Affinage

RNF113A

E3 ubiquitin-protein ligase RNF113A · UniProt O15541

Length
343 aa
Mass
38.8 kDa
Annotated
2026-06-10
19 papers in source corpus 13 papers cited in narrative 13 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

RNF113A is a dual-function protein that operates both as an integral pre-mRNA splicing factor and as a RING-type E3 ubiquitin ligase coordinating responses to genotoxic and oxidative stress (PMID:27994011, PMID:32152280, PMID:35819319). Through its zinc finger domain, RNF113A (and its yeast ortholog Cwc24) binds directly across the 5' splice site of pre-mRNA, joins the spliceosome after the Prp19-associated complex, and is required for proper U5/U6 interactions with the 5' splice site and for fidelity of 5' splice site selection; the RING finger is dispensable for this splicing role (PMID:27994011, PMID:31504764). In human cells RNF113A associates with U2/U4/U6 snRNAs and with PRP19 and BRR2, and is required for efficient splicing (PMID:30506991), where it controls alternative splicing of survival-determining transcripts including MCL-1, SAT1, and Noxa1 to set the apoptosis/ferroptosis/ROS balance upon DNA damage (PMID:32152280). Separately, its RING-dependent E3 ligase activity is governed by a SMYD3-deposited methyl mark that blocks PP4 phosphatase binding and thereby maintains the phosphorylation state required for ligase activation of the ALKBH3-ASCC alkylation-repair complex; this methyl switch is reversed by the demethylase KDM7B/PHF8 (PMID:35819319, PMID:41509214). As an E3 ligase RNF113A directs K48-linked polyubiquitination and proteasomal degradation of substrates including the m6A methyltransferase METTL3 (PMID:37280654). Loss-of-function studies across model systems show RNF113A is required for RAD-51 focus formation at interstrand crosslinks downstream of RPA and for neural progenitor survival via control of p53/Nupr1/Rad51 (PMID:23555887, PMID:35429390). The gene was originally identified as the X-linked ZNF183/RNF113A bearing a C-terminal C3HC4 RING finger (PMID:9224902).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1997 Low

    Established the molecular identity of the gene, defining it as an X-linked, ubiquitously expressed protein bearing a C-terminal C3HC4 RING finger predictive of E3 ligase function.

    Evidence EST database mining, sequence analysis, and Northern blot expression profiling

    PMID:9224902

    Open questions at the time
    • No functional experiment performed on the protein
    • RING-finger ligase activity inferred from sequence only
    • No catalytic substrate or partner identified
  2. 2013 Medium

    Placed the ortholog in the DNA crosslink repair pathway, showing it is required for RAD-51 loading at interstrand crosslinks downstream of RPA.

    Evidence RNAi depletion, DNA damage foci immunofluorescence, and genetic epistasis with rfs-1/RAD51C in C. elegans

    PMID:23555887

    Open questions at the time
    • Ortholog study, not direct human protein
    • Molecular activity (ligase vs splicing) responsible for the phenotype not resolved
    • Direct substrate of RNF-113 at ICL sites not identified
  3. 2017 High

    Defined the spliceosomal function at the mechanistic level, showing direct zinc-finger-dependent binding to the 5' splice site and a requirement before Prp2-mediated remodeling for splice-site fidelity, while the RING finger is dispensable.

    Evidence Yeast genetic analysis, zinc-finger vs RING-finger mutagenesis, spliceosome assembly and RNA-binding assays

    PMID:27994011

    Open questions at the time
    • Established in yeast Cwc24
    • Does not address how splicing and ligase functions are coordinated
    • No structure of the ZF-5'SS complex
  4. 2018 High

    Confirmed the human protein as a functional spliceosome component physically associated with snRNAs and core splicing factors and required for splicing efficiency.

    Evidence Reciprocal Co-IP with U2/U4/U6 snRNAs, PRP19 and BRR2; in vitro splicing gain/loss-of-function with recombinant protein rescue

    PMID:30506991

    Open questions at the time
    • Single lab
    • Direct 5'SS binding by human protein not demonstrated as in yeast
    • Mechanism of splicing inhibition by excess protein unexplained
  5. 2020 High

    Linked the splicing function to cell-fate decisions by identifying survival-related target transcripts whose mis-splicing upon RNF113A loss triggers multiple death pathways.

    Evidence RNA-binding and splicing analysis of MCL-1, SAT1, Noxa1; knockdown with apoptosis, ferroptosis, and ROS readouts and protein stability assays

    PMID:32152280

    Open questions at the time
    • Direct RNA contacts on each target not mapped
    • Relative contribution of each death pathway in vivo unclear
    • Does not integrate ligase activity
  6. 2022 High

    Revealed the post-translational switch controlling E3 ligase activity, showing SMYD3 methylation blocks PP4 binding to maintain the active phosphorylated state needed for ALKBH3-ASCC activation.

