Affinage

ZRSR2

U2 small nuclear ribonucleoprotein auxiliary factor 35 kDa subunit-related protein 2 · UniProt Q15696

Length
482 aa
Mass
58.0 kDa
Annotated
2026-06-11
18 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZRSR2 is an X-linked splicing factor that operates as an essential component of the minor (U12-dependent) spliceosome, where it specifically recognizes U12-type 3' splice sites; its loss causes selective retention of U12-type introns while leaving U2-type splicing largely intact (PMID:25586593, PMID:38088204). The division of labor is sequence-encoded: U2-type and U12-type splice sites are recognized by U2AF1 and ZRSR2 respectively, and nucleotides flanking U12-type sites (notably the absence of an AG dinucleotide at the -1/-2 positions of the 5' splice site) prevent the major spliceosome from acting on them (PMID:38088204). Through this minor-intron recognition activity, ZRSR2 controls the expression of specific downstream targets whose transcripts contain U12-type introns, including the MAPK-pathway kinases MAPK9 and MAPK14 and the transcription factor IRF7, with intron retention reducing their protein output (PMID:34615655, PMID:33691379). Functionally, ZRSR2 loss impairs hematopoietic differentiation and cooperates with Tet2 loss to drive myelodysplastic syndrome (PMID:25586593, PMID:36030305), blunts plasmacytoid dendritic cell activation and apoptosis via IRF7 (PMID:34615655), and partially shares minor-spliceosome function with the paralog ZRSR1 in hematopoietic cells and early embryos (PMID:33691379, PMID:32527007). Disruption of ZRSR2 also produces broad developmental and genome-maintenance phenotypes, including an oral-facial-digital syndrome with abnormal primary cilia driven by mis-splicing of ciliopathy genes (PMID:38158857), a block in oogenesis (PMID:35198906), and attenuated Fanconi Anaemia pathway activation that creates a synthetic-lethal dependency on EXO1 (PMID:41006228).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2015 High

    Established ZRSR2 as a dedicated minor-spliceosome factor by showing its loss selectively impairs U12-type intron removal, defining the molecular defect underlying its role in hematopoiesis.

    Evidence shRNA knockdown with RNA-seq of MDS bone marrow and cell lines, plus in vitro differentiation assays

    PMID:25586593

    Open questions at the time
    • Did not define the direct RNA-binding specificity at the nucleotide level
    • Downstream target transcripts driving the differentiation phenotype not yet identified
  2. 2020 Medium

    Showed ZRSR2 and its paralog ZRSR1 are jointly required for zygotic genome activation and early embryogenesis, indicating partial functional redundancy in minor-intron splicing.

    Evidence Zrsr1/Zrsr2 mutant mice with zinc-finger truncations, RNA-seq of 2-cell embryos, iPSC reprogramming assays

    PMID:32527007

    Open questions at the time
    • Relative contribution of each paralog not quantified
    • Reported intron retention in both U2 and U12 genes leaves the specificity of the developmental defect unresolved
  3. 2021 High

    Connected ZRSR2 mutation to immune-cell dysfunction by tracing impaired pDC activation to IRF7 U12-type intron retention, providing a specific target gene linking splicing defect to phenotype.

    Evidence Disease-associated mutation modeling, RNA-seq intron-retention analysis, in vivo mouse models, pDC functional assays

    PMID:34615655

    Open questions at the time
    • Whether IRF7 mis-splicing fully accounts for the BPDCN phenotype not established
    • Other minor-intron targets contributing to pDC biology not enumerated
  4. 2021 Low

    Extended ZRSR2 function to solid-tumor proliferation, linking its knockdown to cell-cycle delay via the Cyclin D1 pathway in prostate cancer.

    Evidence ZRSR2 knockdown in prostate cancer cell lines, proliferation and cell-cycle assays, CCND1 readouts

    PMID:33568749

    Open questions at the time
    • Single-lab knockdown with limited mechanistic depth
    • Whether CCND1 regulation is splicing-dependent not shown
    • No reciprocal or rescue validation
  5. 2022 High

    Identified MAPK9/MAPK14 as functionally important U12-type intron targets and demonstrated ZRSR1/ZRSR2 cooperativity in hematopoietic minor-intron splicing.

