporter assays\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure + in vitro binding assays + mutagenesis/domain dissection, multiple orthogonal methods\",\n      \"pmids\": [\"28379442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NMR structure determination revealed that the RBM10 OCRE sequence motif forms a 55-residue globular domain with an antiparallel arrangement of six β-strands containing Tyr triplets; this domain is distinct from RNA recognition motifs and is proposed to mediate spliceosome protein–protein interactions.\",\n      \"method\": \"NMR structure determination\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — atomic-resolution NMR structure of the OCRE domain, single study with rigorous structural method\",\n      \"pmids\": [\"26712279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RBM10 cooperatively binds RNA through three domains (RRM1, ZnF1, RRM2): the combination recognizes a specific Fas exon 6 mRNA sequence with 20 nM affinity, whereas individual domains bind with micromolar affinity. NMR structures of RRM1, ZnF1, and the V354del isoform of RRM2 confirmed canonical RNA recognition elements.\",\n      \"method\": \"NMR structure determination, in vitro RNA-binding affinity measurements with domain combinations\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structures + quantitative binding assays, single study, multiple orthogonal methods\",\n      \"pmids\": [\"29450990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RBM10 performs a splicing-independent function in the heart: it associates with the non-canonical poly(A) polymerase Star-PAP (TUT1) via its RRM2 domain binding to the Star-PAP catalytic domain, binds pre-mRNA 3′ UTRs, assembles the Star-PAP complex, and guides it to mRNAs encoding anti-hypertrophy regulators to control their 3′-end processing. RBM10 is downregulated during cardiac hypertrophy and heart failure; re-expression rescues cardiomyocyte hypertrophy.\",\n      \"method\": \"Co-IP, domain mapping (RRM2 binding to Star-PAP catalytic domain), 3′-end processing assays, RBM10 KD/OE in rat cardiomyoblasts (H9c2), cardiac hypertrophy model in Wistar rats\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain-level mapping, in vitro and in vivo functional assays, multiple orthogonal methods\",\n      \"pmids\": [\"30257214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RBM10 iCLIP profiling in mouse embryonic mandibular cells showed preferential binding to intronic pre-mRNA regions consistent with a splicing role; RBM10 also binds spliceosomal snRNAs U2 and U12. RNA-seq of RBM10 KO mouse mandibular and ES cells revealed widespread alternative splicing changes in bound transcripts, and depletion of RBM10 in mouse ES cells caused proliferation defects and altered differentiation potential.\",\n      \"method\": \"iCLIP, RNA-seq (KO cells), CRISPR/Cas9 KO, proliferation assays, differentiation assays\",\n      \"journal\": \"RNA Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — iCLIP + KO RNA-seq + functional phenotypes, multiple orthogonal methods in relevant developmental model\",\n      \"pmids\": [\"27763814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RBM10 and its paralog RBM5 are subunits of the U2 snRNP, associating with precatalytic A/B-like spliceosomes at intronic branch sites genome-wide. A conserved peptide containing a zinc finger motif (separate from known functional domains) mediates the U2 snRNP interaction. Deletion of this peptide disrupts U2 association and renders RBM10 inactive for repression of many alternative exons.\",\n      \"method\": \"Biochemical isolation of chromatin-associated spliceosomal RNP complexes, MS proteomics, branch-site sequencing, domain deletion mutagenesis, splicing reporter assays\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — biochemical reconstitution-level isolation + MS + mutagenesis + transcriptome-wide branch-site mapping in a rigorous single study\",\n      \"pmids\": [\"38537639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Rbm10 controls appropriate splicing of Dnmt3b: Rbm10 deficiency decreases the non-enzymatic isoform Dnmt3b3 and increases the enzymatically active isoform Dnmt3b2. Both isoforms associate with NF-κB, and elevated Dnmt3b2 increases DNA methylation at NF-κB-responsive promoters, suppressing NF-κB-mediated transcription and inflammation in vivo and in vitro.\",\n      \"method\": \"RT-PCR (splicing isoform analysis), ChIP, promoter methylation assay, NF-κB reporter assay, RBM10 KO mice, in vitro Dnmt3b isoform overexpression\",\n      \"journal\": \"International Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (splicing, ChIP, methylation, NF-κB reporter, in vivo KO), mechanism established\",\n      \"pmids\": [\"29309623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Dengue virus NS5 polymerase interacts with RBM10 and triggers its proteasome-mediated degradation. RBM10 is responsible for exon 4 skipping in SAT1 pre-mRNA; its depletion during infection causes exon 4 inclusion generating an NMD-susceptible isoform, reducing SAT1 protein and limiting antiviral defense. RBM10 also interacts with viral RNA and RIG-I and promotes RIG-I ubiquitination (activating it), contributing to innate immune signaling.\",\n      \"method\": \"Co-IP (NS5-RBM10 interaction), proteasome inhibitor rescue, RBM10 KD/OE in infected cells, RT-PCR splicing assay, viral replication assays, RIG-I ubiquitination assay\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, proteasome inhibition, KD/OE, splicing, ubiquitination) in a single study establishing mechanism\",\n      \"pmids\": [\"32432721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"S1-1/RBM10 contains multiple nuclear localization sequences (NLSs): a classical bipartite NLS (NLS1, aa 743–759), an NLS in the RRM1 region (NLS2, aa 60–136), and a novel NLS within the OCRE octamer-repeat region (NLS3, aa 481–540). These three NLSs act cooperatively; removal of all three renders the protein completely cytoplasmic. Nuclear localization is regulated in a cell-type-specific manner.