Affinage

RBM22

Pre-mRNA-splicing factor RBM22 · UniProt Q9NW64

Length
420 aa
Mass
46.9 kDa
Annotated
2026-04-28
16 papers in source corpus 14 papers cited in narrative 14 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RBM22 is a conserved RNA-binding protein that functions at the catalytic core of the spliceosome and as a transcriptional regulator of RNA Polymerase II. Its Torus domain, RRM, and CCCH-type zinc finger form a compact structural unit that directly contacts U6 snRNA (including the internal stem-loop) and pre-mRNA near the 5′ splice site, stabilizing the catalytic RNA conformation required for both steps of splicing in major and minor spliceosomes (PMID:22246180, PMID:32984674, PMID:22407296). Beyond splicing, RBM22 binds hyperphosphorylated RNAPII and occupies gene promoters, where it cooperates with SMARCA4 to regulate promoter-proximal pausing, elongation velocity, transcriptional termination, and chromatin accessibility at cell cycle genes (PMID:38641822, PMID:41803140). RBM22 is essential for vertebrate embryogenesis, neonatal cardiac regeneration, myeloid cell cycle progression, and mRNA stabilization of targets such as LATS1, and its nucleoplasmic distribution is modulated by SUMOylation (PMID:20013661, PMID:41803140, PMID:40268057, PMID:39612045, PMID:41317933).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2006 Medium

    Establishing that RBM22 has functions beyond splicing: the discovery that RBM22 physically interacts with ALG-2 and drives its nuclear translocation revealed RBM22 as a nucleocytoplasmic shuttling protein with protein-interaction roles outside the spliceosome.

    Evidence Yeast two-hybrid and confocal microscopy of fluorescent fusions in NIH 3T3 cells and zebrafish embryos

    PMID:17045351

    Open questions at the time
    • No direct biochemical binding assay (e.g., pull-down with purified proteins) was performed
    • Functional consequence of ALG-2 nuclear translocation unclear
    • Whether shuttling is regulated by signaling remains unknown
  2. 2009 High

    Identifying how RBM22/Cwc2 links the NTC to the spliceosome: direct UV-crosslinking to U6 snRNA demonstrated that Cwc2 physically tethers the NTC to the catalytic RNA core, and depletion caused pre-mRNA accumulation, proving an essential splicing role.

    Evidence UV-crosslinking, snRNA co-IP, RNA binding assays, and yeast depletion genetics

    PMID:19435883

    Open questions at the time
    • Precise binding site on U6 snRNA not mapped at nucleotide resolution
    • Whether human RBM22 performs the identical tethering function was not yet tested
  3. 2009 Medium

    Demonstrating RBM22 is essential for vertebrate development: morpholino knockdown in zebrafish caused developmental arrest with axis truncation, establishing in vivo essentiality.

    Evidence Morpholino knockdown in zebrafish with morphological and molecular phenotyping

    PMID:20013661

    Open questions at the time
    • Morpholino off-target effects not ruled out by genetic mutant
    • Which RBM22-dependent RNAs or transcripts drive the developmental phenotype is unknown
  4. 2012 High

    Resolving the structural basis for RNA recognition: two independent crystal structures of Cwc2 revealed that the Torus domain, RRM, and zinc finger form a single compact unit with a contiguous positively charged RNA-binding surface, and mutagenesis of the connector element or RB loop abolished RNA binding and splicing.

    Evidence X-ray crystallography (1.9 Å resolution), UV-crosslinking/mass spectrometry, structure-guided mutagenesis, splicing assays

    PMID:21957909 PMID:22407296

    Open questions at the time
    • No structure of Cwc2/RBM22 bound to RNA
    • How the compact unit engages multiple RNA elements simultaneously is unclear
  5. 2012 High

    Mapping the catalytic RNA contacts and confirming conservation with human RBM22: crosslinking showed Cwc2 contacts U6 ISL, U6 snRNA, and pre-mRNA intron near the 5′ splice site, and human RBM22 recapitulated these contacts, establishing a conserved role in promoting the active spliceosome conformation.

