{"gene":"RBM22","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2009,"finding":"Cwc2 (yeast ortholog of RBM22) directly crosslinks to U6 snRNA under splicing conditions and associates with U2, U5, and U6 snRNAs; depletion causes pre-mRNA accumulation and reduced snRNA levels; the zinc finger and RRM motifs are both required for function, linking the NineTeen Complex (NTC) to the spliceosome via U6 snRNA.","method":"UV crosslinking, snRNA co-immunoprecipitation, in vitro RNA binding assay, yeast depletion/mutant analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (crosslinking, co-IP, in vitro binding, genetic depletion) in a single focused study establishing direct U6 snRNA contact","pmids":["19435883"],"is_preprint":false},{"year":2012,"finding":"Cwc2/RBM22 functions prior to step 1 of splicing (not required for Prp2-mediated remodeling) and directly contacts catalytically important RNA elements including the U6 internal stem-loop (ISL) and regions of U6 and pre-mRNA near the 5' splice site, promoting an active conformation of the spliceosome catalytic centre; these contacts are evolutionarily conserved in human RBM22.","method":"Yeast genetic depletion, UV-induced RNA-protein crosslinking, splicing assays, comparative studies with human RBM22","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic depletion combined with UV crosslinking mapping, with evolutionary conservation validated using human RBM22","pmids":["22246180"],"is_preprint":false},{"year":2012,"finding":"Crystal structure of Cwc2 functional core reveals a Torus domain, RRM, and zinc finger (ZnF) integrated in a compact folding unit with the ZnF pivotal to overall architecture; UV crosslinking coupled to mass spectrometry identified six RNA-contacting sites (four near RRM, one in ZnF, one on a connector/Torus–RRM element); the connector element is essential for splicing.","method":"X-ray crystallography, UV-induced crosslinking with mass spectrometry, mutational analysis in yeast","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus crosslinking-MS plus mutagenesis in a single rigorous study","pmids":["22407296"],"is_preprint":false},{"year":2012,"finding":"X-ray structure (1.9 Å) of Cwc2 core domain shows that the CCCH-type zinc finger and RRM form a single folding unit held by hydrophobic interactions and hydrogen bonds; the intervening RB loop and conserved positively charged β-strand residues form an extended basic surface strip essential for RNA binding.","method":"X-ray crystallography, structure-guided mutagenesis, in vitro RNA binding assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — independent crystal structure with mutagenesis confirming RNA-binding residues, consistent with EMBO journal structure","pmids":["21957909"],"is_preprint":false},{"year":2014,"finding":"Cwc2 stabilizes U2-U6 snRNA helix I during splicing; genetic interactions link Cwc2 to the U6 ACAGAGA box, U6 ISL, and helix I; Cwc2 mutation suppresses the cold-sensitive prp16-302 phenotype; the prp16-302 allele stabilizes Cwc2-U6 interactions and destabilizes Cwc2-pre-mRNA contacts, indicating Prp16 remodels the spliceosome partly by antagonizing Cwc2 function.","method":"Yeast genetic epistasis (suppressor analysis, double mutants), RNA co-immunoprecipitation, UV crosslinking","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — epistasis plus crosslinking, single lab, multiple orthogonal methods","pmids":["24848011"],"is_preprint":false},{"year":2006,"finding":"RBM22 interacts with the calcium-binding protein ALG-2 (identified by yeast two-hybrid); RBM22 is nuclear and can shuttle to the cytoplasm; co-expression of RBM22 induces nuclear translocation of cytoplasmic ALG-2 in NIH 3T3 cells and in zebrafish embryos, with >95% co-localization in the nucleus.","method":"Yeast two-hybrid, fluorescence confocal microscopy of RFP/GFP fusion proteins in mammalian cells and zebrafish embryos","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid plus live-cell imaging in two model systems, but no biochemical reconstitution of the interaction","pmids":["17045351"],"is_preprint":false},{"year":2010,"finding":"Under cellular stress (heat shock or thapsigargin treatment), RBM22 enhances cytoplasmic translocation of the spliceosomal protein hSlu7, while ALG-2 co-expressed with RBM22 remains nuclear under both stress conditions; ER stress differentially affects splicing of XBP-1.","method":"Fluorescence microscopy of fusion proteins in NIH 3T3 cells under stress conditions, RT-PCR splicing assay (XBP-1)","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — live-cell imaging under multiple conditions, single lab, no biochemical reconstitution","pmids":["21122810"],"is_preprint":false},{"year":2020,"finding":"Human RBM22 binds the U12-U6atac snRNA complex of the minor spliceosome specifically and with similar affinity to U2-U6 snRNA (mean Kd ~3.4 μM for U2-U6 and ~8.0 μM for U12-U6atac), suggesting RBM22 performs the same catalytic-centre remodeling role in both the major and minor spliceosomes.","method":"Electrophoretic mobility shift assay (EMSA), fluorescence binding assay, solution NMR (for snRNA topology)","journal":"ACS omega","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — two orthogonal binding assays (EMSA + fluorescence) with defined Kd values, single study, no mutagenesis","pmids":["32984674"],"is_preprint":false},{"year":2024,"finding":"RBM22 occupies RNAPII-transcribed gene loci genome-wide; loss of RBM22 promotes RNAPII pause release, reduces elongation velocity, and causes transcriptional readthrough; RBM22 preferentially binds hyperphosphorylated RNAPII and