Affinage

RBM22

Pre-mRNA-splicing factor RBM22 · UniProt Q9NW64

Length
420 aa
Mass
46.9 kDa
Annotated
2026-06-10
16 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2009 High

    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

    PMID:19435883

    Open questions at the time
    • Did not resolve the precise nucleotide register of U6 contacts
    • Did not establish the catalytic step affected
  2. 2009 Medium

    Demonstrated an organismal requirement for RBM22 in vertebrate development, extending its relevance beyond yeast splicing biochemistry.

    Evidence Morpholino knockdown in zebrafish with morphological analysis

    PMID:20013661

    Open questions at the time
    • No molecular pathway placement for the developmental phenotype
    • Morpholino specificity not genetically validated
  3. 2012 High

    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

    PMID:22246180

    Open questions at the time
    • Did not provide a structural model of the engaged complex
    • Functional consequence of each contact not dissected
  4. 2012 High

    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)

    PMID:21957909 PMID:22407296

    Open questions at the time
    • Structures are of the isolated core, not the assembled spliceosome
    • RNA was not co-crystallized
  5. 2014 High

    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

    PMID:24848011

    Open questions at the time
    • Mechanism of Prp16 antagonism not structurally defined
    • Did not address human RBM22 remodeling
  6. 2020 Medium

    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

    PMID:32984674

    Open questions at the time
    • No mutagenesis to confirm binding determinants
    • Functional role in minor splicing not assayed
  7. 2024 High

    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

    PMID:38641822

    Open questions at the time
    • Direct vs. indirect basis for 7SK-P-TEFb homeostasis not separated
    • Whether RNA binding mediates chromatin occupancy is unresolved
  8. 2024 Medium

    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

    PMID:39612045

    Open questions at the time
    • Direct binding not reconstituted in vitro
    • Stabilization mechanism not defined
  9. 2022 Medium

    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

    PMID:36089245

    Open questions at the time
    • Effects attributed to splicing without direct target binding evidence
    • Causality between specific splicing events and phenotype unestablished
  10. 2025 Medium

    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

    PMID:40268057

    Open questions at the time
    • No molecular pathway mechanistically resolved
    • Link to splicing vs. transcription roles not dissected
  11. 2026 High

    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

    PMID:41803140

    Open questions at the time
    • How promoter selectivity is achieved is unknown
    • Relationship between SMARCA4 cooperation and the 7SK-P-TEFb role unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RBM22's spliceosomal RNA-binding function mechanistically integrates with its chromatin-associated transcriptional and mRNA-stability roles remains unresolved.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 6 GO:0140098 catalytic activity, acting on RNA 2 GO:0140110 transcription regulator activity 2
Localization
GO:0000228 nuclear chromosome 2 GO:0005634 nucleus 2 GO:0005654 nucleoplasm 1
Pathway
R-HSA-8953854 Metabolism of RNA 4 R-HSA-1640170 Cell Cycle 2 R-HSA-74160 Gene expression (Transcription) 2
Partners
ALG-2HSLU7RNAPIISMARCA4SOX2SPT5
Complex memberships
NineTeen Complex (NTC)minor spliceosomespliceosome