\",\n      \"method\": \"Deletion and substitution mutagenesis, EGFP/FLAG fusion reporter assays, subcellular localization imaging\",\n      \"journal\": \"Biology of the Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic mutagenesis with reporter assays, single lab, two orthogonal methods (deletion mutagenesis + reporter imaging)\",\n      \"pmids\": [\"23294349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Src family tyrosine kinase Fyn induces translocation of RBM10 from the nucleus to cell peripheries in a kinase activity-dependent manner. At the cell periphery, RBM10 colocalizes with the Rac-specific GAP FilGAP and is required for peripheral FilGAP localization. RBM10 depletion abolishes FilGAP-mediated suppression of cell spreading and ruffle formation, suggesting RBM10 stimulates FilGAP RacGAP activity in a Src-regulated manner.\",\n      \"method\": \"Co-IP (RBM10-FilGAP interaction), siRNA knockdown, immunofluorescence localization, cell spreading assay, membrane ruffle assay, kinase-dead Fyn mutant\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + localization + functional KD assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"26751795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RBM10 suppresses lung adenocarcinoma cell proliferation via a RAP1/AKT/CREB signaling pathway: RBM10 overexpression decreases RAP1 activation; EPAC stimulation/inhibition abolishes the effects of RBM10 KD/OE; and RBM10 reduces CREB phosphorylation through AKT, independently of MAPK/ERK and P38/MAPK pathways.\",\n      \"method\": \"cDNA microarray, RBM10 OE/KD, EPAC pharmacological modulation, Western blot (pCREB, pAKT), in vitro and in vivo proliferation assays\",\n      \"journal\": \"Journal of Cellular and Molecular Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis + multiple signaling pathway readouts, single lab\",\n      \"pmids\": [\"30955253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RBM10 modulates alternative splicing of Bcl-x to regulate the ratio of proapoptotic Bcl-xS to antiapoptotic Bcl-xL isoforms. RBM10 deficiency decreases this ratio, diminishing EGFR inhibitor-mediated apoptosis. Coinhibition of Bcl-xL and mutant EGFR overcomes RBM10-deficiency-induced resistance.\",\n      \"method\": \"Patient-derived EGFR-mutant tumor models (in vitro and in vivo), RT-PCR (Bcl-x isoform ratio), apoptosis assays, genetic RBM10 inactivation, pharmacological Bcl-xL inhibition\",\n      \"journal\": \"Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — patient-derived models + splicing assay + apoptosis assay + pharmacological rescue, multiple orthogonal methods\",\n      \"pmids\": [\"35579943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RBM10 overexpression in HepG2 cells causes M-phase growth arrest with monopolar spindle due to impaired centriole duplication. Nuclear RBM10 sequesters centriole duplication regulators PLK4, STIL, and SAS6 into large nuclear domains, depleting them from centrioles. This requires nuclear localization (cytoplasmic NES-forced RBM10 does not cause arrest). RBM10 depletion increases cytoplasmic PLK4 and supernumerary centrioles in HepG2 but not A549 cells, indicating cell-type specificity.\",\n      \"method\": \"HepG2 RBM10 KO cell lines, doxycycline-inducible re-expression, flow cytometry (M-phase arrest), immunofluorescence (centriole markers), NES mutant forcing cytoplasmic localization, siRNA KD\",\n      \"journal\": \"Genes to Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO + inducible re-expression + localization mutant + imaging, single lab, multiple methods\",\n      \"pmids\": [\"31820547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RBM10 nuclear localization is regulated by sequestration in S1-1 nuclear bodies (NBs). Two NB-targeting sequences (NBTSs) are identified: one in the KEKE motif region and one in the C2H2 zinc finger (ZnF). These NBTSs act synergistically; the C2H2 ZnF is also essential for alternative splicing regulation. NB-localization of RBM10 increases when cellular transcription decreases, suggesting NBs sequester RBM10 to control its splicing activity.\",\n      \"method\": \"Deletion mutagenesis, reporter constructs, immunofluorescence, transcription inhibition experiments\",\n      \"journal\": \"International Journal of Molecular Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — systematic mutagenesis with imaging and functional splicing readouts, single lab\",\n      \"pmids\": [\"34638866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RBM10 knockdown alters splicing of SMN2 pre-mRNA in multiple cancer and normal cell lines, resulting in preferential expression of the full-length exon-7-retaining SMN2 transcript and increased full-length SMN protein. Re-expression of RBM10 in a stable KD line reverted this effect, confirming specificity.\",\n      \"method\": \"siRNA KD, RT-PCR splicing array platform, Western blot, re-expression rescue, primary SMA patient fibroblasts\",\n      \"journal\": \"BMC Molecular Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD + rescue re-expression + multiple cell lines + protein-level validation, single lab\",\n      \"pmids\": [\"28728573\"],\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 RIP-Seq and Western blotting in an RBM5-null SCLC cell line. In this context, RBM10 promotes (rather than suppresses) cell proliferation and other transformation-associated processes.