regulates the homeostasis of the 7SK-P-TEFb complex and the association between RNAPII and elongation factor SPT5 at chromatin.","method":"ChIP-seq/ChIP, RNAPII elongation rate assays, co-immunoprecipitation (RBM22 with RNAPII), RBM22 depletion in human cells","journal":"Genome biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq, elongation rate measurement, Co-IP with RNAPII, multiple orthogonal methods in one study","pmids":["38641822"],"is_preprint":false},{"year":2024,"finding":"RBM22 directly interacts with LATS1 mRNA (shown by RNA immunoprecipitation) and stabilizes it, thereby maintaining LATS1 expression; knockdown of RBM22 reduces LATS1 levels and promotes NSCLC proliferation, invasion, and stemness in vitro and in vivo.","method":"RNA immunoprecipitation (RIP), overexpression/knockdown with proliferation and invasion assays, in vivo xenograft model","journal":"Journal of molecular histology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RIP plus functional assays in vitro and in vivo, single lab, no direct binding reconstitution","pmids":["39612045"],"is_preprint":false},{"year":2025,"finding":"SUMO modification of RBM22 (promoted by lncRNA ST7-AS2) alters its nucleoplasmic distribution; RBM22 binds SOX2 and upregulates VEGFR2 promoter transcriptional activity, driving vasculogenic mimicry in glioma.","method":"SUMO modification assay, chromatin/promoter reporter assay, protein-protein interaction (RBM22–SOX2), xenograft tumor model","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — SUMO modification and promoter binding shown, but single lab and limited mechanistic detail in abstract","pmids":["41317933"],"is_preprint":false},{"year":2026,"finding":"RBM22 selectively binds proximal promoters of key cell-cycle genes (Cdk4, Ccna2, Ccne1) and cooperates with chromatin remodeler SMARCA4 to enhance transcriptional accessibility; RBM22 is required for gene-specific recruitment of RNAPII to these loci; cardiomyocyte-specific deletion impairs neonatal heart regeneration and post-infarction remodeling.","method":"ChIP, co-immunoprecipitation (RBM22–SMARCA4), cardiomyocyte-specific knockout, AAV9-mediated overexpression in mice, hiPSC-derived cardiomyocyte proliferation assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP plus Co-IP plus genetic KO plus in vivo rescue, multiple orthogonal methods, single lab","pmids":["41803140"],"is_preprint":false},{"year":2009,"finding":"RBM22 (zRBM22) is required for normal zebrafish embryogenesis; morpholino-mediated knockdown causes developmental arrest with truncated axis and defective head/tail development by 15–32 hpf.","method":"Morpholino knockdown in zebrafish, in situ hybridization, morphological analysis","journal":"Genetics and molecular research","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — morpholino knockdown with developmental phenotype but no pathway placement","pmids":["20013661"],"is_preprint":false},{"year":2025,"finding":"RBM22 depletion in human hematopoietic stem/progenitor cells and myeloid cell lines delays progression through G1, S, and G2/M phases, causes endomitosis, and impairs megakaryocyte differentiation, establishing RBM22 as a cell-cycle regulator in myeloid cells.","method":"siRNA/shRNA depletion, flow cytometry cell-cycle analysis, differentiation assays in primary HSPCs and myeloid cell lines","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KD with defined cell-cycle phenotypes, but no molecular pathway mechanistically resolved; single lab","pmids":["40268057"],"is_preprint":false},{"year":2022,"finding":"RBM22 overexpression in prostate cancer cells dysregulates alternative splicing of numerous genes and downregulates CDK1, CCND1, and EPAS1 at the mRNA/protein level, reducing proliferation, migration, and tumorsphere/colony formation in vitro and in vivo.","method":"RNA-seq splicing analysis, nCounter pathway panel, overexpression in LNCaP/22Rv1/PC-3 cell lines, xenograft in vivo model","journal":"Translational research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq plus functional assays plus in vivo model, but mechanism is largely attributed to splicing without direct binding evidence for specific targets","pmids":["36089245"],"is_preprint":false}],"current_model":"RBM22 (Cwc2 in yeast) is a multipartite RNA-binding spliceosomal protein with a Torus–RRM–ZnF architecture that directly contacts U6 snRNA (including the ISL) and pre-mRNA near the 5' splice site to promote an active catalytic conformation of the spliceosome, stabilizes U2-U6 helix I, and is antagonized by the ATPase Prp16 during spliceosome remodeling; beyond splicing, RBM22 also coordinates RNAPII transcription by regulating pause-release, elongation velocity, and termination through the 7SK-P-TEFb complex and SPT5, binds proximal promoters of cell-cycle genes together with SMARCA4, stabilizes specific mRNAs (e.g., LATS1), interacts with the calcium sensor ALG-2 to regulate its nuclear localization, and is required for normal cell-cycle progression and embryonic development."