    Evidence UV-crosslinking, mutational analysis, spliceosome fractionation, functional complementation with human RBM22

    PMID:22246180

    Open questions at the time
    • Whether RBM22 actively remodels or passively stabilizes the RNA fold is unresolved
    • No reconstitution with purified human spliceosomes
  6. 2014 High

    Revealing dynamic remodeling of RBM22/Cwc2 contacts between splicing steps: genetic and crosslinking evidence showed Cwc2 stabilizes U2-U6 helix I and is a target of Prp16-mediated remodeling, with antagonistic contacts to U6 snRNA versus pre-mRNA shifting between steps 1 and 2.

    Evidence Genetic suppressor screen (cwc2/prp16 epistasis), snRNA co-IP, UV-crosslinking in yeast

    PMID:24848011

    Open questions at the time
    • Structural basis of Prp16-dependent remodeling of Cwc2 contacts is unknown
    • Whether this dynamic remodeling is conserved in human RBM22 is untested
  7. 2020 Medium

    Extending the catalytic core role to the minor spliceosome: quantitative binding showed RBM22 binds U12-U6atac snRNA with affinity comparable to U2-U6, indicating it performs equivalent catalytic center stabilization in both major and minor spliceosomes.

    Evidence EMSA and fluorescence binding assays with in vitro-transcribed snRNA duplexes, solution NMR

    PMID:32984674

    Open questions at the time
    • Binding measured with isolated RNA duplexes, not in assembled minor spliceosomes
    • Functional requirement of RBM22 in minor intron splicing not tested in cells
  8. 2024 High

    Uncovering a direct transcriptional regulatory function: genome-wide profiling revealed RBM22 occupies RNAPII-transcribed loci, binds hyperphosphorylated RNAPII, and controls pause release, elongation velocity, and termination by modulating the 7SK-P-TEFb axis and SPT5-RNAPII association.

    Evidence ChIP-seq, nascent RNA sequencing, co-immunoprecipitation, RBM22 depletion with genome-wide readouts

    PMID:38641822

    Open questions at the time
    • Whether the transcriptional and splicing functions of RBM22 are separable or coupled is unknown
    • Direct versus indirect effects on elongation velocity not fully delineated
  9. 2024 Medium

    Identifying a post-transcriptional mRNA stabilization function: RBM22 directly binds LATS1 mRNA and stabilizes it, suppressing NSCLC proliferation, invasion, and tumor formation.

    Evidence RNA immunoprecipitation, overexpression/knockdown, in vivo xenograft in NSCLC models

    PMID:39612045

    Open questions at the time
    • Single RIP without CLIP-level mapping of binding sites on LATS1 mRNA
    • Genome-wide scope of RBM22's mRNA stabilization function not assessed
    • Mechanism of stabilization (e.g., blocking decay factors) not determined
  10. 2025 Medium

    Revealing SUMOylation as a regulatory input: lncRNA ST7-AS2 promotes SUMO modification of RBM22, altering its nucleoplasmic distribution and enabling binding to SOX2 for VEGFR2 promoter activation in glioma.

    Evidence SUMOylation assay, reporter assay, protein-DNA binding, knockdown/overexpression with in vivo xenograft

    PMID:41317933

    Open questions at the time
    • SUMO site(s) on RBM22 not mapped
    • Whether SUMOylation affects splicing or other transcriptional functions of RBM22 is unknown
    • Single-lab finding, not independently confirmed
  11. 2025 Medium

    Establishing RBM22 as a cell cycle regulator in hematopoietic cells: depletion delays G1, S, and G2/M transitions and causes endomitosis, linking RBM22 to cell cycle progression beyond its known transcriptional targets.

    Evidence siRNA/shRNA depletion, flow cytometry, live-cell imaging in HSPCs and myeloid cell lines

    PMID:40268057

    Open questions at the time
    • Whether cell cycle defects arise from splicing, transcriptional, or mRNA stability functions of RBM22 is unresolved
    • Single-lab study
  12. 2026 High

    Demonstrating a gene-specific transcriptional mechanism with SMARCA4: RBM22 binds proximal promoters of cell cycle genes (Cdk4, Ccna2, Ccne1), cooperates with SMARCA4 to increase chromatin accessibility, and recruits RNAPII; cardiomyocyte-specific deletion impairs neonatal heart regeneration.

