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ZRANB2

Zinc finger Ran-binding domain-containing protein 2 · UniProt O95218

Length
330 aa
Mass
37.4 kDa
Annotated
2026-06-11
25 papers in source corpus 14 papers cited in narrative 14 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

ZRANB2 is a nuclear SR-domain splicing regulator that controls alternative splice-site selection through two RanBP2-type C4 zinc finger domains, each of which folds around a coordinated Zn(II) ion and recognizes single-stranded AGGUAA RNA motifs with high specificity, with the tandem domains engaging AGGUAA(Nx)AGGUAA double sites via base-specific hydrogen bonds and a guanine-tryptophan-guanine 'ladder' (PMID:19304800, PMID:12657633, PMID:39681856). As a component of the supraspliceosome that interacts with the essential splicing factors U1-70K and U2AF35 and the spliceosomal protein XE7/SFRS17A, ZRANB2 modulates the splicing of numerous transcripts and acts as a splicing repressor in minigene assays for targets including Tra2-beta1, GluR-B, and SMN2 (PMID:11448987, PMID:16982639, PMID:23666063, PMID:17805964). It binds DRD2 pre-mRNA at a site disrupted by the rs1076560 SNP to alter isoform ratios, and cooperates with SYF2 on ECT2 exon 5 inclusion to drive doxorubicin resistance in breast cancer cells (PMID:26347318, PMID:31943118). The integrity of this RNA-binding activity is governed by zinc coordination: arsenite displaces Zn(II) from both zinc fingers and impairs splicing of TRA2B, an effect blocked by zinc supplementation, and H2S-mediated persulfidation of the zinc-coordinating cysteines likewise abolishes RNA binding in a reductant-reversible manner (PMID:32274925, PMID:35764259, PMID:39681856, PMID:41558086). Beyond splicing, ZRANB2 suppresses BMP signaling by forming a nuclear complex with Smad1/5/8 through its glutamine-rich domain, inhibiting Smad transcriptional activity without affecting Smad phosphorylation, nuclear localization, or DNA binding (PMID:22021003).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2001 High

    Established ZRANB2 as a bona fide splicing factor by linking it physically to the core splicing machinery and demonstrating functional control over splice-site choice.

    Evidence Reciprocal Co-IP, yeast two-hybrid, confocal colocalization, and Tra2-beta1 minigene splicing assay

    PMID:11448987

    Open questions at the time
    • Did not define the RNA sequence recognized
    • Mechanism of splice-site selection not resolved
  2. 2003 High

    Resolved the fold of a single RanBP2-type zinc finger, showing it is a zinc-stabilized RNA-binding module rather than a protein-interaction motif.

    Evidence NMR solution structure, zinc-binding UV spectroscopy, RNA gel-shift on recombinant domain

    PMID:12657633

    Open questions at the time
    • RNA sequence specificity unknown
    • Role of the second tandem domain not addressed
  3. 2006 Medium

    Expanded the ZRANB2 interactome within nuclear speckles by identifying the spliceosomal protein XE7/SFRS17A as a partner.

    Evidence Yeast two-hybrid screen with Co-IP and confocal colocalization

    PMID:16982639

    Open questions at the time
    • Functional consequence of the XE7 interaction for splicing unresolved
    • Single-lab interaction
  4. 2007 Medium

    Demonstrated that ZRANB2 acts as a splicing repressor on defined disease-relevant targets, broadening its regulatory repertoire.

    Evidence GluR-B and SMN2 minigene splicing assays with mouse ortholog plus localization imaging

    PMID:17805964

    Open questions at the time
    • Direct binding to these pre-mRNAs not shown
    • Ortholog context
  5. 2009 High

    Defined the molecular code of ZRANB2 RNA recognition, showing each zinc finger reads an AGGUAA motif with the tandem pair binding double sites.