},"narrative":{"mechanistic_narrative":"RBM22 (yeast Cwc2) is a multipartite RNA-binding spliceosomal protein that links the NineTeen Complex to the spliceosomal catalytic centre by directly contacting U6 snRNA and pre-mRNA [PMID:19435883]. It acts prior to the first catalytic step, binding catalytically important RNA elements including the U6 internal stem-loop and regions near the 5' splice site to promote an active conformation of the spliceosome, and these contacts are conserved between yeast Cwc2 and human RBM22 [PMID:22246180]. Structurally, its functional core integrates a Torus domain, an RRM, and a CCCH-type zinc finger into a single compact folding unit in which the ZnF is pivotal to the overall architecture, with a basic surface strip and connector element essential for RNA binding [PMID:22407296, PMID:21957909]. During spliceosome remodeling RBM22 stabilizes U2-U6 helix I and is antagonized by the ATPase Prp16, which destabilizes Cwc2-pre-mRNA contacts to drive conformational transitions [PMID:24848011]. The same catalytic-centre remodeling role extends to the minor spliceosome, as human RBM22 binds the U12-U6atac snRNA complex with affinity comparable to U2-U6 [PMID:32984674]. Beyond splicing, RBM22 occupies RNAPII-transcribed loci genome-wide, preferentially binds hyperphosphorylated RNAPII, and controls pause-release, elongation velocity, and termination through the 7SK-P-TEFb complex and the elongation factor SPT5 [PMID:38641822], and it cooperates with the chromatin remodeler SMARCA4 at proximal promoters of cell-cycle genes to direct gene-specific RNAPII recruitment [PMID:41803140]. RBM22 is required for normal cell-cycle progression and is essential for embryonic and cardiac developmental programs [PMID:41803140, PMID:20013661, PMID:40268057].","teleology":[{"year":2009,"claim":"Established the molecular link between the NineTeen Complex and the spliceosome by showing the RBM22 ortholog directly contacts U6 snRNA.","evidence":"UV crosslinking, snRNA co-IP, in vitro RNA binding, and depletion in yeast","pmids":["19435883"],"confidence":"High","gaps":["Did not resolve the precise nucleotide register of U6 contacts","Did not establish the catalytic step affected"]},{"year":2009,"claim":"Demonstrated an organismal requirement for RBM22 in vertebrate development, extending its relevance beyond yeast splicing biochemistry.","evidence":"Morpholino knockdown in zebrafish with morphological analysis","pmids":["20013661"],"confidence":"Medium","gaps":["No molecular pathway placement for the developmental phenotype","Morpholino specificity not genetically validated"]},{"year":2012,"claim":"Defined when and where RBM22/Cwc2 acts catalytically, showing it functions before step 1 and contacts the U6 ISL and 5' splice site region to promote an active spliceosome conformation, conserved to human.","evidence":"Yeast depletion, UV crosslinking mapping, splicing assays, human RBM22 comparison","pmids":["22246180"],"confidence":"High","gaps":["Did not provide a structural model of the engaged complex","Functional consequence of each contact not dissected"]},{"year":2012,"claim":"Resolved the protein architecture, revealing an integrated Torus-RRM-ZnF folding unit and mapping discrete RNA-contacting surfaces required for splicing.","evidence":"X-ray crystallography, crosslinking-MS, and mutagenesis in yeast (two independent structures)","pmids":["22407296","21957909"],"confidence":"High","gaps":["Structures are of the isolated core, not the assembled spliceosome","RNA was not co-crystallized"]},{"year":2014,"claim":"Placed RBM22 within the dynamics of spliceosome remodeling, showing it stabilizes U2-U6 helix I and is antagonized by the ATPase Prp16.","evidence":"Yeast genetic epistasis/suppressor analysis, RNA co-IP, UV crosslinking","pmids":["24848011"],"confidence":"High","gaps":["Mechanism of Prp16 antagonism not structurally defined","Did not address human RBM22 remodeling"]},{"year":2020,"claim":"Extended the catalytic-centre remodeling role to the minor spliceosome by showing human RBM22 binds U12-U6atac with affinity comparable to U2-U6.","evidence":"EMSA, fluorescence binding assay, solution NMR for snRNA topology","pmids":["32984674"],"confidence":"Medium","gaps":["No mutagenesis to confirm binding determinants","Functional role in minor splicing not assayed"]},{"year":2024,"claim":"Revealed a splicing-independent role at the RNAPII transcription cycle, controlling pause-release, elongation, and termination via 7SK-P-TEFb and SPT5.","evidence":"ChIP-seq, RNAPII elongation rate assays, Co-IP with RNAPII, depletion in human cells","pmids":["38641822"],"confidence":"High","gaps":["Direct vs. indirect basis for 7SK-P-TEFb homeostasis not separated","Whether RNA binding mediates chromatin occupancy is unresolved"]},{"year":2024,"claim":"Linked RBM22 to mRNA stability control, showing it binds and stabilizes LATS1 mRNA to restrain tumor cell behavior.","evidence":"RNA immunoprecipitation, knockdown/overexpression functional assays, xenograft in NSCLC","pmids":["39612045"],"confidence":"Medium","gaps":["Direct binding not reconstituted in vitro","Stabilization mechanism not defined"]},{"year":2022,"claim":"Connected RBM22 dosage to cell-cycle gene expression in cancer, showing overexpression downregulates CDK1/CCND1/EPAS1 and suppresses proliferation.","evidence":"RNA-seq splicing analysis, pathway panel, overexpression in prostate cancer lines, xenograft","pmids":["36089245"],"confidence":"Medium","gaps":["Effects attributed to splicing without direct target binding evidence","Causality between specific splicing events and phenotype unestablished"]},{"year":2025,"claim":"Established RBM22 as a functional cell-cycle regulator in hematopoietic cells, with depletion delaying cell-cycle phases and impairing megakaryocyte differentiation.","evidence":"siRNA/shRNA depletion, flow cytometry cell-cycle analysis, differentiation assays in HSPCs and myeloid lines","pmids":["40268057"],"confidence":"Medium","gaps":["No molecular pathway mechanistically resolved","Link to splicing vs. transcription roles not dissected"]},{"year":2026,"claim":"Defined a gene-specific transcriptional mechanism, showing RBM22 cooperates with SMARCA4 at