Affinage

RNF113A

E3 ubiquitin-protein ligase RNF113A · UniProt O15541

Length
343 aa
Mass
38.8 kDa
Annotated
2026-04-28
18 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RNF113A is a RING-finger E3 ubiquitin ligase and RNA-binding spliceosome component that couples pre-mRNA splicing fidelity to cell survival and DNA damage responses. Its zinc finger domain directly contacts pre-mRNA at the 5' splice site and is essential for proper U5/U6–splice-site interactions and spliceosome activation, while the RING domain is dispensable for splicing function (PMID:27994011, PMID:31504764); in human cells, RNF113A associates with U2, U4, and U6 snRNPs and the splicing factors PRP19 and BRR2, and its depletion severely impairs splicing efficiency (PMID:30506991). RNF113A regulates alternative splicing of cell survival factors including MCL-1, SAT1, and Noxa1 to protect against DNA-damage-induced apoptosis and ferroptosis (PMID:32152280), and mediates K48-linked polyubiquitination and degradation of the m6A methyltransferase METTL3 (PMID:37280654). RNF113A activity is governed by a methylation–phosphorylation switch in which SMYD3 methylation stimulates its E3 ligase function and interaction with the ALKBH3–ASCC alkylation repair complex, while loss of RNF113A activates NRF2-dependent oxidative stress responses and sensitizes cells to reactive oxygen species (PMID:35819319, PMID:38741949).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1997 Low

    Identification of RNF113A as a RING-finger-containing gene on Xq24 established its domain architecture (C3HC4 RING finger, zinc finger) and ubiquitous expression, providing the foundation for later functional studies.

    Evidence Computational sequence analysis and EST mapping of the ZNF183 locus

    PMID:9224902

    Open questions at the time
    • No functional data; domain roles entirely inferred from sequence homology
    • No expression at the protein level confirmed
  2. 2013 Medium

    Work in C. elegans first linked RNF-113 to DNA repair by showing it is required for RAD-51 loading onto RPA-coated ssDNA at interstrand crosslinks, placing it in the RAD51C/RFS-1 pathway.

    Evidence RNAi depletion, immunofluorescence focus assays, and genetic epistasis in C. elegans

    PMID:23555887

    Open questions at the time
    • Mechanism of RPA-1 displacement not biochemically defined
    • Not confirmed in mammalian cells
    • Whether the E3 ligase activity is required for this DNA repair function is unknown
  3. 2017 High

    Studies of yeast Cwc24 established that the zinc finger domain directly binds pre-mRNA at the 5' splice site and is essential for spliceosome activation and splice-site fidelity, while the RING domain is dispensable—resolving which domain mediates the splicing role.

    Evidence In vitro splicing reconstitution, domain deletion/mutation, and RNA-protein binding assays in S. cerevisiae

    PMID:27994011

    Open questions at the time
    • Whether human RNF113A zinc finger functions identically was not yet shown
    • Role of the RING domain in non-splicing contexts remained open
  4. 2018 High

    Human RNF113A was confirmed as a spliceosome component by demonstrating its association with U2, U4, U6 snRNAs and splicing factors PRP19/BRR2, with functional rescue by recombinant protein after CRISPR depletion.

    Evidence Co-immunoprecipitation with snRNAs and splicing factors, in vitro splicing assays, CRISPR editing, and recombinant protein add-back in human cells

    PMID:30506991

    Open questions at the time
    • Direct RNA-binding of human RNF113A to the 5' splice site not demonstrated at this stage
    • Structural basis of spliceosome integration unknown
  5. 2019 High

    Refined mutagenesis of the Cwc24 zinc finger showed it confers specificity for the 5' splice site; its loss causes aberrant U5/U6/Prp8 interactions and atypical cleavage, establishing the zinc finger as the fidelity determinant.

    Evidence Domain mutation combined with in vitro splicing and spliceosome association assays in yeast

    PMID:31504764

    Open questions at the time
    • Whether similar mis-splicing occurs upon human RNF113A zinc finger mutation is untested
    • No structural model of zinc finger–RNA interaction
  6. 2020 High

    RNF113A was shown to be an RNA-binding protein whose depletion causes mis-splicing of survival factors MCL-1, SAT1, and Noxa1, linking its splicing role to protection against cisplatin-induced apoptosis, ferroptosis, and oxidative stress.