    Evidence X-ray crystallography, RNA-binding assays, mutagenesis

    PMID:19304800

    Open questions at the time
    • Which endogenous transcripts contain functional AGGUAA sites not mapped
    • Link to spliceosome assembly not structural
  6. 2012 Medium

    Revealed a splicing-independent role for ZRANB2 as a nuclear repressor of BMP/Smad transcriptional output.

    Evidence Smad1 pulldown, Co-IP, deletion mapping, C2C12 BMP reporter assays, zebrafish mRNA injection

    PMID:22021003

    Open questions at the time
    • Mechanism of Smad transcriptional suppression not defined
    • Whether this competes with splicing function unknown
  7. 2013 Medium

    Placed ZRANB2 in the supraspliceosome and showed its position is phosphorylation-regulated, with transcriptome-wide splicing effects.

    Evidence Glycerol gradient fractionation, Western blot, Affymetrix exon array profiling

    PMID:23666063

    Open questions at the time
    • Direct binding to the altered transcripts not demonstrated
    • Kinase responsible not identified
  8. 2015 Medium

    Connected ZRANB2 RNA binding to a human genetic variant by showing the DRD2 rs1076560 SNP disrupts its binding site and isoform regulation.

    Evidence RNA-protein binding assay and allele-specific DRD2 minigene splicing assay

    PMID:26347318

    Open questions at the time
    • In vivo relevance of altered DRD2 isoforms not established
    • Single-lab functional assay
  9. 2020 Medium

    Identified ZRANB2 as a zinc-displacement target of arsenite, linking environmental toxicant exposure to impaired splicing function.

    Evidence Synthetic peptide binding assays, LC-MS/MS, RT-qPCR, immunoblotting, TRA2B splicing assay in HaCaT cells

    PMID:32274925

    Open questions at the time
    • Full-length protein behavior versus peptides not tested
    • Downstream physiological consequences unresolved
  10. 2020 Medium

    Showed ZRANB2 drives a chemoresistance splicing program with SYF2 by converging on ECT2 exon 5 inclusion.

    Evidence RNAi screen, RNA-seq, RIP, antisense oligonucleotide rescue, xenograft model

    PMID:31943118

    Open questions at the time
    • Direct versus indirect role in ECT2 splicing not fully separated from SYF2
    • Mechanism of cooperation with SYF2 unknown
  11. 2022 Medium

    Confirmed the zinc-coordination model in cells by showing zinc supplementation rescues arsenite-induced ZRANB2 splicing dysfunction.

    Evidence Zinc supplementation, RT-PCR splicing assay, immunoblotting in HaCaT cells

    PMID:35764259

    Open questions at the time
    • Direct measurement of intracellular zinc occupancy not performed
    • Single cell type
  12. 2024 High

    Quantified how zinc and RNA reshape each zinc finger, establishing that both domains require Zn(II) for folding and high-affinity TRA2B binding.

    Evidence Co(II)/Zn(II) UV-vis titrations, circular dichroism, HDX-MS, fluorescence anisotropy

    PMID:39681856

    Open questions at the time
    • Behavior in the context of the full supraspliceosome not addressed
    • Cellular zinc regulation of these dynamics not measured
  13. 2026 High

    Identified persulfidation of zinc-coordinating cysteines as a reversible redox switch that inactivates ZRANB2 RNA binding.

    Evidence In vitro persulfidation, fluorescence anisotropy, CD, cellular H2S treatment with RT-PCR splicing readout, reductant rescue

    PMID:41558086

    Open questions at the time
    • Physiological signaling context of H2S regulation unclear
    • In vivo persulfidation occupancy not quantified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ZRANB2's two distinct activities — AGGUAA-directed alternative splicing and Smad-mediated BMP repression — are coordinated, and how metal/redox sensing tunes them under physiological conditions, remains unresolved.
  • No integrated model linking splicing and BMP roles
  • Genome-wide endogenous binding map lacking
  • Physiological signals controlling zinc/persulfidation states unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 6 GO:0098772 molecular function regulator activity 3 GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 3 GO:0005654 nucleoplasm 3
Pathway
R-HSA-8953854 Metabolism of RNA 4 R-HSA-162582 Signal Transduction 1
Partners
SFRS17ASMAD1SMAD5SYF2U1-70KU2AF35
Complex memberships
supraspliceosome