    Evidence ChIP, Co-IP (RBM22-SMARCA4), ATAC-seq, cardiomyocyte-specific conditional KO, AAV9 rescue in mouse

    PMID:41803140

    Open questions at the time
    • Whether SMARCA4 interaction is direct or bridged by other factors is not established
    • How RBM22 selects specific promoters for binding is unknown
    • Relative contribution of splicing versus transcriptional functions in heart regeneration not dissected

Open questions

Synthesis pass · forward-looking unresolved questions
  • A central unresolved question is how RBM22's splicing, transcriptional, and mRNA stabilization functions are coordinated or partitioned — whether they reflect distinct protein pools, post-translational modification states, or are mechanistically coupled through co-transcriptional splicing.
  • No separation-of-function mutants that selectively ablate splicing versus transcription roles
  • No structural model of RBM22 in an assembled human spliceosome or on chromatin
  • SUMO and other PTM regulation of RBM22 function poorly characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 7 GO:0140110 transcription regulator activity 3
Localization
GO:0005654 nucleoplasm 4 GO:0005694 chromosome 2
Pathway
R-HSA-8953854 Metabolism of RNA 5 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1640170 Cell Cycle 2
Partners
ALG-2POLR2ASMARCA4SOX2SPT5
Complex memberships
NineTeen Complex (NTC/Prp19 complex)Spliceosome (Bact/C complex)