\",\n      \"method\": \"RNA immunoprecipitation sequencing (RIP-Seq), Western blotting, transcriptome analysis, functional cell proliferation assays\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP-Seq + Western blot + functional assays, single lab\",\n      \"pmids\": [\"28662214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In fission yeast, Rbm10 (ortholog of human RBM10) associates with the histone deacetylase Clr6 complex and chromatin remodelers important for heterochromatin silencing. Deletion of Rbm10 causes severe heterochromatin defects and significant reduction of Clr6 at heterochromatin, without major effects on genome-wide splicing, revealing a splicing-independent role in heterochromatin assembly.\",\n      \"method\": \"Proteomics (Rbm10 interactome), ChIP-seq (Clr6 localization), deep RNA-seq, genetic deletion, silencing reporter assays\",\n      \"journal\": \"Epigenetics & Chromatin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomic interaction + ChIP + functional heterochromatin assays, single lab, fission yeast ortholog\",\n      \"pmids\": [\"33468217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RBM10 has a splicing-independent role in DNA replication fork stability: it associates with active DNA replication forks via interaction with DNA Primase Subunit 1 (PRIM1), recruits HDAC1 to facilitate H4K16 deacetylation, and maintains R-loop homeostasis. WEE1 inhibition is synthetically lethal with RBM10 deficiency (identified by CRISPR-Cas9 SL screen), and this lethality is mechanistically linked to replication stress.\",\n      \"method\": \"CRISPR-Cas9 synthetic lethality screen, DNA fiber assay (replication fork), iPOND/replication fork proteomics, HDAC1 recruitment assay, H4K16 acetylation ChIP, R-loop quantification, in vitro and in vivo WEE1 inhibitor treatment\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — CRISPR SL screen + DNA fiber assay + ChIP + in vivo validation, multiple orthogonal methods establishing novel mechanism\",\n      \"pmids\": [\"39080280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RBM10 promotes exon 18 skipping of ASPM pre-mRNA by interacting with SRSF2. The C761Y mutation in the RBM10 C2H2-type zinc finger domain impairs its interaction with SRSF2, causing loss of ASPM exon 18 skipping, generating the ASPM203 isoform which stabilizes DVL2 and enhances β-catenin/Wnt signaling to promote cholangiocarcinoma progression.\",\n      \"method\": \"RNA-seq (alternative splicing), minigene reporter assays, Co-IP (RBM10-SRSF2 interaction with WT vs C761Y), Western blot, functional tumor assays\",\n      \"journal\": \"Journal of Experimental & Clinical Cancer Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP showing interaction disrupted by mutation + minigene + functional assays + downstream pathway validation, multiple orthogonal methods\",\n      \"pmids\": [\"38576051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RBM10 binds MALAT1 lncRNA (highest binding peak among ncRNAs by CLIP-Seq), and RBM10 inhibits invasion/migration of NSCLC by recruiting METTL3 to suppress m6A methylation of MALAT1, thereby affecting PI3K/AKT/mTOR pathway phosphorylation.\",\n      \"method\": \"CLIP-Seq, RIP assay (RBM10-MALAT1), MeRIP-qPCR (m6A methylation), Co-IP (RBM10-METTL3), transwell invasion/migration assays, Western blot\",\n      \"journal\": \"Life Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — CLIP-Seq + RIP + MeRIP + Co-IP + functional assays, single lab\",\n      \"pmids\": [\"36608868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Star-PAP global mRNA association depends on RBM10: knockdown of RBM10 causes global loss of Star-PAP binding to target mRNAs and compromises 3′-end processing of Star-PAP target mRNAs while also regulating stability/turnover of another set of mRNAs.\",\n      \"method\": \"HITS-CLIP (Star-PAP binding landscape), RBM10 KD, 3′-end processing assays, mRNA stability assays\",\n      \"journal\": \"International Journal of Molecular Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — HITS-CLIP + KD + 3′-processing assays, single lab, multiple methods\",\n      \"pmids\": [\"34576144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"cSrc kinase phosphorylates RBM10 at three tyrosine residues (Y81, Y500, Y971). This phosphorylation is induced during cardiac hypertrophy, promotes nuclear localization of RBM10 and its interaction with Star-PAP, and is required for anti-hypertrophy gene expression and 3′-end mRNA formation. Inhibition of cSrc or phospho-deficient RBM10 mutations prevent reversal of cardiac hypertrophy even when RBM10 levels are restored.\",\n      \"method\": \"In vitro kinase assay (cSrc phosphorylating RBM10), phospho-deficient mutants (Y→F), cSrc inhibitor treatment, isoproterenol-induced rat heart hypertrophy model, Co-IP (phospho-RBM10–Star-PAP), nuclear localization assay\",\n      \"journal\": \"Life Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assay + phospho-deficient mutagenesis + in vivo animal model + Co-IP, multiple orthogonal methods\",\n      \"pmids\": [\"38309577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RBM10 promotes exclusion of hTERT exons 7 and 8 to generate the non-functional hTERT-s isoform in pancreatic cancer, suppressing telomerase activity and telomere maintenance. This was confirmed by RNA-IP and RNA pulldown assays. RBM10 gain or loss significantly changed pancreatic cancer cell proliferation in vitro and in xenografts.\",\n      \"method\": \"RNA-IP, RNA pulldown, minigene/splicing assays, RBM10 OE/KD, telomerase activity assay, xenograft tumor growth\",\n      \"journal\": \"American Journal of Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-IP + pulldown + functional assays, single lab\",\n      \"pmids\": [\"33520366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-335 directly targets the 3′UTR of RBM10 mRNA (confirmed by luciferase reporter assay), downregulating RBM10 protein post-transcriptionally. This reduces RBM10-mediated exon skipping in NUMB pre-mRNA, increasing the Numb long isoform (Numb-L), which promotes endometrial cancer tumor growth in xenograft models.