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 The two RanBP2-type zinc finger (ZnF) domains of ZRANB2 are single-stranded RNA-binding domains that each recognize an AGGUAA motif with high affinity and specificity; the two domains combine to recognize AGGUAA(Nx)AGGUAA double sites. X-ray crystallography revealed that recognition is dominated by side-chain hydrogen bonds to the bases and formation of a guanine-tryptophan-guanine 'ladder.' X-ray crystallography, RNA-binding assays, mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 19304800
2001 ZRANB2 (ZNF265) interacts with the essential splicing factors U1-70K and U2AF35, co-immunoprecipitates with mRNA from splicing extracts, alters splicing patterns of Tra2-beta1 transcripts in a dose-dependent manner, and colocalizes with SMN, U1-70K, SC35, p300 and YY1 in the nucleus. Nuclear localization requires the RS domain. Co-immunoprecipitation, yeast two-hybrid, confocal microscopy, transfection of EGFP fusions, minigene splicing assay The Journal of cell biology High 11448987
2003 A single RanBP2-type zinc finger domain from ZNF265 forms a stable, monomeric structure with zinc, adopting a novel zinc-ribbon-like fold of two stacked beta-hairpins oriented ~80° to each other sandwiching the zinc ion, and is capable of binding RNA as demonstrated by gel-shift assay. NMR solution structure determination, zinc-binding characterization (UV spectroscopy), RNA gel-shift assay The Journal of biological chemistry High 12657633
2006 ZRANB2 (ZNF265) interacts with the novel spliceosomal protein XE7 (SFRS17A); this interaction was identified by yeast two-hybrid with ZNF265 as bait and confirmed by co-immunoprecipitation. ZRANB2 and XE7 colocalize in nuclear speckles. Yeast two-hybrid screen, co-immunoprecipitation, confocal microscopy Nucleic acids research Medium 16982639
2013 ZRANB2 is a component of the supraspliceosome, as shown by glycerol-gradient fractionation of nuclear supernatants. Tyrosine kinase-induced phosphorylation affects ZRANB2's subcellular location within the supraspliceosome. Overexpression of ZRANB2 in HeLa cells altered the alternative splicing of at least 12 primary transcripts including CENTB1, WDR78, CAPN10, SALL1, and others. Glycerol gradient fractionation, Western blotting, Affymetrix exon array transcriptome profiling Molecular biology reports Medium 23666063
2012 ZRANB2 (Zranb2) interacts with Smad1, Smad5, and Smad8 (strongly) and Smad4 (weakly) in the nucleus. The glutamine-rich domain mediates interaction with Smad1, and the SR domain is required for BMP inhibitory activity and nuclear localization. Overexpression inhibits BMP signaling in C2C12 cells; knockdown enhances BMP activity. Zranb2 suppresses Smad transcriptional activity without affecting Smad phosphorylation, nuclear localization, or DNA binding. Proteomics pulldown (Smad1-binding protein screen), co-immunoprecipitation, deletion analysis, C2C12 overexpression/knockdown BMP reporter assay, zebrafish mRNA injection Journal of cellular biochemistry Medium 22021003
2015 ZRANB2 binds the DRD2 pre-mRNA at a site containing the rs1076560 SNP; the rs1076560(T) variant disrupts the ZRANB2 binding site, diminishes binding affinity between DRD2 pre-mRNA and ZRANB2, and abolishes ZRANB2-mediated modulation of short:long DRD2 isoform-expression ratios in cell culture minigene assays. RNA-protein binding assay, DRD2 minigene splicing assay in cell culture, genetic association study (mechanistic component) Molecular psychiatry Medium 26347318