    Evidence In vitro methyltransferase assays, RNF113A-PP4 Co-IP, phosphorylation analysis, SMYD3 inhibition with alkylation-sensitivity readouts

    PMID:35819319

    Open questions at the time
    • Specific methylated residue(s) and kinase opposing PP4 not fully defined
    • How ALKBH3-ASCC is ubiquitin-activated mechanistically unclear
    • Eraser of the methyl mark not yet identified at this stage
  7. 2022 Medium

    Demonstrated a developmental requirement, showing the protein is needed for neural progenitor survival, proliferation, and differentiation via p53/Nupr1/Rad51.

    Evidence Knockdown in primary mouse neural stem cells and in vivo cortex with apoptosis, proliferation, and differentiation readouts

    PMID:35429390

    Open questions at the time
    • Direct molecular target(s) driving p53/Nupr1/Rad51 upregulation unknown
    • Splicing vs ligase contribution not separated
    • Single lab
  8. 2023 Medium

    Identified a defined ubiquitination substrate, showing RNF113A directs K48-linked degradation of METTL3 and thereby lowers mRNA m6A levels.

    Evidence Co-IP, K48-linkage-specific ubiquitination assays, proteasome inhibitor rescue, and m6A level measurement in AML cells

    PMID:37280654

    Open questions at the time
    • Single lab
    • Studied within a circRNA context
    • Structural basis of substrate recognition unknown
  9. 2023 Low

    Implicated RNF113A in proliferation and autophagy control in cervical cancer through a CXCR4/CXCL12/AKT/ERK/Beclin1 axis acting independently of direct Beclin1 ubiquitination.

    Evidence Co-IP, DIA proteomics, knockdown/overexpression phenotyping, xenograft, dual-luciferase reporter

    PMID:37164050

    Open questions at the time
    • Indirect mechanism with no direct substrate defined here
    • Single lab
    • Link to ligase catalytic activity not established
  10. 2024 Medium

    Connected RNF113A loss to oxidative stress homeostasis, showing knockout activates NRF2, raises ROS, depletes glutathione, and sensitizes cells to oxidative death.

    Evidence CRISPR KO, RNA-seq, NRF2 fractionation/IF, ROS and glutathione assays, GLUT1 analysis, stress granule assays in HeLa

    PMID:38741949

    Open questions at the time
    • Mechanism partly inferred from correlation
    • Direct molecular link from RNF113A to NRF2/GLUT1 not defined
    • Single lab
  11. 2026 Medium

    Completed the reversible methylation switch by identifying KDM7B/PHF8 as the demethylase that erases SMYD3 marks to limit ALKBH3-ASCC activation and alkylation resistance.

    Evidence Biochemical demethylase assays, CRISPR on/off in SCLC mouse models, xenograft alkylation sensitivity, mass spectrometry (preprint)

    PMID:41509214

    Open questions at the time
    • Preprint, not peer-reviewed
    • Exact demethylated residue(s) not pinpointed
    • Therapeutic window of targeting the switch untested clinically
  12. 2026 Low

    Extended the substrate repertoire by showing RNF113A drives CRL-dependent K48-linked degradation of CXCR4, with EIF4A3/circRNA coupling upstream RNA regulation to this activity.

    Evidence RNA-protein interaction assays, EIF4A3-RNF113A Co-IP, K48-linkage ubiquitination, proteasome inhibitor rescue in angiogenic endothelial cells

    PMID:42119231

    Open questions at the time
    • Single lab, circRNA context
    • Limited mechanistic depth on RNF113A itself
    • Reconciliation with cervical-cancer CXCR4 signaling role unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the spliceosomal RNA-binding function and the RING-dependent E3 ligase function are mechanistically integrated within a single protein, and which activity drives each downstream phenotype, remains unresolved.
  • No structure coordinating ZF-RNA binding with RING catalysis
  • Substrate recognition determinants of the ligase undefined
  • Whether splicing and ligase roles are spatially or temporally separated unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 4 GO:0016874 ligase activity 2 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-8953854 Metabolism of RNA 3 R-HSA-73894 DNA Repair 2 R-HSA-392499 Metabolism of proteins 1
Partners
BRR2CXCR4EIF4A3KDM7BMETTL3PP4PRP19SMYD3
Complex memberships
spliceosome