\",\n      \"method\": \"Luciferase reporter assay (miR-335 targeting RBM10 3′UTR), Western blot, xenograft mouse model, RT-PCR (NUMB splicing)\",\n      \"journal\": \"Kaohsiung Journal of Medical Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter + in vivo xenograft + splicing assay, single lab\",\n      \"pmids\": [\"31894898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RBM10 interacts directly with NPTX1 mRNA (demonstrated by RIP assay) and regulates NPTX1 mRNA stability, as confirmed by actinomycin D mRNA decay experiments in pancreatic cancer cells.\",\n      \"method\": \"RIP assay, actinomycin D mRNA stability assay, RT-qPCR, Western blot\",\n      \"journal\": \"Oncology Letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single RIP assay + mRNA stability experiment, single lab, limited mechanistic detail\",\n      \"pmids\": [\"35836482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBM10 loss in thyroid cancer causes exon inclusion events in cytoskeletal and ECM transcripts (vinculin VCL, tenascin C TNC, CD44), leading to RAC1 activation and increased cell velocity and invasiveness. Knockdown of the specific exon inclusion isoforms of VCL (reduced velocity), TNC, or CD44 (reduced invasiveness) reverses these phenotypes. In a mouse HrasG12V/Rbm10KO thyrocyte model, metastases develop and are reversed by RBM10 re-expression or combined knockdown of the three inclusion isoforms.\",\n      \"method\": \"RNA-seq (exon inclusion analysis), isoform-specific siRNA KD, RAC1-GTP pulldown assay, cell velocity assay, invasion assay, mouse genetic model (Rbm10KO), RBM10 re-expression rescue\",\n      \"journal\": \"Journal of Experimental Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RNA-seq, isoform-specific KD, RAC1 activity, mouse model, rescue) establishing splicing-to-metastasis mechanism\",\n      \"pmids\": [\"39992626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBM10 interacts with RORB transcription factor in liquid condensates in neuroblastoma cells, repressing RORB transactivation. A small peptide blocking the RBM10-RORB interaction suppresses lysosomal biogenesis, tumorigenesis, and aggressiveness by derepressing NR1D1/RIOK3-mediated suppression of NF-κB activity.\",\n      \"method\": \"Co-IP, immunofluorescence, liquid condensate assays, small-peptide inhibitor, functional tumor assays\",\n      \"journal\": \"Advanced Science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP + peptide inhibitor + functional assays, single lab, limited mechanistic depth in abstract\",\n      \"pmids\": [\"40899609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RBM10 forms a trimeric complex with YBX1 and phosphatase PPM1B; PPM1B dephosphorylates YBX1 within this complex. RBM10 knockdown attenuates the YBX1-PPM1B association, leading to elevated YBX1 phosphorylation and nuclear translocation, promoting breast cancer proliferation and migration. PPM1B overexpression reverses the tumorigenic effects of RBM10 depletion.\",\n      \"method\": \"Co-IP (triple complex), Western blot (YBX1 phosphorylation, nuclear fractionation), RBM10 KD, PPM1B OE rescue, xenograft assay\",\n      \"journal\": \"Experimental Cell Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + genetic rescue + in vivo validation, single lab, multiple methods\",\n      \"pmids\": [\"38246397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HIV-1 Vpu interacts with RBM10 (identified by APEX2-proximity labeling + IP-MS) and promotes its degradation through the ubiquitin-proteasome pathway. RBM10 inhibits HIV-1 replication by binding to viral RNA and reducing incompletely spliced HIV-1 transcripts, and promotes transcription of antiviral genes.\",\n      \"method\": \"APEX2-proximity labeling + mass spectrometry, IP-MS, Co-IP, proteasome inhibitor rescue, RNA-IP (RBM10-viral RNA), viral replication assays\",\n      \"journal\": \"mSystems\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple interaction methods (APEX2-MS, IP-MS, Co-IP) + functional assays, single lab\",\n      \"pmids\": [\"40742131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RBM10 directly binds intronic flanking sequences of circHIPK3 and circSMARCA5 pre-mRNAs (PAR-CLIP + RNA pulldown). Binding to the 3′ flanking region more efficiently promotes exon skipping and circularization than 5′ binding. RBM10 loss impairs formation of these circRNAs; RBM10 point mutants with defective exon skipping also fail to regulate circRNA production. Modulation of circHIPK3 and circSMARCA5 phenocopies RBM10 restoration in mutant LUAD cells. RBM10 interacts with SF3B1 as an upstream event governing circHIPK3 biogenesis.\",\n      \"method\": \"PAR-CLIP, RNA pulldown, splicing reporter assay, RBM10 point mutants, functional tumor assays, Co-IP (RBM10-SF3B1), subcellular fractionation\",\n      \"journal\": \"Biomarker Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PAR-CLIP + pulldown + reporter assay + mutagenesis + functional rescue, single lab\",\n      \"pmids\": [\"41673707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"DXS8237E (the gene later identified as RBM10) was isolated from human fetal brain cDNA, maps within 20 kb upstream of UBE1 at Xp11.23, and is subject to X inactivation (unlike its neighbor UBE1 which escapes X inactivation), as demonstrated in somatic cell hybrids containing an inactive human X chromosome.