2016 Zebrafish ZRANB2 is a maternal LPS-binding protein; recombinant ZRANB2 acts as a pattern recognition receptor binding LPS and Gram-negative bacteria and directly kills bacteria. The first ZnF_RBZ domain (residues 11–37) is indispensable for antimicrobial activity. Microinjection of recombinant ZRANB2 into zebrafish embryos enhanced resistance to bacterial challenge. Recombinant protein binding assays, bacterial killing assays, domain deletion analysis, microinjection into zebrafish embryos, antibody neutralization The Journal of biological chemistry Medium 26740623
2020 Arsenite (As3+) binds to and displaces Zn2+ from both C4 zinc finger motifs of ZRANB2, altering ZRANB2 structure and impairing its splicing function on TRA2B mRNA. As3+ exposure also induces ZRANB2 protein (but not mRNA) expression as a homeostatic response. Zinc can displace As3+ from As3+-bound ZRANB2 zinc finger peptides in a cell-free system. Synthetic peptide binding assays (intrinsic fluorescence, UV spectrophotometry, colorimetric zinc assay, LC-MS/MS), RT-qPCR, immunoblotting, RT-PCR splicing assay in HaCaT cells Chemical research in toxicology Medium 32274925
2020 ZRANB2 and SYF2 control overlapping alternative splicing programs in doxorubicin-resistant breast cancer cells that converge on inclusion of ECT2 exon 5 (ECT2-Ex5+). Both ZRANB2 and SYF2 associate with ECT2 pre-mRNA, and depletion of either partially reverses doxorubicin resistance and affects S-phase accumulation. RNAi screen on splicing factors, RNA-seq, RNA immunoprecipitation (RIP), antisense oligonucleotide functional rescue, xenograft tumor model Nucleic acids research Medium 31943118
2022 Zinc supplementation prevents arsenite-induced dysregulation of ZRANB2 splicing function on TRA2B and blocks the induction of ZRANB2 protein expression in human keratinocytes (HaCaT cells), consistent with the model that iAs disrupts zinc coordination in ZRANB2 zinc fingers. Zinc supplementation experiments in HaCaT cells, RT-PCR splicing assay, immunoblotting Environmental toxicology and pharmacology Medium 35764259
2024 Both ZF domains of ZRANB2 require Zn(II) coordination for proper folding and RNA binding; HDX-MS revealed that Zn binding induces a more rigid structure in each domain (greater effect in ZF1), while RNA binding produces greater protection in ZF2. High-affinity RNA binding to TRA2B pre-mRNA requires Zn coordination by both domains. Competitive Co(II)/Zn(II) UV-vis titrations, circular dichroism, hydrogen-deuterium exchange mass spectrometry (HDX-MS), fluorescence anisotropy RNA binding assay Biochemistry High 39681856
2026 Persulfidation of ZRANB2 cysteine residues by H2S (with superoxide as an intermediate) causes loss of Zn(II)-dependent structure and abrogates RNA binding to TRA2B pre-mRNA and optimized RNA oligonucleotides. This modification is reversible by reductant in vitro. Cellular treatment with H2S decreases formation of a TRA2B splice product, linking persulfidation to impaired ZRANB2 splicing function in cells. In vitro persulfidation assay with recombinant ZRANB2-2D, fluorescence anisotropy RNA binding, circular dichroism, cellular H2S treatment with RT-PCR splicing readout, reductant rescue Journal of inorganic biochemistry High 41558086
2007 Mouse ZNF265-1 (ZRANB2 ortholog) inhibits exon inclusion in GluR-B (Flop exon) and SMN2 (exon 7) minigene splicing assays, demonstrating its role as a splicing repressor for these pre-mRNA targets. Both isoforms localize to the nucleus. Minigene splicing assay in cell culture, subcellular localization by imaging Neurochemical research Medium 17805964