    Evidence Zrsr2 KO mice with siRNA depletion of Zrsr1, RNA-seq, and western blotting for MAPK9/MAPK14

    PMID:33691379

    Open questions at the time
    • Whether reduced MAPK9/MAPK14 alone drives the hematopoietic phenotype not isolated
    • Mechanism of ZRSR1/ZRSR2 cooperation at the spliceosome unresolved
  6. 2022 Medium

    Demonstrated cell-autonomous cooperation between Zrsr2 mutation and Tet2 loss in driving MDS, with the MAPK pathway as the dominant mis-spliced target.

    Evidence CRISPR/Cas9 double-mutant mice, transplantation assays, whole-transcriptome RNA-seq

    PMID:36030305

    Open questions at the time
    • Molecular basis of Zrsr2/Tet2 epistasis not defined
    • Single lab
  7. 2022 Medium

    Established a developmental requirement for ZRSR2 in oogenesis, linking minor-intron retention in meiotic and centriole genes to a follicle-stage block.

    Evidence Three Zrsr2 mutant mouse lines, RNA-seq of secondary follicles, alternative splicing analysis

    PMID:35198906

    Open questions at the time
    • Causal target gene(s) for the oogenesis block not pinpointed
    • Single lab
  8. 2022 Medium

    Confirmed conserved, organism-wide essentiality of ZRSR2 by showing zebrafish loss causes embryonic lethality with broad minor-intron retention and metabolic pathway downregulation.

    Evidence CRISPR/Cas9 knockout zebrafish, global RNA-seq at 3 dpf

    PMID:36142581

    Open questions at the time
    • Specific lethal targets not identified
    • Single model organism, single lab
  9. 2023 Medium

    Established ZRSR2 as a Mendelian disease gene, linking germline frameshift variants to an oral-facial-digital syndrome and connecting minor-intron mis-splicing of ciliopathy genes to abnormal primary cilia.

    Evidence Exome sequencing, splicing analysis in patient lymphoblastoid and fibroblast lines, primary cilia microscopy

    PMID:38158857

    Open questions at the time
    • Whether TMEM107/CIBAR1 mis-splicing alone causes the cilia defect not isolated
    • Single study
  10. 2023 Medium

    Defined the sequence rules of ZRSR2 splice-site recognition, showing U12-type 3' sites are recognized by ZRSR2 (vs U2AF1 for U2-type) and that flanking nucleotides dictate spliceosome identity.

    Evidence Global binding-site mapping, mutational analysis converting a U12 site to U2 via a single substitution, transcriptome analysis

    PMID:38088204

    Open questions at the time
    • Structural basis of ZRSR2 recognition not resolved
    • Single study
  11. 2025 Medium

    Placed ZRSR2 in genome maintenance by showing its deficiency attenuates Fanconi Anaemia pathway activation and creates an EXO1-dependent synthetic lethality, revealing a therapeutic vulnerability.

    Evidence CRISPR synthetic-lethality screen, cisplatin sensitivity and radial chromosome assays, EXO1 nuclease activity experiments

    PMID:41006228

    Open questions at the time
    • Whether the FA defect is splicing-mediated and via which target not defined
    • Mechanism linking ZRSR2 loss to replication-coupled repair unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ZRSR2's single minor-spliceosome activity produces such divergent tissue-specific outcomes — hematopoiesis, immunity, ciliogenesis, oogenesis, and DNA repair — through distinct target sets remains unresolved.
  • No unified map of which U12-type targets dominate in each tissue
  • No structural model of ZRSR2 within the minor spliceosome
  • Mechanistic link between minor-intron splicing and the Fanconi Anaemia/replication-repair defect undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 2 GO:0140098 catalytic activity, acting on RNA 2
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-74160 Gene expression (Transcription) 2
Partners
ZRSR1
Complex memberships
minor (U12-dependent) spliceosome