    Evidence RNA-binding assays, splicing analysis, apoptosis/ferroptosis/ROS assays upon RNF113A knockdown and overexpression in human cancer cells

    PMID:32152280

    Open questions at the time
    • Direct binding to specific pre-mRNA substrates not mapped at nucleotide resolution
    • Whether E3 ligase activity contributes to cell survival phenotypes is unclear
  7. 2022 High

    A methylation–phosphorylation switch was uncovered: SMYD3 methylates RNF113A, impairing its interaction with phosphatase PP4, thereby sustaining RNF113A phosphorylation and E3 ligase activity required for alkylation damage repair via the ALKBH3–ASCC complex.

    Evidence In vitro methyltransferase assays, Co-IP, phosphorylation analysis, SMYD3 inhibition, and alkylation damage response assays

    PMID:35819319

    Open questions at the time
    • The specific ubiquitination substrate(s) of RNF113A in the alkylation repair pathway not identified
    • Structural basis of the methylation-phosphorylation cross-talk unknown
  8. 2022 Medium

    Rnf113a1 was shown to be essential for neural progenitor survival and differentiation, with its loss triggering p53/Nupr1/Rad51-associated apoptosis in embryonic cortical progenitors.

    Evidence shRNA knockdown in mouse cortical neural stem cells and in vivo cortex, apoptosis and proliferation/differentiation assays

    PMID:35429390

    Open questions at the time
    • Whether splicing defects underlie the neural phenotype is not established
    • No rescue experiment reported
    • Pathway connecting RNF113A to p53/Nupr1 not mechanistically resolved
  9. 2023 Medium

    RNF113A was identified as the E3 ligase mediating K48-linked polyubiquitination and proteasomal degradation of the m6A writer METTL3, connecting RNF113A to epitranscriptomic regulation in AML.

    Evidence Co-IP, ubiquitination assay specifying K48-linked chains, proteasome inhibitor treatment, knockdown/overexpression in AML cells

    PMID:37280654

    Open questions at the time
    • Not independently replicated
    • Whether METTL3 degradation depends on RNF113A methylation status is unknown
    • In vivo relevance in leukemogenesis not established
  10. 2024 Medium

    RNF113A knockout activates the NRF2 oxidative stress pathway, elevates ROS, reduces glutathione via decreased GLUT1-mediated glucose uptake, and enhances stress granule formation, revealing a role in redox homeostasis.

    Evidence CRISPR KO in HeLa cells, RNA-seq, immunofluorescence, ROS/glutathione/glucose uptake assays

    PMID:38741949

    Open questions at the time
    • Whether NRF2 activation is a direct consequence of RNF113A E3 ligase loss or secondary to splicing defects is unresolved
    • Mechanism linking RNF113A to GLUT1 expression not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of direct ubiquitination substrates of RNF113A within the spliceosome and alkylation repair complex, the structural basis of zinc finger–5' splice site recognition in humans, and whether the splicing and E3 ligase functions are mechanistically coupled or independent.
  • No structural model of human RNF113A bound to RNA or within the spliceosome
  • Comprehensive substrate catalogue for E3 ligase activity is lacking
  • Relationship between splicing function and ubiquitin ligase activity not dissected

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 2
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-8953854 Metabolism of RNA 4 R-HSA-392499 Metabolism of proteins 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-73894 DNA Repair 2
Partners
ALKBH3BRR2METTL3PP4PRP19SMYD3
Complex memberships
ALKBH3-ASCC alkylation repair complexspliceosome (activated/Bact complex)