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 Yeast ortholog Cwc24 (RNF113A) binds directly to pre-mRNA at the 5' splice site, spanning the splice junction. The zinc finger domain is essential for this function, while the RING finger domain is dispensable. Cwc24 joins the spliceosome after the Prp19-associated complex and is released upon Prp2 action; its presence before Prp2-mediated remodeling is required for proper U5 and U6 interactions with the 5' splice site and for fidelity of 5' splice site selection. Yeast genetic analysis, domain mutagenesis (zinc finger vs. RING finger), spliceosome assembly assays, RNA-binding assays Molecular and cellular biology High 27994011
2019 The zinc finger (ZF) motif of Cwc24/RNF113A is required for specific interaction with the 5' splice site: deletion or mutation of conserved ZF residues weakens spliceosome association, lowers affinity and specificity for the 5' splice site, causes atypical interactions of U5, U6, and Prp8 with the 5' splice site, and results in aberrant cleavage at the 5' splice site. ZF domain deletion/point mutagenesis, spliceosome association assays, RNA-binding affinity measurements, splicing fidelity assays in yeast Nucleic acids research High 31504764
2018 Human RNF113A co-immunoprecipitates with U2, U4, and U6 snRNAs and with spliceosome proteins PRP19 and BRR2. Addition of excess recombinant RNF113A to in vitro splicing reactions inhibits splicing; CRISPR-mediated reduction of RNF113A severely impairs in vitro splicing efficiency, which is partially restored by addition of recombinant GST-RNF113A. Co-immunoprecipitation with snRNAs and proteins, in vitro splicing assays with recombinant protein addition, CRISPR knockdown followed by splicing rescue Journal of cellular biochemistry High 30506991
2020 RNF113A is an RNA-binding protein that regulates alternative splicing of multiple targets involved in cell survival, including MCL-1, SAT1, and Noxa1. RNF113A deficiency destabilizes the prosurvival protein MCL-1 (promoting apoptosis), enhances SAT1 expression (promoting ferroptosis), and alters Noxa1 expression (increasing ROS), thereby triggering cell death upon DNA damage. RNA-binding assays, splicing analysis of target transcripts, RNAi/knockdown with cell death phenotype readouts (apoptosis, ferroptosis, ROS measurement), protein stability assays Nature communications High 32152280
2022 SMYD3 methylates RNF113A, and this methylation impairs RNF113A's interaction with the phosphatase PP4, thereby controlling RNF113A phosphorylation levels. This methylation-phosphorylation cross-talk acts as a key switch promoting and maintaining RNF113A E3 ligase activity, which is essential for its role in alkylation damage response (activating the ALKBH3-ASCC repair complex). In vitro methyltransferase assays, co-immunoprecipitation of RNF113A with PP4, phosphorylation analysis, SMYD3 inhibition with alkylating agent sensitivity readouts Cancer discovery High 35819319
2013 C. elegans RNF-113 (ortholog of RNF113A) is required for RAD-51 focus formation after interstrand crosslink (ICL) induction, acting downstream of RPA-1 focus formation but upstream of RAD-51 loading. Epistasis analysis shows RNF-113 and RFS-1/RAD51C interact to promote displacement of RPA-1 by RAD-51 on single-stranded DNA at ICL sites; rnf-113;rfs-1 double mutants suppress the persistence of RPA-1 foci seen in rnf-113 single mutants. RNAi depletion, immunofluorescence for DNA damage foci (RPA-1, FCD-2/FANCD2, RAD-51), genetic epistasis with rfs-1/rad51C mutants, embryonic lethality assays PloS one Medium 23555887
2022 Rnf113a1 knockdown in mouse embryonic cortical neural stem/progenitor cells triggers apoptosis through combined upregulation of p53, Nupr1, and Rad51, and impairs proliferation and neuronal differentiation. Knockdown in primary mouse neural stem cells and in vivo mouse cortex, apoptosis assays, proliferation and differentiation markers, molecular analysis of p53/Nupr1/Rad51 levels Stem cells (Dayton, Ohio) Medium 35429390
2023 RNF113A mediates K48-linked polyubiquitination and proteasomal degradation of METTL3, an m6A methyltransferase, thereby decreasing mRNA m6A modification levels in AML cells. Co-immunoprecipitation, ubiquitination assays (K48-linkage specificity), proteasome inhibitor rescue, overexpression/knockdown with m6A level measurement Biomarker research Medium 37280654
2024 RNF113A knockout in HeLa cells upregulates NRF2 pathway-associated genes, promotes nuclear localization of NRF2, elevates intracellular ROS, decreases glutathione levels (attributed to reduced GLUT1 expression and glucose uptake), and increases sensitivity to H2O2-induced cell death and stress granule formation under arsenite-induced oxidative stress. CRISPR KO, RNA-seq transcriptome profiling, NRF2 nuclear localization by fractionation/immunofluorescence, ROS measurement, glutathione assays, GLUT1 expression analysis, stress granule assays Animal cells and systems Medium 38741949
2026 KDM7B/PHF8 is the demethylase that removes SMYD3-deposited methyl marks from RNF113A, establishing a reversible non-histone methylation switch. KDM7B antagonizes SMYD3 activity by maintaining low methylated-RNF113A levels, thereby limiting activation of the ALKBH3-ASCC repair complex and sensitizing cancer cells to alkylating agents. Biochemical demethylase assays identifying KDM7B as the eraser, CRISPR on/off modulation of KDM7B in genetically engineered SCLC mouse models, xenograft alkylation sensitivity assays, mass spectrometry bioRxivpreprint Medium 41509214
2023 RNF113A promotes cervical cancer cell proliferation and suppresses autophagy via the CXCR4/CXCL12/AKT/ERK/Beclin1 signaling axis (not through direct ubiquitination of Beclin1). Co-IP confirmed RNF113A interaction within this pathway. Co-IP, DIA proteomics, knockdown/overexpression with proliferation and autophagy readouts, nude mouse xenograft, dual-luciferase reporter Experimental cell research Low 37164050
2026 RNF113A mediates CRL-dependent K48-linked ubiquitination and proteasomal degradation of CXCR4 in endothelial cells. EIF4A3 interacts with both circRNA_0023016 and RNF113A at the protein level, linking upstream RNA regulation to RNF113A-mediated CXCR4 degradation. RNA-protein interaction assays, co-immunoprecipitation of EIF4A3 with RNF113A, ubiquitination assays (K48-linkage), proteasome inhibitor rescue, flow-sorted angiogenic endothelial cells International immunopharmacology Low 42119231
1997 ZNF183/RNF113A was identified as a ubiquitously expressed gene on Xq24-25 containing a C3HC4 RING finger domain at its C-terminus, with sequence features suggesting E3 ubiquitin ligase function. EST database mining, sequence analysis, expression profiling by Northern blot Gene Low 9224902