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 ZRSR2 is an essential component of the minor spliceosome (U12-dependent) assembly. shRNA-mediated knockdown of ZRSR2 leads to impaired splicing of U12-type introns, causing their retention, while splicing of U2-type introns remains mostly unaffected. ZRSR2-deficient cells also exhibit reduced proliferation potential and distinct alterations in myeloid and erythroid differentiation in vitro. shRNA knockdown, RNA-sequencing of MDS bone marrow and cell lines, in vitro differentiation assays Nature communications High 25586593
2021 ZRSR2 loss-of-function mutation impairs plasmacytoid dendritic cell (pDC) activation and apoptosis after inflammatory stimuli, associated with U12-type intron retention in IRF7 transcripts and inability to upregulate the transcription factor IRF7. In vivo, BPDCN-associated ZRSR2 mutations promote pDC expansion and signatures of decreased activation. Genetic modeling of disease-associated mutations, RNA-seq (intron retention analysis), in vivo mouse models, functional assays for pDC activation and apoptosis Cancer discovery High 34615655
2022 ZRSR1 cooperates with ZRSR2 in splicing of U12-type introns in murine hematopoietic cells. Zrsr2-deficient mice alone showed only moderate U12-type intron retention; depletion of Zrsr1 in Zrsr2 KO myeloid cells exacerbated retention of U12-type introns. Aberrant retention of U12-type introns in MAPK9 and MAPK14 leads to their reduced protein expression. Zrsr2 knockout mice (genetic), siRNA depletion of Zrsr1 in KO cells, RNA-seq, western blotting for MAPK9/MAPK14 protein Haematologica High 33691379
2024 Binding site analysis revealed that U2-type and U12-type splice sites are recognized by U2AF1 and ZRSR2, respectively. Nucleotides flanking U12-type splice sites (including absence of AG dinucleotide at positions -1 and -2 of U12-type 5' splice sites) prevent recognition by the U2-type spliceosome. A single nucleotide substitution at the -2 position introducing AG can convert a U12-type splice site to a U2-type site. Global binding site mapping (CLIP-seq or equivalent), mutational analysis of splice sites, transcriptome analysis Nucleic acids research Medium 38088204
2022 Zrsr2 loss in zebrafish results in embryonic lethality by 8 dpf with multiple developmental defects, and causes aberrant retention of minor (U12-type) introns in approximately one-third of all minor intron-containing genes. Loss of Zrsr2 results in downregulation of essential metabolic pathways. CRISPR/Cas9 knockout zebrafish, global transcriptome analysis (RNA-seq) at 3 dpf International journal of molecular sciences Medium 36142581
2020 Both Zrsr1 and Zrsr2 are required for zygotic genome activation and early embryo development. Double heterozygous Zrsr1/Zrsr2 mutant embryos stop developing between the 2- and 4-cell stages. Loss of both factors causes significant increase in intron retention in both U2 and U12 intron-containing genes. Both Zrsr1 and Zrsr2 are required for conversion of mouse iPSCs into 2C-like cells. Zrsr1 and Zrsr2 mutant mice with truncating mutations in the second zinc finger domain, RNA-seq of 2-cell embryos, iPSC reprogramming assays International journal of molecular sciences Medium 32527007
2022 Zrsr2 mutation combined with Tet2 loss (Zrsr2m/mTet2-/-) in mice promotes MDS, with the MAPK pathway identified as the most affected target by aberrant mRNA splicing. Animals showed peripheral blood cytopenia, splenomegaly, extramedullary hematopoiesis, multi-lineage dysplasia, and expansion of LT-HSC and MPP2 progenitors. The phenotype was cell-autonomous as shown by transplantation. CRISPR/Cas9 double-mutant mice, transplantation assays, whole-transcriptome RNA-seq analysis Leukemia Medium 36030305
2022 Zrsr2 mutations in mice cause oogenesis block at the secondary follicle stage and alter splicing of U12-type introns in follicles. Intron retention events were preferentially associated with centriole replication, protein phosphorylation, DNA damage checkpoint genes, and 50 meiotic genes. Three Zrsr2 mutant mouse lines, RNA-seq of secondary follicles, alternative splicing analysis iScience Medium 35198906
2023 Germline ZRSR2 frameshift variants cause a novel type of oral-facial-digital (OFD) syndrome with brain anomalies. Patient samples show significant enrichment of minor intron retention in ciliopathy-related genes including TMEM107 and CIBAR1. Primary fibroblasts with ZRSR2 variant had abnormally elongated cilia, establishing a link between defective U12-type intron splicing and abnormal primary cilia formation. Exome sequencing, alternative splicing analysis in patient lymphoblastoid and fibroblast cell lines, primary cilia structure analysis by microscopy Genetics in medicine Medium 38158857
2025 ZRSR2-deficient cells are attenuated for Fanconi Anaemia (FA) pathway activation, exhibiting cisplatin sensitivity and radial chromosome formation. ZRSR2 is synthetic lethal with loss of EXO1 (identified by CRISPR screening), and FA or ZRSR2 deficiency depends on EXO1 nuclease activity. ZRSR2 deficiency is associated with dysregulated replication-coupled repair. CRISPR screening for synthetic lethality, cisplatin sensitivity assays, radial chromosome formation assays, EXO1 nuclease activity experiments Nature communications Medium 41006228
2021 ZRSR2 knockdown reduced prostate cancer cell proliferation and delayed cell cycle progression at least partially through inhibition of the Cyclin D1 (CCND1) pathway. ZRSR2 knockdown in PCa cell lines, cell proliferation assays, cell cycle analysis, CCND1 pathway readouts Prostate cancer and prostatic diseases Low 33568749
1995 Mouse U2af1-rs2 (Zrsr2 ortholog) encodes a 462 amino acid protein with 72.7% identity to U2af1-rs1 and 35.8% identity to U2 snRNP auxiliary factor. The gene maps to the distal region of the X chromosome. cDNA cloning, sequence analysis, interspecific backcross mapping Genomics Low 7558001