\",\n      \"method\": \"cDNA cloning, somatic cell hybrid analysis, Northern blot (expression), X-inactivation assay\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct X-inactivation assay in somatic cell hybrids, single study, genomic localization experiment\",\n      \"pmids\": [\"8808293\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RBM10 is a nuclear RNA-binding protein that functions primarily as an alternative splicing regulator by binding pre-mRNA at intronic and exonic sites (via cooperative action of RRM1, ZnF1, and RRM2 domains, with an additional U2 snRNP-interaction domain containing a zinc finger motif), promoting exon skipping of target genes including NUMB (suppressing Notch signaling), Fas, Bcl-x, Dnmt3b, hTERT, and cytoskeletal/ECM transcripts; it also performs splicing-independent functions including 3′-end mRNA processing in the heart by associating with the poly(A) polymerase Star-PAP (regulated by cSrc-mediated phosphorylation at Y81/Y500/Y971), regulation of DNA replication fork stability via HDAC1 recruitment and H4K16 deacetylation, interaction with FilGAP to modulate Rac-mediated cytoskeletal dynamics, and antiviral roles through RIG-I ubiquitination and viral RNA binding; it autoregulates its own expression and cross-regulates RBM5 through AS-coupled nonsense-mediated decay, and its nuclear localization is controlled by multiple cooperative NLS sequences and regulated sequestration into nuclear bodies.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RBM10 is a nuclear RNA-binding protein that functions principally as an alternative splicing regulator, binding pre-mRNA near splice sites to promote exon skipping across a large set of target transcripts [#0, #8]. It is a subunit of the U2 snRNP, associating with precatalytic A/B-like spliceosomes at intronic branch sites genome-wide through a conserved zinc-finger-containing peptide whose deletion abolishes U2 association and splicing repression activity [#9]. High-fidelity target recognition arises from cooperative RNA binding by tandem RRM1, ZnF1, and RRM2 domains: the RRM1-ZnF module reads a GGA-centered exonic motif while RRM2 recognizes C-rich intronic sequence, and the combined module binds target RNA with nanomolar affinity versus micromolar affinity for isolated domains [#4, #6]; an additional OCRE domain forms a distinct β-stranded fold implicated in spliceosomal protein interactions [#5]. Through these activities RBM10 controls splicing of genes governing proliferation, apoptosis, and differentiation, including exon 9 skipping of NUMB to suppress Notch-driven proliferation [#2], Fas and Bcl-x splicing to set apoptotic isoform balance [#1, #15], Dnmt3b isoform choice to modulate NF-κB-responsive DNA methylation [#10], and hTERT exon exclusion to limit telomerase activity [#26]. RBM10 also negatively autoregulates its own expression and cross-regulates its paralog RBM5 via alternative-splicing-coupled nonsense-mediated decay [#3]. Beyond canonical splicing, RBM10 performs splicing-independent roles: it assembles the non-canonical poly(A) polymerase Star-PAP complex via RRM2 binding to direct 3'-end mRNA processing of anti-hypertrophy transcripts in the heart, an activity gated by cSrc phosphorylation at Y81/Y500/Y971 [#7, #24, #25]; it stabilizes DNA replication forks by associating with PRIM1 and recruiting HDAC1 for H4K16 deacetylation, with RBM10 deficiency being synthetically lethal with WEE1 inhibition [#21]; and it acts in antiviral defense by binding viral RNA and being targeted for proteasomal degradation by dengue NS5 and HIV-1 Vpu [#11, #32]. Loss-of-function mutations in RBM10, including LUAD-associated splice-site and RRM2 mutations and a cholangiocarcinoma C2H2 zinc-finger C761Y mutation that disrupts SRSF2 interaction, impair its splicing activity and promote tumorigenesis [#2, #3, #22], and RBM10 splicing defects were confirmed in a patient carrying an RBM10 mutation [#0].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Before functional characterization, the gene's chromosomal identity was established, placing DXS8237E/RBM10 at Xp11.23 and showing it is subject to X inactivation.\",\n      \"evidence\": \"cDNA cloning and X-inactivation assay in somatic cell hybrids carrying an inactive X chromosome\",\n      \"pmids\": [\"8808293\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No protein function assigned at this stage\", \"No RNA-binding or splicing activity tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The core function was defined: RBM10 binds pre-mRNA near splice sites and acts as an alternative-splicing regulator promoting exon skipping, with disease relevance shown through patient-derived splicing defects.\",\n      \"evidence\": \"PAR-CLIP binding-site mapping, KD/OE and minigene assays in human cells, plus patient cell analysis\",\n      \"pmids\": [\"24000153\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domain basis of RNA recognition not yet resolved\", \"Spliceosomal context of action unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Nuclear access of RBM10 was shown to require three cooperative NLSs, establishing that its function depends on regulated nuclear import.\",\n      \"evidence\": \"Deletion/substitution mutagenesis and EGFP/FLAG reporter localization imaging\",\n      \"pmids\": [\"23294349\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Import receptors not identified\", \"Mechanism of cell-type-specific regulation unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"RBM10 was linked to apoptotic isoform control by directing Fas exon skipping and Bcl-x 5'-splice-site selection, with a proposed consensus binding motif.\",\n      \"evidence\": \"Minigene assays, KD/OE, and RT-PCR in human cell lines\",\n      \"pmids\": [\"24530524\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding to these targets not structurally validated here\", \"Physiological apoptotic consequence not tested in vivo\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The OCRE motif was shown to fold into a discrete β-stranded globular domain distinct from RRMs, implicating it in spliceosomal protein-protein interactions rather than RNA binding.\",\n      \"evidence\": \"NMR structure determination of the OCRE domain\",\n      \"pmids\": [\"26712279\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific protein partners of OCRE not identified\", \"Functional requirement for splicing not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"RBM10 was connected to growth control via NUMB exon 9 skipping to suppress Notch signaling, and cancer mutations were shown to uncouple RNA binding from splicing activity.