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 Yeast Cwc2 (human RBM22) contacts catalytically important RNA elements in active spliceosomes, including the U6 internal stem-loop (ISL) and regions of U6 and pre-mRNA intron near the 5' splice site. Human RBM22 recapitulates these conserved RNA contacts, and Cwc2 functions prior to step 1 of splicing to promote an active conformation of the spliceosome's catalytic RNA elements, analogous to how RNA tertiary interactions induce an active conformation of domain V in group II introns. UV-crosslinking, mutational analysis, spliceosome fractionation, functional complementation with human RBM22 The EMBO journal High 22246180
2009 Yeast Cwc2 (human RBM22 ortholog) links the NineTeen Complex (NTC) to the spliceosome through direct binding to U6 snRNA. Cwc2 contains a zinc finger and RRM required for RNA binding; depletion causes pre-mRNA accumulation and reduced snRNA levels. Under splicing conditions, Cwc2 can be directly UV-crosslinked specifically to U6 snRNA, both before and after the first step of splicing. UV-crosslinking, snRNA co-immunoprecipitation, in vitro RNA binding assay, yeast depletion genetics Nucleic acids research High 19435883
2012 The crystal structure of Cwc2 (RBM22 ortholog) reveals a novel multipartite RNA-binding architecture comprising a Torus domain, RRM, and zinc finger (ZnF) integrated in a compact unit. The ZnF is pivotal for the overall architecture. Six RNA-contacting sites were identified by UV-crosslinking/mass spectrometry: four near the RRM, one in the ZnF, and one on a connector element between Torus and RRM domains. A contiguous conserved positively charged surface forms an expanded RNA-binding interface. Mutations in the connector element abolish splicing. X-ray crystallography, UV-crosslinking coupled to mass spectrometry, mutagenesis, splicing assay The EMBO journal High 22407296
2012 The 1.9 Å X-ray crystal structure of Cwc2 (RBM22 ortholog) core domain reveals that the CCCH-type zinc finger and RRM form a single folding unit via hydrophobic interactions and hydrogen bonds. Structure-guided mutagenesis shows the intervening RB loop between ZnF and RRM and conserved positively charged residues on RRM β-strands are essential for RNA binding. X-ray crystallography (1.9 Å), structure-guided mutagenesis, RNA binding assays The Biochemical journal High 21957909
2014 Cwc2 (RBM22 ortholog) stabilizes U2-U6 snRNA helix I during splicing and is a target for Prp16-mediated spliceosome remodeling between the first and second steps. Genetic interactions show Cwc2 cooperates with Isy1/NTC30, and a cwc2 mutation suppresses the cold-sensitive prp16-302 phenotype. The prp16-302 mutation stabilizes Cwc2-U6 snRNA interactions and destabilizes Cwc2-pre-mRNA interactions, revealing antagonistic functions. Genetic epistasis (suppressor screen), snRNA co-immunoprecipitation, UV-crosslinking Nucleic acids research High 24848011
2006 RBM22 physically interacts with the calcium-binding protein ALG-2 (identified by yeast two-hybrid). When co-expressed, RBM22 induces nuclear translocation of ALG-2, which is otherwise cytoplasmic, indicating RBM22 can shuttle between cytoplasm and nucleus and directs ALG-2 to the nucleus. This co-localization (>95%) was confirmed in both NIH 3T3 cells and zebrafish embryos. Yeast two-hybrid, fluorescent fusion protein co-expression (confocal microscopy), zebrafish mRNA microinjection Biochimica et biophysica acta Medium 17045351
2010 RBM22 enhances cytoplasmic translocation of the spliceosomal protein hSlu7 under stress conditions (especially thapsigargin-induced ER stress). Conversely, ALG-2 remains nuclear (co-translocated by RBM22) under both heat shock and thapsigargin stress. ER stress differentially affects splicing of XBP-1, linking RBM22 to stress-responsive spliceosomal protein redistribution. Fluorescent protein co-expression, confocal microscopy, RT-PCR splicing assay Biochimica et biophysica acta Medium 21122810
2020 Human RBM22 binds the U12-U6atac snRNA complex of the minor spliceosome specifically and with similar affinity as to the major spliceosome U2-U6 snRNA complex (mean Kd ~3.4 μM for U2-U6 and ~8.0 μM for U12-U6atac), suggesting RBM22 performs equivalent catalytic center remodeling in both major and minor spliceosomes. Electrophoretic mobility shift assay (EMSA), fluorescence binding assay, solution NMR for RNA structure ACS omega Medium 32984674
2024 RBM22 directly occupies RNAPII-transcribed gene loci and coordinates multiple steps of RNA Polymerase II transcription. Loss of RBM22 promotes RNAPII pause release, reduces elongation velocity, and causes transcriptional readthrough genome-wide. RBM22 preferentially binds hyperphosphorylated, transcriptionally engaged RNAPII and regulates transcription by controlling homeostasis of the 7SK-P-TEFb complex and the association between RNAPII and SPT5 at chromatin. ChIP-seq, nascent RNA sequencing, co-immunoprecipitation, RBM22 loss-of-function (depletion) with genome-wide readouts Genome biology High 38641822
2024 RBM22 directly interacts with LATS1 mRNA (confirmed by RNA immunoprecipitation) and stabilizes LATS1 mRNA expression, thereby suppressing NSCLC proliferation, invasion, and stemness in vitro and tumor formation and metastasis in vivo. RNA immunoprecipitation (RIP), overexpression/knockdown, in vivo xenograft Journal of molecular histology Medium 39612045
2025 LncRNA ST7-AS2 promotes SUMO modification of RBM22, which alters RBM22's nucleoplasmic distribution. In the nucleus, RBM22 binds SOX2 and upregulates VEGFR2 promoter transcriptional activity, promoting vasculogenic mimicry in glioma. SUMOylation assay, reporter assay, protein-DNA binding, knockdown/overexpression in vitro and in vivo xenograft Cellular signalling Medium 41317933
2026 RBM22 selectively binds to proximal promoters of key cell cycle genes (Cdk4, Ccna2, Ccne1) and cooperates with the chromatin remodeler SMARCA4 to enhance transcriptional accessibility. RBM22 is required for gene-specific recruitment of RNA Polymerase II to these loci. Cardiomyocyte-specific Rbm22 deletion impairs neonatal heart regeneration and worsens post-infarction remodeling in mice. ChIP, co-immunoprecipitation (RBM22-SMARCA4), cardiomyocyte-specific conditional KO, ATAC-seq, AAV9 delivery rescue experiment Nature communications High 41803140
2009 RBM22 (zebrafish ortholog) is required for normal vertebrate embryogenesis. Morpholino-mediated knockdown of zRBM22 causes developmental arrest with truncated axis and defective head and tail formation by 32 hpf, demonstrating an essential role in early development. Morpholino knockdown in zebrafish, in situ hybridization, RT-PCR, morphological analysis Genetics and molecular research Medium 20013661
2025 RBM22 depletion in human haematopoietic stem and progenitor cells and myeloid cell lines delays progression through G1, S, and G2/M phases, causes endomitosis, and impairs megakaryocyte differentiation, establishing RBM22 as an essential regulator of cell cycle progression in myeloid cells. siRNA/shRNA depletion, flow cytometry cell cycle analysis, live-cell imaging of mitosis, differentiation assays Biochimica et biophysica acta. Molecular cell research Medium 40268057

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 1 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