cell-cycle gene promoters to direct RNAPII recruitment, with physiological consequences for cardiac regeneration.","evidence":"ChIP, Co-IP with SMARCA4, cardiomyocyte-specific knockout, AAV9 overexpression, hiPSC-cardiomyocyte assays","pmids":["41803140"],"confidence":"High","gaps":["How promoter selectivity is achieved is unknown","Relationship between SMARCA4 cooperation and the 7SK-P-TEFb role unresolved"]},{"year":null,"claim":"How RBM22's spliceosomal RNA-binding function mechanistically integrates with its chromatin-associated transcriptional and mRNA-stability roles remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking U6/pre-mRNA binding to RNAPII regulation","Determinants of promoter and target-mRNA selectivity unknown","Structural basis of RNAPII/SPT5/SMARCA4 engagement uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,2,3,7,9]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[8,11]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[1,4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,6]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[10]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[8,11]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,4,7]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[8,11]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[11,13]}],"complexes":["spliceosome","NineTeen Complex (NTC)","minor spliceosome"],"partners":["ALG-2","SPT5","RNAPII","SMARCA4","SOX2","HSLU7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NW64","full_name":"Pre-mRNA-splicing factor RBM22","aliases":["RNA-binding motif protein 22","Zinc finger CCCH domain-containing protein 16"],"length_aa":420,"mass_kda":46.9,"function":"Required for pre-mRNA splicing as component of the activated spliceosome (PubMed:28076346, PubMed:28502770, PubMed:29301961, PubMed:29360106, PubMed:29361316, PubMed:30705154). Involved in the first step of pre-mRNA splicing. Binds directly to the internal stem-loop (ISL) domain of the U6 snRNA and to the pre-mRNA intron near the 5' splice site during the activation and catalytic phases of the spliceosome cycle. Involved in both translocations of the nuclear SLU7 to the cytoplasm and the cytosolic calcium-binding protein PDCD6 to the nucleus upon cellular stress responses","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9NW64/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/RBM22","classification":"Common Essential","n_dependent_lines":1208,"n_total_lines":1208,"dependency_fraction":1.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000086589","cell_line_id":"CID001476","localizations":[{"compartment":"chromatin","grade":3}],"interactors":[{"gene":"CD2BP2","stoichiometry":0.2},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"DDX39B","stoichiometry":0.2},{"gene":"FUS","stoichiometry":0.2},{"gene":"PRPF4B","stoichiometry":0.2},{"gene":"THOC1","stoichiometry":0.2},{"gene":"RBM39","stoichiometry":0.2},{"gene":"RBM42","stoichiometry":0.2},{"gene":"SF3A1","stoichiometry":0.2},{"gene":"SF3A2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001476","total_profiled":1310},"omim":[{"mim_id":"612430","title":"RNA-BINDING MOTIF PROTEIN 22; RBM22","url":"https://www.omim.org/entry/612430"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RBM22"},"hgnc":{"alias_symbol":["FLJ10290","ZC3H16","fSAP47","Cwc2"],"prev_symbol":[]},"alphafold":{"accession":"Q9NW64","domains":[{"cath_id":"-","chopping":"13-220","consensus_level":"medium","plddt":86.9014,"start":13,"end":220},{"cath_id":"3.30.70.330","chopping":"232-311","consensus_level":"high","plddt":85.5691,"start":232,"end":311}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NW64","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NW64-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NW64-F1-predicted_aligned_error_v6.png","plddt_mean":76.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RBM22","jax_strain_url":"https://www.jax.org/strain/search?query=RBM22"},"sequence":{"accession":"Q9NW64","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NW64.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NW64/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NW64"}},"corpus_meta":[{"pmid":"22246180","id":"PMC_22246180","title":"Cwc2 and its human homologue RBM22 promote an active conformation of the spliceosome catalytic centre.","date":"2012","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/22246180","citation_count":60,"is_preprint":false},{"pmid":"15813738","id":"PMC_15813738","title":"Blue light negatively regulates the sexual filamentation via the Cwc1 and Cwc2 proteins in Cryptococcus neoformans.","date":"2005","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/15813738","citation_count":47,"is_preprint":false},{"pmid":"17045351","id":"PMC_17045351","title":"Nuclear translocation of the calcium-binding protein ALG-2 induced by the RNA-binding protein RBM22.","date":"2006","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/17045351","citation_count":35,"is_preprint":false},{"pmid":"19435883","id":"PMC_19435883","title":"The RNA binding protein Cwc2 interacts directly with the U6 snRNA to link the nineteen complex to the spliceosome during pre-mRNA splicing.","date":"2009","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/19435883","citation_count":32,"is_preprint":false},{"pmid":"22407296","id":"PMC_22407296","title":"Crystal structure of Cwc2 reveals a novel architecture of a multipartite RNA-binding protein.","date":"2012","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/22407296","citation_count":23,"is_preprint":false},{"pmid":"24848011","id":"PMC_24848011","title":"Remodeling