\",\n      \"evidence\": \"Xenograft assays, minigene and RNA-binding assays, structural modeling, mutation analysis (including V354E)\",\n      \"pmids\": [\"26853560\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which V354E disrupts splicing without abolishing binding unresolved\", \"Generality across other targets not addressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Transcriptome-wide binding and KO analysis in a developmental model confirmed preferential intronic binding and a requirement for RBM10 in proliferation and differentiation, while binding to U2/U12 snRNAs hinted at a spliceosomal association.\",\n      \"evidence\": \"iCLIP, KO RNA-seq, CRISPR/Cas9 KO, proliferation and differentiation assays in mouse cells\",\n      \"pmids\": [\"27763814\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct snRNP incorporation not yet demonstrated biochemically\", \"Developmental phenotype mechanism not dissected\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"A cytoplasmic, splicing-independent role was uncovered: Fyn-driven RBM10 translocation to the cell periphery supports FilGAP RacGAP activity controlling cell spreading and ruffling.\",\n      \"evidence\": \"Co-IP, siRNA KD, immunofluorescence, cell spreading/ruffle assays, kinase-dead Fyn mutant\",\n      \"pmids\": [\"26751795\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab Co-IP without reciprocal structural mapping\", \"Physiological significance of cytoplasmic pool unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"RBM10 was shown to autoregulate its own expression and cross-regulate RBM5 through AS-coupled NMD, defining a feedback architecture relevant to LUAD mutations.\",\n      \"evidence\": \"Computational analysis, RT-PCR/qPCR, minigene assays, NMD inhibition, patient mutation analysis\",\n      \"pmids\": [\"28586478\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of feedback to homeostasis unresolved\", \"Trigger for differential exon choice unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The structural logic of target recognition was established: RRM1-ZnF reads an exonic GGA motif and RRM2 reads C-rich intronic sequence, with domain cooperativity giving high-affinity, high-fidelity binding.\",\n      \"evidence\": \"NMR structures of RRM1/ZnF1/RRM2, in vitro binding, domain dissection, splicing reporters\",\n      \"pmids\": [\"28379442\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How motif engagement translates to spliceosome modulation not fully defined\", \"OCRE contribution not integrated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"RBM10 was tied to epigenetic and inflammatory output through Dnmt3b isoform control, linking splicing to NF-κB-responsive promoter methylation.\",\n      \"evidence\": \"Splicing RT-PCR, ChIP, methylation assay, NF-κB reporter, RBM10 KO mice\",\n      \"pmids\": [\"29309623\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding to Dnmt3b pre-mRNA not mapped\", \"Breadth of methylation changes not genome-wide\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"RBM10 was shown to influence SMN2 exon 7 inclusion, raising potential relevance to spinal muscular atrophy splicing, with rescue confirming specificity.\",\n      \"evidence\": \"siRNA KD, splicing array RT-PCR, Western blot, re-expression rescue, SMA patient fibroblasts\",\n      \"pmids\": [\"28728573\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding to SMN2 not demonstrated\", \"Single-lab observation\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Context-dependent regulation was revealed: in an RBM5-null SCLC background, RBM5 post-transcriptionally regulates specific RBM10 splice variants and RBM10 promotes rather than suppresses proliferation.\",\n      \"evidence\": \"RIP-Seq, Western blotting, transcriptome and proliferation assays\",\n      \"pmids\": [\"28662214\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of context-dependent reversal of growth effect unclear\", \"Single cell-line context\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Cooperative tri-domain RNA recognition was quantitatively confirmed, showing nanomolar Fas-exon-6 binding by RRM1-ZnF1-RRM2 versus micromolar by single domains, and structural integrity of the V354del RRM2.\",\n      \"evidence\": \"NMR structures and quantitative in vitro binding affinity measurements\",\n      \"pmids\": [\"29450990\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the full tri-domain-RNA complex not solved\", \"Dynamics of cooperative assembly not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"A major splicing-independent function was defined in the heart: RBM10 assembles and directs the Star-PAP 3'-end processing complex toward anti-hypertrophy transcripts, with loss promoting hypertrophy.\",\n      \"evidence\": \"Reciprocal Co-IP, RRM2 domain mapping, 3'-end processing assays, H9c2 KD/OE, rat cardiac hypertrophy model\",\n      \"pmids\": [\"30257214\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of Star-PAP target mRNAs not enumerated here\", \"Relationship between splicing and 3'-processing roles unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"A signaling axis was proposed for tumor suppression: RBM10 dampens RAP1/AKT/CREB signaling to limit LUAD proliferation, independent of MAPK pathways.\",\n      \"evidence\": \"Microarray, OE/KD, EPAC pharmacological epistasis, Western blot, in vitro/in vivo proliferation\",\n      \"pmids\": [\"30955253\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the effect is splicing-mediated not established\", \"Direct molecular link between RBM10 and RAP1 unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"RBM10 was assigned antiviral function: dengue NS5 degrades it, and RBM10 controls SAT1 splicing while binding viral RNA and promoting activating RIG-I ubiquitination.