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 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. UV crosslinking, snRNA co-immunoprecipitation, in vitro RNA binding assay, yeast depletion/mutant analysis Nucleic acids research High 19435883
2012 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. Yeast genetic depletion, UV-induced RNA-protein crosslinking, splicing assays, comparative studies with human RBM22 The EMBO journal High 22246180
2012 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. X-ray crystallography, UV-induced crosslinking with mass spectrometry, mutational analysis in yeast The EMBO journal High 22407296
2012 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. X-ray crystallography, structure-guided mutagenesis, in vitro RNA binding assay The Biochemical journal High 21957909
2014 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. Yeast genetic epistasis (suppressor analysis, double mutants), RNA co-immunoprecipitation, UV crosslinking Nucleic acids research High 24848011
2006 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. Yeast two-hybrid, fluorescence confocal microscopy of RFP/GFP fusion proteins in mammalian cells and zebrafish embryos Biochimica et biophysica acta Medium 17045351
2010 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. Fluorescence microscopy of fusion proteins in NIH 3T3 cells under stress conditions, RT-PCR splicing assay (XBP-1) Biochimica et biophysica acta Medium 21122810
2020 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. Electrophoretic mobility shift assay (EMSA), fluorescence binding assay, solution NMR (for snRNA topology) ACS omega Medium 32984674
2024 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. ChIP-seq/ChIP, RNAPII elongation rate assays, co-immunoprecipitation (RBM22 with RNAPII), RBM22 depletion in human cells Genome biology High 38641822
2024 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. RNA immunoprecipitation (RIP), overexpression/knockdown with proliferation and invasion assays, in vivo xenograft model Journal of molecular histology Medium 39612045
2025 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. SUMO modification assay, chromatin/promoter reporter assay, protein-protein interaction (RBM22–SOX2), xenograft tumor model Cellular signalling Medium 41317933
2026 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. ChIP, co-immunoprecipitation (RBM22–SMARCA4), cardiomyocyte-specific knockout, AAV9-mediated overexpression in mice, hiPSC-derived cardiomyocyte proliferation assay Nature communications High 41803140
2009 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. Morpholino knockdown in zebrafish, in situ hybridization, morphological analysis Genetics and molecular research Medium 20013661
2025 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. siRNA/shRNA depletion, flow cytometry cell-cycle analysis, differentiation assays in primary HSPCs and myeloid cell lines Biochimica et biophysica acta. Molecular cell research Medium 40268057
2022 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. RNA-seq splicing analysis, nCounter pathway panel, overexpression in LNCaP/22Rv1/PC-3 cell lines, xenograft in vivo model Translational research Medium 36089245

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Cwc2 and its human homologue RBM22 promote an active conformation of the spliceosome catalytic centre. The EMBO journal 60 22246180
2005 Blue light negatively regulates the sexual filamentation via the Cwc1 and Cwc2 proteins in Cryptococcus neoformans. Molecular microbiology 47 15813738
2006 Nuclear translocation of the calcium-binding protein ALG-2 induced by the RNA-binding protein RBM22. Biochimica et biophysica acta 35 17045351
2009 The RNA binding protein Cwc2 interacts directly with the U6 snRNA to link the nineteen complex to the spliceosome during pre-mRNA splicing. Nucleic acids research 32 19435883
2012 Crystal structure of Cwc2 reveals a novel architecture of a multipartite RNA-binding protein. The EMBO journal 23 22407296
2014 Remodeling of U2-U6 snRNA helix I during pre-mRNA splicing by Prp16 and the NineTeen Complex protein Cwc2. Nucleic acids research 13 24848011
2012 Structure of the mRNA splicing complex component Cwc2: insights into RNA recognition. The Biochemical journal 13 21957909
2010 Stress induced subcellular distribution of ALG-2, RBM22 and hSlu7. Biochimica et biophysica acta 12 21122810
2022 Tumor suppressor role of RBM22 in prostate cancer acting as a dual-factor regulating alternative splicing and transcription of key oncogenic genes. Translational research : the journal of laboratory and clinical medicine 9 36089245
2024 RBM22 regulates RNA polymerase II 5' pausing, elongation rate, and termination by coordinating 7SK-P-TEFb complex and SPT5. Genome biology 8 38641822
2009 RNA-binding motif protein RBM22 is required for normal development of zebrafish embryos. Genetics and molecular research : GMR 7 20013661
2020 Topology of the U12-U6atac snRNA Complex of the Minor Spliceosome and Binding by NTC-Related Protein RBM22. ACS omega 3 32984674
2026 Restoration of RBM22 overcomes the transcriptional and epigenetic barriers of cardiomyocyte proliferation for heart regeneration. Nature communications 0 41803140
2025 RBM22-depletion delays progression through all steps of cell cycle and increases ploidy in myeloid cells. Biochimica et biophysica acta. Molecular cell research 0 40268057
2025 Mechanism of LncRNA ST7-AS2/RBM22/SOX2 axis regulating vasculogenic mimicry of glioma. Cellular signalling 0 41317933
2024 RNA binding protein RBM22 suppresses non-small cell lung cancer tumorigenesis by stabilizing LATS1 mRNA. Journal of molecular histology 0 39612045

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