of U2-U6 snRNA helix I during pre-mRNA splicing by Prp16 and the NineTeen Complex protein Cwc2.","date":"2014","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/24848011","citation_count":13,"is_preprint":false},{"pmid":"21957909","id":"PMC_21957909","title":"Structure of the mRNA splicing complex component Cwc2: insights into RNA recognition.","date":"2012","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/21957909","citation_count":13,"is_preprint":false},{"pmid":"21122810","id":"PMC_21122810","title":"Stress induced subcellular distribution of ALG-2, RBM22 and hSlu7.","date":"2010","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/21122810","citation_count":12,"is_preprint":false},{"pmid":"36089245","id":"PMC_36089245","title":"Tumor suppressor role of RBM22 in prostate cancer acting as a dual-factor regulating alternative splicing and transcription of key oncogenic genes.","date":"2022","source":"Translational research : the journal of laboratory and clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36089245","citation_count":9,"is_preprint":false},{"pmid":"38641822","id":"PMC_38641822","title":"RBM22 regulates RNA polymerase II 5' pausing, elongation rate, and termination by coordinating 7SK-P-TEFb complex and SPT5.","date":"2024","source":"Genome biology","url":"https://pubmed.ncbi.nlm.nih.gov/38641822","citation_count":8,"is_preprint":false},{"pmid":"20013661","id":"PMC_20013661","title":"RNA-binding motif protein RBM22 is required for normal development of zebrafish embryos.","date":"2009","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/20013661","citation_count":7,"is_preprint":false},{"pmid":"32984674","id":"PMC_32984674","title":"Topology of the U12-U6atac snRNA Complex of the Minor Spliceosome and Binding by NTC-Related Protein RBM22.","date":"2020","source":"ACS omega","url":"https://pubmed.ncbi.nlm.nih.gov/32984674","citation_count":3,"is_preprint":false},{"pmid":"40268057","id":"PMC_40268057","title":"RBM22-depletion delays progression through all steps of cell cycle and increases ploidy in myeloid cells.","date":"2025","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/40268057","citation_count":0,"is_preprint":false},{"pmid":"39612045","id":"PMC_39612045","title":"RNA binding protein RBM22 suppresses non-small cell lung cancer tumorigenesis by stabilizing LATS1 mRNA.","date":"2024","source":"Journal of molecular histology","url":"https://pubmed.ncbi.nlm.nih.gov/39612045","citation_count":0,"is_preprint":false},{"pmid":"41803140","id":"PMC_41803140","title":"Restoration of RBM22 overcomes the transcriptional and epigenetic barriers of cardiomyocyte proliferation for heart regeneration.","date":"2026","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41803140","citation_count":0,"is_preprint":false},{"pmid":"41317933","id":"PMC_41317933","title":"Mechanism of LncRNA ST7-AS2/RBM22/SOX2 axis regulating vasculogenic mimicry of glioma.","date":"2025","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/41317933","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9812,"output_tokens":3780,"usd":0.043068,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11498,"output_tokens":3604,"usd":0.073795,"stage2_stop_reason":"end_turn"},"total_usd":0.116863,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"Cwc2 (yeast ortholog of RBM22) directly crosslinks to U6 snRNA under splicing conditions and associates with U2, U5, and U6 snRNAs; depletion causes pre-mRNA accumulation and reduced snRNA levels; the zinc finger and RRM motifs are both required for function, linking the NineTeen Complex (NTC) to the spliceosome via U6 snRNA.\",\n      \"method\": \"UV crosslinking, snRNA co-immunoprecipitation, in vitro RNA binding assay, yeast depletion/mutant analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (crosslinking, co-IP, in vitro binding, genetic depletion) in a single focused study establishing direct U6 snRNA contact\",\n      \"pmids\": [\"19435883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Cwc2/RBM22 functions prior to step 1 of splicing (not required for Prp2-mediated remodeling) and directly contacts catalytically important RNA elements including the U6 internal stem-loop (ISL) and regions of U6 and pre-mRNA near the 5' splice site, promoting an active conformation of the spliceosome catalytic centre; these contacts are evolutionarily conserved in human RBM22.\",\n      \"method\": \"Yeast genetic depletion, UV-induced RNA-protein crosslinking, splicing assays, comparative studies with human RBM22\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic depletion combined with UV crosslinking mapping, with evolutionary conservation validated using human RBM22\",\n      \"pmids\": [\"22246180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structure of Cwc2 functional core reveals a Torus domain, RRM, and zinc finger (ZnF) integrated in a compact folding unit with the ZnF pivotal to overall architecture; UV crosslinking coupled to mass spectrometry identified six RNA-contacting sites (four near RRM, one in ZnF, one on a connector/Torus–RRM element); the connector element is essential for splicing.\",\n      \"method\": \"X-ray crystallography, UV-induced crosslinking with mass spectrometry, mutational analysis in yeast\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus crosslinking-MS plus mutagenesis in a single rigorous study\",\n      \"pmids\": [\"22407296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"X-ray structure (1.9 Å) of Cwc2 core domain shows that the CCCH-type zinc finger and RRM form a single folding unit held by hydrophobic interactions and hydrogen bonds; the intervening RB loop and conserved positively charged β-strand residues form an extended basic surface strip essential for RNA binding.