\",\n      \"evidence\": \"Co-IP, proteasome inhibitor rescue, KD/OE in infected cells, splicing RT-PCR, RIG-I ubiquitination assay\",\n      \"pmids\": [\"32432721\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of RIG-I ubiquitin transfer not defined\", \"Direct E3 ligase activity of RBM10 not demonstrated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Upstream control of RBM10 levels was shown through miR-335 targeting its 3'UTR, linking RBM10 downregulation to NUMB-L accumulation and tumor growth.\",\n      \"evidence\": \"Luciferase reporter, Western blot, xenograft, NUMB splicing RT-PCR\",\n      \"pmids\": [\"31894898\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Other regulatory inputs to RBM10 not surveyed\", \"Single-context observation\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Sequestration of RBM10 into S1-1 nuclear bodies was shown to regulate its splicing activity, with two NBTSs and a requirement of the C2H2 ZnF for both NB targeting and splicing.\",\n      \"evidence\": \"Deletion mutagenesis, reporter constructs, immunofluorescence, transcription inhibition\",\n      \"pmids\": [\"34638866\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological signals controlling NB sequestration unknown\", \"Composition of S1-1 NBs not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A nuclear, splicing-independent role in centriole control was revealed: nuclear RBM10 sequesters PLK4/STIL/SAS6 to restrain centriole duplication in a cell-type-specific manner.\",\n      \"evidence\": \"HepG2 KO and inducible re-expression, flow cytometry, centriole-marker imaging, NES mutant\",\n      \"pmids\": [\"31820547\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding to centriole regulators not shown\", \"Basis of HepG2-versus-A549 specificity unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"RBM10's contribution to 3'-end processing was generalized: it is globally required for Star-PAP mRNA association and target 3'-end processing.\",\n      \"evidence\": \"HITS-CLIP of Star-PAP, RBM10 KD, 3'-end processing and stability assays\",\n      \"pmids\": [\"34576144\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab dataset\", \"Overlap with splicing targets not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"An m6A regulatory role was reported: RBM10 binds MALAT1 and recruits METTL3 to alter MALAT1 m6A and PI3K/AKT/mTOR signaling, suppressing NSCLC invasion.\",\n      \"evidence\": \"CLIP-Seq, RIP, MeRIP-qPCR, Co-IP with METTL3, transwell assays\",\n      \"pmids\": [\"36608868\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between m6A change and signaling not fully established\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A splicing-independent heterochromatin function emerged from the fission yeast ortholog, which associates with the Clr6 HDAC complex and is required for heterochromatin silencing.\",\n      \"evidence\": \"Proteomics, Clr6 ChIP-seq, deep RNA-seq, genetic deletion, silencing reporters\",\n      \"pmids\": [\"33468217\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conservation of this role in human RBM10 not demonstrated\", \"Direct Clr6/HDAC binding interface not mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"RBM10's Bcl-x splicing role was tied to therapy response: deficiency lowers the Bcl-xS/Bcl-xL ratio, conferring EGFR-inhibitor resistance reversible by Bcl-xL co-inhibition.\",\n      \"evidence\": \"Patient-derived EGFR-mutant models, Bcl-x isoform RT-PCR, apoptosis assays, genetic inactivation, pharmacological rescue\",\n      \"pmids\": [\"35579943\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct RBM10 binding to Bcl-x not re-mapped here\", \"Generalizability across EGFR genotypes not fully tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"RBM10 was shown to regulate NPTX1 mRNA stability, extending its post-transcriptional repertoire beyond splicing.\",\n      \"evidence\": \"RIP assay and actinomycin D mRNA decay experiments in pancreatic cancer cells\",\n      \"pmids\": [\"35836482\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single RIP plus stability experiment without reciprocal validation\", \"Mechanism of stability control undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"RBM10 was shown to suppress telomerase by excluding hTERT exons 7/8 to produce the inactive hTERT-s isoform, affecting pancreatic cancer growth.\",\n      \"evidence\": \"RNA-IP, RNA pulldown, minigene/splicing assays, OE/KD, telomerase assay, xenograft\",\n      \"pmids\": [\"33520366\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding-site mapping limited\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The biochemical basis of RBM10's spliceosomal action was established: it (with RBM5) is a U2 snRNP subunit binding precatalytic spliceosomes at branch sites via a conserved zinc-finger peptide required for exon repression.\",\n      \"evidence\": \"Chromatin-associated RNP isolation, MS proteomics, branch-site sequencing, domain deletion, splicing reporters\",\n      \"pmids\": [\"38537639\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of the RBM10-U2 contact not solved\", \"How U2 association drives exon skipping mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The cardiac Star-PAP function was shown to be switched on by cSrc phosphorylation of RBM10 at Y81/Y500/Y971, which drives nuclear localization and Star-PAP binding needed to reverse hypertrophy.