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 The zinc fingers of the SR-like protein ZRANB2 are single-stranded RNA-binding domains that recognize 5' splice site-like sequences. Proceedings of the National Academy of Sciences of the United States of America 75 19304800
2001 ZNF265--a novel spliceosomal protein able to induce alternative splicing. The Journal of cell biology 63 11448987
2019 ZRANB2/SNHG20/FOXK1 Axis regulates Vasculogenic mimicry formation in glioma. Journal of experimental & clinical cancer research : CR 52 30744670
2020 ZRANB2 and SYF2-mediated splicing programs converging on ECT2 are involved in breast cancer cell resistance to doxorubicin. Nucleic acids research 36 31943118
1997 Zis: a developmentally regulated gene expressed in juxtaglomerular cells. The American journal of physiology 34 9374836
2003 The structure of the zinc finger domain from human splicing factor ZNF265 fold. The Journal of biological chemistry 32 12657633
2013 ZRANB2 localizes to supraspliceosomes and influences the alternative splicing of multiple genes in the transcriptome. Molecular biology reports 31 23666063
2015 A splicing-regulatory polymorphism in DRD2 disrupts ZRANB2 binding, impairs cognitive functioning and increases risk for schizophrenia in six Han Chinese samples. Molecular psychiatry 27 26347318
2016 Identification of the Zinc Finger Protein ZRANB2 as a Novel Maternal Lipopolysaccharide-binding Protein That Protects Embryos of Zebrafish against Gram-negative Bacterial Infections. The Journal of biological chemistry 23 26740623
2020 Arsenite Exposure Displaces Zinc from ZRANB2 Leading to Altered Splicing. Chemical research in toxicology 22 32274925
2002 Differential expression of ribosomal L31, Zis, gas-5 and mitochondrial mRNAs following oxidant induction of proliferative vascular smooth muscle cell phenotypes. Atherosclerosis 21 11849648
2006 XE7: a novel splicing factor that interacts with ASF/SF2 and ZNF265. Nucleic acids research 19 16982639
2012 Identification and functional analysis of Zranb2 as a novel Smad-binding protein that suppresses BMP signaling. Journal of cellular biochemistry 15 22021003
2020 LncRNA FAM181A-AS1 promotes gliomagenesis by sponging miR-129-5p and upregulating ZRANB2. Aging 11 33080570
2007 ZRANB2: structural and functional insights into a novel splicing protein. The international journal of biochemistry & cell biology 11 17905639
1998 Identification, characterization and mapping of the human ZIS (zinc-finger, splicing) gene. Gene 11 9931435
2007 Expression pattern and splicing function of mouse ZNF265. Neurochemical research 10 17805964
2009 Expression of IL-1alpha, IL-6, TGF-beta, FasL and ZNF265 during sertoli cell infection by ureaplasma urealyticum. Cellular & molecular immunology 9 19567205
2022 Zinc supplementation prevents arsenic-induced dysregulation of ZRANB2 splice function. Environmental toxicology and pharmacology 8 35764259
2022 HLA-DQB1-AS1 Promotes Cell Proliferation, Inhibits Apoptosis, and Binds with ZRANB2 Protein in Hepatocellular Carcinoma. Journal of oncology 7 35602293
2012 Intron Retention and TE Exonization Events in ZRANB2. Comparative and functional genomics 6 22778693
2024 Zinc and RNA Binding Is Linked to the Conformational Flexibility of ZRANB2: A CCCC-Type Zinc Finger Protein. Biochemistry 3 39681856
2008 Crystallization of a ZRANB2-RNA complex. Acta crystallographica. Section F, Structural biology and crystallization communications 3 19052380
2025 Long noncoding RNA ZRANB2-AS2 promotes endothelial cell dysfunction by inhibiting phosphorylation of acetyl-CoA carboxylase 1 in diabetes. Experimental cell research 1 40273967
2026 Persulfidation of the zinc finger protein ZRANB2 modulates its RNA binding and alternative splicing function. Journal of inorganic biochemistry 0 41558086

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