\",\n      \"method\": \"X-ray crystallography, structure-guided mutagenesis, in vitro RNA binding assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — independent crystal structure with mutagenesis confirming RNA-binding residues, consistent with EMBO journal structure\",\n      \"pmids\": [\"21957909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Cwc2 stabilizes U2-U6 snRNA helix I during splicing; genetic interactions link Cwc2 to the U6 ACAGAGA box, U6 ISL, and helix I; Cwc2 mutation suppresses the cold-sensitive prp16-302 phenotype; the prp16-302 allele stabilizes Cwc2-U6 interactions and destabilizes Cwc2-pre-mRNA contacts, indicating Prp16 remodels the spliceosome partly by antagonizing Cwc2 function.\",\n      \"method\": \"Yeast genetic epistasis (suppressor analysis, double mutants), RNA co-immunoprecipitation, UV crosslinking\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis plus crosslinking, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"24848011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"RBM22 interacts with the calcium-binding protein ALG-2 (identified by yeast two-hybrid); RBM22 is nuclear and can shuttle to the cytoplasm; co-expression of RBM22 induces nuclear translocation of cytoplasmic ALG-2 in NIH 3T3 cells and in zebrafish embryos, with >95% co-localization in the nucleus.\",\n      \"method\": \"Yeast two-hybrid, fluorescence confocal microscopy of RFP/GFP fusion proteins in mammalian cells and zebrafish embryos\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid plus live-cell imaging in two model systems, but no biochemical reconstitution of the interaction\",\n      \"pmids\": [\"17045351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Under cellular stress (heat shock or thapsigargin treatment), RBM22 enhances cytoplasmic translocation of the spliceosomal protein hSlu7, while ALG-2 co-expressed with RBM22 remains nuclear under both stress conditions; ER stress differentially affects splicing of XBP-1.\",\n      \"method\": \"Fluorescence microscopy of fusion proteins in NIH 3T3 cells under stress conditions, RT-PCR splicing assay (XBP-1)\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — live-cell imaging under multiple conditions, single lab, no biochemical reconstitution\",\n      \"pmids\": [\"21122810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Human RBM22 binds the U12-U6atac snRNA complex of the minor spliceosome specifically and with similar affinity to U2-U6 snRNA (mean Kd ~3.4 μM for U2-U6 and ~8.0 μM for U12-U6atac), suggesting RBM22 performs the same catalytic-centre remodeling role in both the major and minor spliceosomes.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA), fluorescence binding assay, solution NMR (for snRNA topology)\",\n      \"journal\": \"ACS omega\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — two orthogonal binding assays (EMSA + fluorescence) with defined Kd values, single study, no mutagenesis\",\n      \"pmids\": [\"32984674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RBM22 occupies RNAPII-transcribed gene loci genome-wide; loss of RBM22 promotes RNAPII pause release, reduces elongation velocity, and causes transcriptional readthrough; RBM22 preferentially binds hyperphosphorylated RNAPII and regulates the homeostasis of the 7SK-P-TEFb complex and the association between RNAPII and elongation factor SPT5 at chromatin.\",\n      \"method\": \"ChIP-seq/ChIP, RNAPII elongation rate assays, co-immunoprecipitation (RBM22 with RNAPII), RBM22 depletion in human cells\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq, elongation rate measurement, Co-IP with RNAPII, multiple orthogonal methods in one study\",\n      \"pmids\": [\"38641822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RBM22 directly interacts with LATS1 mRNA (shown by RNA immunoprecipitation) and stabilizes it, thereby maintaining LATS1 expression; knockdown of RBM22 reduces LATS1 levels and promotes NSCLC proliferation, invasion, and stemness in vitro and in vivo.\",\n      \"method\": \"RNA immunoprecipitation (RIP), overexpression/knockdown with proliferation and invasion assays, in vivo xenograft model\",\n      \"journal\": \"Journal of molecular histology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RIP plus functional assays in vitro and in vivo, single lab, no direct binding reconstitution\",\n      \"pmids\": [\"39612045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SUMO modification of RBM22 (promoted by lncRNA ST7-AS2) alters its nucleoplasmic distribution; RBM22 binds SOX2 and upregulates VEGFR2 promoter transcriptional activity, driving vasculogenic mimicry in glioma.\",\n      \"method\": \"SUMO modification assay, chromatin/promoter reporter assay, protein-protein interaction (RBM22–SOX2), xenograft tumor model\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — SUMO modification and promoter binding shown, but single lab and limited mechanistic detail in abstract\",\n      \"pmids\": [\"41317933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RBM22 selectively binds proximal promoters of key cell-cycle genes (Cdk4, Ccna2, Ccne1) and cooperates with chromatin remodeler SMARCA4 to enhance transcriptional accessibility; RBM22 is required for gene-specific recruitment of RNAPII to these loci; cardiomyocyte-specific deletion impairs neonatal heart regeneration and post-infarction remodeling.