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 A novel X-linked trichothiodystrophy associated with a nonsense mutation in RNF113A. Journal of medical genetics 47 25612912
2023 EIF4A3-induced Circ_0001187 facilitates AML suppression through promoting ubiquitin-proteasomal degradation of METTL3 and decreasing m6A modification level mediated by miR-499a-5p/RNF113A pathway. Biomarker research 39 37280654
2020 The X-linked trichothiodystrophy-causing gene RNF113A links the spliceosome to cell survival upon DNA damage. Nature communications 39 32152280
2022 SMYD3 Impedes Small Cell Lung Cancer Sensitivity to Alkylation Damage through RNF113A Methylation-Phosphorylation Cross-talk. Cancer discovery 25 35819319
2017 Role of Cwc24 in the First Catalytic Step of Splicing and Fidelity of 5' Splice Site Selection. Molecular and cellular biology 19 27994011
1997 Identification of a new member (ZNF183) of the Ring finger gene family in Xq24-25. Gene 19 9224902
2019 A novel truncating variant in ring finger protein 113A (RNF113A) confirms the association of this gene with X-linked trichothiodystrophy. American journal of medical genetics. Part A 17 31880405
2018 Human RNF113A participates of pre-mRNA splicing in vitro. Journal of cellular biochemistry 12 30506991
2019 Second report of RING finger protein 113A (RNF113A) involvement in a Mendelian disorder. American journal of medical genetics. Part A 11 31793730
2013 C. elegans ring finger protein RNF-113 is involved in interstrand DNA crosslink repair and interacts with a RAD51C homolog. PloS one 11 23555887
2023 RNF113A targeted by miR-197 promotes proliferation and inhibits autophagy via CXCR4/CXCL12/AKT/ERK/Beclin1 axis in cervical cancer. Experimental cell research 10 37164050
2024 Effect of RNF113A deficiency on oxidative stress-induced NRF2 pathway. Animal cells and systems 9 38741949
2022 The Neurodevelopmental Disorders Associated Gene Rnf113a Regulates Survival and Differentiation Properties of Neural Stem Cells. Stem cells (Dayton, Ohio) 9 35429390
2019 The functional role of RNF113A in cervical carcinogenesis. International journal of clinical and experimental pathology 4 31934207
2019 Functional analysis of Cwc24 ZF-domain in 5' splice site selection. Nucleic acids research 3 31504764
2026 KDM7B-mediated demethylation of RNF113A regulates small cell lung cancer sensitivity to alkylation damage. bioRxiv : the preprint server for biology 0 41509214
2026 Novel RNF113A Variant Underlying X-Linked Trichothiodystrophy With Presumed Mosaicism in an Unaffected Mother. American journal of medical genetics. Part A 0 41531333
2026 Twins With Pathogenic RNF113A Variant Presenting With Testicular Regression Syndrome. JCEM case reports 0 41684880
2026 Exosomal circRNA_0023016 suppresses hepatocellular carcinoma progression by regulating the EIF4A3/RNF113A/CXCR4 axis in endothelial cells. International immunopharmacology 0 42119231

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