\",\n      \"evidence\": \"In vitro kinase assay, Y-to-F phospho-deficient mutants, cSrc inhibitor, isoproterenol rat heart model, Co-IP, localization assay\",\n      \"pmids\": [\"38309577\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether these sites affect splicing functions not tested\", \"Upstream activator of cSrc in this context unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A splicing-independent role in replication fork stability was defined: RBM10 binds active forks via PRIM1, recruits HDAC1 for H4K16 deacetylation and R-loop control, and its loss is synthetically lethal with WEE1 inhibition.\",\n      \"evidence\": \"CRISPR-Cas9 synthetic lethality screen, DNA fiber assay, iPOND proteomics, HDAC1 recruitment, H4K16 ChIP, R-loop quantification, in vivo WEE1 inhibitor\",\n      \"pmids\": [\"39080280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA-dependence of fork association not fully separated from protein interactions\", \"Direct PRIM1 binding interface not mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A cholangiocarcinoma driver mechanism was defined: RBM10-SRSF2 cooperation promotes ASPM exon 18 skipping, and the C2H2 ZnF C761Y mutation disrupts SRSF2 binding to enhance Wnt/β-catenin signaling.\",\n      \"evidence\": \"RNA-seq, minigene reporters, Co-IP of WT vs C761Y with SRSF2, Western blot, tumor assays\",\n      \"pmids\": [\"38576051\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of SRSF2 partnership across targets unknown\", \"Structural basis of C761Y disruption unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A non-RNA scaffolding role was reported: RBM10 nucleates a YBX1-PPM1B trimeric complex enabling PPM1B to dephosphorylate YBX1, restraining YBX1 nuclear translocation and breast cancer growth.\",\n      \"evidence\": \"Co-IP of triple complex, YBX1 phospho/fractionation Western blot, KD, PPM1B OE rescue, xenograft\",\n      \"pmids\": [\"38246397\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding interfaces not mapped\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"RBM10 splicing of cytoskeletal/ECM transcripts was mechanistically tied to metastasis: loss causes VCL/TNC/CD44 exon inclusion that activates RAC1 and drives invasion, reversible by isoform knockdown or RBM10 re-expression.\",\n      \"evidence\": \"RNA-seq, isoform-specific siRNA, RAC1-GTP pulldown, velocity/invasion assays, Rbm10KO mouse model, rescue\",\n      \"pmids\": [\"39992626\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding to each target intron not mapped\", \"How RAC1 is activated by the inclusion isoforms not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A condensate-based transcriptional repression role was reported: RBM10 interacts with RORB in liquid condensates to repress its transactivation and downstream lysosomal/NF-κB programs.\",\n      \"evidence\": \"Co-IP, immunofluorescence, condensate assays, peptide inhibitor, tumor assays in neuroblastoma\",\n      \"pmids\": [\"40899609\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Limited mechanistic depth; not independently confirmed\", \"Direct condensate composition and stoichiometry undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"RBM10's antiviral role was extended to HIV-1: Vpu degrades RBM10, and RBM10 inhibits replication by binding viral RNA, reducing incompletely spliced transcripts and promoting antiviral gene transcription.\",\n      \"evidence\": \"APEX2-proximity labeling + IP-MS, Co-IP, proteasome inhibitor rescue, RNA-IP, viral replication assays\",\n      \"pmids\": [\"40742131\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RBM10-Vpu interface not mapped\", \"Mechanism of antiviral transcription promotion unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"RBM10 was shown to drive circRNA biogenesis by binding intronic flanking sequences (preferentially 3') of circHIPK3/circSMARCA5 and acting with SF3B1, linking its exon-skipping activity to circularization in LUAD suppression.\",\n      \"evidence\": \"PAR-CLIP, RNA pulldown, splicing reporters, point mutants, Co-IP with SF3B1, fractionation, tumor assays\",\n      \"pmids\": [\"41673707\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genome-wide scope of circRNA regulation unknown\", \"Mechanistic relationship between exon skipping and back-splicing not fully resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how RBM10's many activities — canonical U2-coupled splicing, Star-PAP 3'-end processing, replication fork protection, circRNA biogenesis, and non-RNA scaffolding — are coordinated and partitioned within a single protein, and which are direct versus indirect.\",\n      \"evidence\": \"No single study integrates the splicing-dependent and splicing-independent functions or defines the regulatory logic switching between them\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified structural/functional model across roles\", \"Tissue- and context-specific deployment of each function undefined\", \"Hierarchy between phosphorylation, NB sequestration, and partner choice unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 4, 6, 8, 9, 23, 26, 33]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 2, 1, 9, 29]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [0, 9, 3]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7, 24, 31]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [12, 16, 17, 25]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [9, 17]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [21]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 3, 4, 9]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [9, 10]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [21]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [11, 32]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3, 22, 29]}\n    ],\n    \"complexes\": [\n      \"U2 snRNP\",\n      \"Star-PAP (TUT1) 3'-end processing complex\"\n    ],\n    \"partners\": [\n      \"RBM5\",\n      \"Star-PAP/TUT1\",\n      \"SRSF2\",\n      \"SF3B1\",\n      \"HDAC1\",\n      \"PRIM1\",\n      \"FilGAP\",\n      \"YBX1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}