\",\n      \"method\": \"ChIP, co-immunoprecipitation (RBM22–SMARCA4), cardiomyocyte-specific knockout, AAV9-mediated overexpression in mice, hiPSC-derived cardiomyocyte proliferation assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus Co-IP plus genetic KO plus in vivo rescue, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"41803140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RBM22 (zRBM22) is required for normal zebrafish embryogenesis; morpholino-mediated knockdown causes developmental arrest with truncated axis and defective head/tail development by 15–32 hpf.\",\n      \"method\": \"Morpholino knockdown in zebrafish, in situ hybridization, morphological analysis\",\n      \"journal\": \"Genetics and molecular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — morpholino knockdown with developmental phenotype but no pathway placement\",\n      \"pmids\": [\"20013661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBM22 depletion in human hematopoietic stem/progenitor cells and myeloid cell lines delays progression through G1, S, and G2/M phases, causes endomitosis, and impairs megakaryocyte differentiation, establishing RBM22 as a cell-cycle regulator in myeloid cells.\",\n      \"method\": \"siRNA/shRNA depletion, flow cytometry cell-cycle analysis, differentiation assays in primary HSPCs and myeloid cell lines\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KD with defined cell-cycle phenotypes, but no molecular pathway mechanistically resolved; single lab\",\n      \"pmids\": [\"40268057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RBM22 overexpression in prostate cancer cells dysregulates alternative splicing of numerous genes and downregulates CDK1, CCND1, and EPAS1 at the mRNA/protein level, reducing proliferation, migration, and tumorsphere/colony formation in vitro and in vivo.\",\n      \"method\": \"RNA-seq splicing analysis, nCounter pathway panel, overexpression in LNCaP/22Rv1/PC-3 cell lines, xenograft in vivo model\",\n      \"journal\": \"Translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq plus functional assays plus in vivo model, but mechanism is largely attributed to splicing without direct binding evidence for specific targets\",\n      \"pmids\": [\"36089245\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RBM22 (Cwc2 in yeast) is a multipartite RNA-binding spliceosomal protein with a Torus–RRM–ZnF architecture that directly contacts U6 snRNA (including the ISL) and pre-mRNA near the 5' splice site to promote an active catalytic conformation of the spliceosome, stabilizes U2-U6 helix I, and is antagonized by the ATPase Prp16 during spliceosome remodeling; beyond splicing, RBM22 also coordinates RNAPII transcription by regulating pause-release, elongation velocity, and termination through the 7SK-P-TEFb complex and SPT5, binds proximal promoters of cell-cycle genes together with SMARCA4, stabilizes specific mRNAs (e.g., LATS1), interacts with the calcium sensor ALG-2 to regulate its nuclear localization, and is required for normal cell-cycle progression and embryonic development.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RBM22 (yeast Cwc2) is a multipartite RNA-binding spliceosomal protein that links the NineTeen Complex to the spliceosomal catalytic centre by directly contacting U6 snRNA and pre-mRNA [#0]. It acts prior to the first catalytic step, binding catalytically important RNA elements including the U6 internal stem-loop and regions near the 5' splice site to promote an active conformation of the spliceosome, and these contacts are conserved between yeast Cwc2 and human RBM22 [#1]. Structurally, its functional core integrates a Torus domain, an RRM, and a CCCH-type zinc finger into a single compact folding unit in which the ZnF is pivotal to the overall architecture, with a basic surface strip and connector element essential for RNA binding [#2, #3]. During spliceosome remodeling RBM22 stabilizes U2-U6 helix I and is antagonized by the ATPase Prp16, which destabilizes Cwc2-pre-mRNA contacts to drive conformational transitions [#4]. The same catalytic-centre remodeling role extends to the minor spliceosome, as human RBM22 binds the U12-U6atac snRNA complex with affinity comparable to U2-U6 [#7]. Beyond splicing, RBM22 occupies RNAPII-transcribed loci genome-wide, preferentially binds hyperphosphorylated RNAPII, and controls pause-release, elongation velocity, and termination through the 7SK-P-TEFb complex and the elongation factor SPT5 [#8], and it cooperates with the chromatin remodeler SMARCA4 at proximal promoters of cell-cycle genes to direct gene-specific RNAPII recruitment [#11]. RBM22 is required for normal cell-cycle progression and is essential for embryonic and cardiac developmental programs [#11, #12, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established the molecular link between the NineTeen Complex and the spliceosome by showing the RBM22 ortholog directly contacts U6 snRNA.\",\n      \"evidence\": \"UV crosslinking, snRNA co-IP, in vitro RNA binding, and depletion in yeast\",\n      \"pmids\": [\"19435883\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the precise nucleotide register of U6 contacts\", \"Did not establish the catalytic step affected\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated an organismal requirement for RBM22 in vertebrate development, extending its relevance beyond yeast splicing biochemistry.\",\n      \"evidence\": \"Morpholino knockdown in zebrafish with morphological analysis\",\n      \"pmids\": [\"20013661\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular pathway placement for the developmental phenotype\", \"Morpholino specificity not genetically validated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined when and where RBM22/Cwc2 acts catalytically, showing it functions before step 1 and contacts the U6 ISL and 5' splice site region to promote an active spliceosome conformation, conserved to human.