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Aberrant splicing of U12-type introns is the hallmark of ZRSR2 mutant myelodysplastic syndrome. Nature communications 202 25586593
2021 Sex-Biased ZRSR2 Mutations in Myeloid Malignancies Impair Plasmacytoid Dendritic Cell Activation and Apoptosis. Cancer discovery 78 34615655
2015 Mutations in the Spliceosomal Machinery Genes SRSF2, U2AF1, and ZRSR2 and Response to Decitabine in Myelodysplastic Syndrome. Anticancer research 27 25964599
2020 Minor Splicing Factors Zrsr1 and Zrsr2 Are Essential for Early Embryo Development and 2-Cell-Like Conversion. International journal of molecular sciences 22 32527007
2022 ZRSR1 co-operates with ZRSR2 in regulating splicing of U12-type introns in murine hematopoietic cells. Haematologica 20 33691379
1995 Cloning and mapping of the U2af1-rs2 gene with a high transmission distortion in interspecific backcross progeny. Genomics 14 7558001
2022 Concurrent Zrsr2 mutation and Tet2 loss promote myelodysplastic neoplasm in mice. Leukemia 9 36030305
2022 Zrsr2 Is Essential for the Embryonic Development and Splicing of Minor Introns in RNA and Protein Processing Genes in Zebrafish. International journal of molecular sciences 7 36142581
2021 Insights into the functions and RNA binding of Trypanosoma brucei ZC3H22, RBP9 and DRBD7. Parasitology 7 33536101
2017 Refractory macrocytic anemias in patients with clonal hematopoietic disorders and isolated mutations of the spliceosome gene ZRSR2. Leukemia research 7 28942350
2022 Zrsr2 and functional U12-dependent spliceosome are necessary for follicular development. iScience 6 35198906
2023 Mutated ZRSR2 and CUL3 accelerate clonal evolution and confer venetoclax resistance via RAS signaling pathway in blastic plasmacytoid dendritic cell neoplasm. International journal of hematology 4 37029861
2024 Global analysis of binding sites of U2AF1 and ZRSR2 reveals RNA elements required for mutually exclusive splicing by the U2- and U12-type spliceosome. Nucleic acids research 3 38088204
2023 Differential alternative splicing analysis links variation in ZRSR2 to a novel type of oral-facial-digital syndrome. Genetics in medicine : official journal of the American College of Medical Genetics 3 38158857
2021 ZRSR2 overexpression is a frequent and early event in castration-resistant prostate cancer development. Prostate cancer and prostatic diseases 2 33568749
2025 EXO1 as a therapeutic target for Fanconi Anaemia, ZRSR2 and BRCA1-A complex deficient cancers. Nature communications 1 41006228
2019 ZRSR2 mutation in a child with refractory macrocytic anemia and Down Syndrome. Pediatric hematology and oncology 1 31361176
2025 Diagnostic Challenges in a Young Man with a Suspected Mast Cell Disorder, Dysplastic Bone Marrow Morphology, and a ZRSR2 Mutation. Hematology reports 0 41440762

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