\",\n      \"evidence\": \"Yeast depletion, UV crosslinking mapping, splicing assays, human RBM22 comparison\",\n      \"pmids\": [\"22246180\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not provide a structural model of the engaged complex\", \"Functional consequence of each contact not dissected\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved the protein architecture, revealing an integrated Torus-RRM-ZnF folding unit and mapping discrete RNA-contacting surfaces required for splicing.\",\n      \"evidence\": \"X-ray crystallography, crosslinking-MS, and mutagenesis in yeast (two independent structures)\",\n      \"pmids\": [\"22407296\", \"21957909\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures are of the isolated core, not the assembled spliceosome\", \"RNA was not co-crystallized\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed RBM22 within the dynamics of spliceosome remodeling, showing it stabilizes U2-U6 helix I and is antagonized by the ATPase Prp16.\",\n      \"evidence\": \"Yeast genetic epistasis/suppressor analysis, RNA co-IP, UV crosslinking\",\n      \"pmids\": [\"24848011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of Prp16 antagonism not structurally defined\", \"Did not address human RBM22 remodeling\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended the catalytic-centre remodeling role to the minor spliceosome by showing human RBM22 binds U12-U6atac with affinity comparable to U2-U6.\",\n      \"evidence\": \"EMSA, fluorescence binding assay, solution NMR for snRNA topology\",\n      \"pmids\": [\"32984674\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mutagenesis to confirm binding determinants\", \"Functional role in minor splicing not assayed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a splicing-independent role at the RNAPII transcription cycle, controlling pause-release, elongation, and termination via 7SK-P-TEFb and SPT5.\",\n      \"evidence\": \"ChIP-seq, RNAPII elongation rate assays, Co-IP with RNAPII, depletion in human cells\",\n      \"pmids\": [\"38641822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs. indirect basis for 7SK-P-TEFb homeostasis not separated\", \"Whether RNA binding mediates chromatin occupancy is unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked RBM22 to mRNA stability control, showing it binds and stabilizes LATS1 mRNA to restrain tumor cell behavior.\",\n      \"evidence\": \"RNA immunoprecipitation, knockdown/overexpression functional assays, xenograft in NSCLC\",\n      \"pmids\": [\"39612045\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding not reconstituted in vitro\", \"Stabilization mechanism not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected RBM22 dosage to cell-cycle gene expression in cancer, showing overexpression downregulates CDK1/CCND1/EPAS1 and suppresses proliferation.\",\n      \"evidence\": \"RNA-seq splicing analysis, pathway panel, overexpression in prostate cancer lines, xenograft\",\n      \"pmids\": [\"36089245\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effects attributed to splicing without direct target binding evidence\", \"Causality between specific splicing events and phenotype unestablished\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established RBM22 as a functional cell-cycle regulator in hematopoietic cells, with depletion delaying cell-cycle phases and impairing megakaryocyte differentiation.\",\n      \"evidence\": \"siRNA/shRNA depletion, flow cytometry cell-cycle analysis, differentiation assays in HSPCs and myeloid lines\",\n      \"pmids\": [\"40268057\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular pathway mechanistically resolved\", \"Link to splicing vs. transcription roles not dissected\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined a gene-specific transcriptional mechanism, showing RBM22 cooperates with SMARCA4 at cell-cycle gene promoters to direct RNAPII recruitment, with physiological consequences for cardiac regeneration.\",\n      \"evidence\": \"ChIP, Co-IP with SMARCA4, cardiomyocyte-specific knockout, AAV9 overexpression, hiPSC-cardiomyocyte assays\",\n      \"pmids\": [\"41803140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How promoter selectivity is achieved is unknown\", \"Relationship between SMARCA4 cooperation and the 7SK-P-TEFb role unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RBM22's spliceosomal RNA-binding function mechanistically integrates with its chromatin-associated transcriptional and mRNA-stability roles remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking U6/pre-mRNA binding to RNAPII regulation\", \"Determinants of promoter and target-mRNA selectivity unknown\", \"Structural basis of RNAPII/SPT5/SMARCA4 engagement uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 2, 3, 7, 9]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [8, 11]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [8, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 4, 7]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [8, 11]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [11, 13]}\n    ],\n    \"complexes\": [\"spliceosome\", \"NineTeen Complex (NTC)\", \"minor spliceosome\"],\n    \"partners\": [\"ALG-2\", \"SPT5\", \"RNAPII\", \"SMARCA4\", \"SOX2\", \"hSlu7\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}