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 RNF113A (then called ZNF183) was identified as a novel gene located at Xq24-25 containing a C3HC4 RING finger domain at its C-terminus and shown to be ubiquitously expressed. Database searching, EST mapping, sequence analysis Gene Low 9224902
2017 Cwc24 (yeast ortholog of RNF113A) binds directly to pre-mRNA at the 5' splice site spanning the splice junction after spliceosome activation; its zinc finger domain is essential for function while the RING finger domain is dispensable. Cwc24 promotes proper U5 and U6 interactions with the 5' splice site for fidelity of 5' splice site selection, and must associate prior to Prp2-mediated remodeling for the spliceosome to become active. In vitro splicing assays, domain deletion/mutation analysis, spliceosome association assays, RNA-protein binding assays Molecular and cellular biology High 27994011
2018 Human RNF113A associates with the spliceosome by co-immunoprecipitating with U2, U4, and U6 snRNAs and with proteins PRP19 and BRR2; excess recombinant RNF113A inhibits in vitro splicing, and CRISPR-mediated reduction of RNF113A severely impairs in vitro splicing efficiency, which is partially rescued by adding recombinant GST-RNF113A. Co-immunoprecipitation, in vitro splicing assay, CRISPR editing, recombinant protein add-back Journal of cellular biochemistry High 30506991
2019 The zinc finger (ZF) motif of Cwc24 (yeast ortholog of RNF113A) is required for specific interaction with the 5' splice site; ZF deletion or mutation weakens spliceosome association, reduces affinity/specificity for the 5' splice site, and leads to atypical interactions of U5, U6, and Prp8 with aberrant cleavage at the 5' splice site. Domain deletion/mutation analysis, spliceosome association assays, RNA-protein binding assays, in vitro splicing Nucleic acids research High 31504764
2013 C. elegans RNF-113 (ortholog of RNF113A) is required for RAD-51 focus formation after interstrand DNA crosslink (ICL) induction; its depletion causes persistent RPA-1 foci and increased embryonic lethality after ICL treatment. Epistasis experiments show RNF-113 functions in the same pathway as RFS-1/RAD51C, suggesting RNF-113 promotes displacement of RPA-1 by RAD-51 on ssDNA from ICLs. RNAi depletion, immunofluorescence focus formation assays, genetic epistasis (double mutant analysis), embryonic lethality assay PloS one Medium 23555887
2020 RNF113A is an RNA-binding protein that regulates splicing of multiple candidates involved in cell survival; RNF113A deficiency triggers apoptosis through destabilization of the prosurvival protein MCL-1, ferroptosis through enhanced SAT1 expression, and increased ROS through altered Noxa1 expression upon DNA damage. RNF113A protects cells from Cisplatin-dependent death. RNA-binding assay, splicing analysis, RNF113A knockdown/overexpression with cell death assays (apoptosis, ferroptosis, ROS measurement), protein level analysis 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 switch promoting RNF113A E3 ligase activity essential for the alkylation damage response. SMYD3 inhibition restores sensitivity to alkylating chemotherapy. Methyltransferase assay, co-immunoprecipitation, phosphorylation analysis, SMYD3 inhibition, cell viability/damage assays Cancer discovery High 35819319
2022 Rnf113a1 knockdown in mouse embryonic cortical neural stem/progenitor cells triggers apoptosis involving p53, Nupr1, and Rad51, and impairs survival, proliferation, and differentiation of neural progenitors, establishing Rnf113a1 as a regulator of cell death and neurogenesis during brain development. shRNA knockdown in cortical NSCs and mouse cortex, apoptosis assays, proliferation/differentiation assays, protein level analysis Stem cells Medium 35429390
2023 RNF113A functions as an E3 ubiquitin ligase mediating K48-linked polyubiquitination and proteasomal degradation of METTL3, thereby decreasing mRNA m6A modification levels in AML cells. Co-immunoprecipitation, ubiquitination assay (K48-linked polyubiquitin chain type specification), proteasome inhibitor treatment, knockdown/overexpression Biomarker research Medium 37280654
2023 RNF113A promotes proliferation and suppresses autophagy in cervical cancer via the CXCR4/CXCL12/AKT/ERK/Beclin1 signaling axis, not through direct ubiquitination of Beclin1; miR-197 directly targets and suppresses RNF113A expression. Co-IP, dual-luciferase reporter assay, DIA proteomic analysis, knockdown/overexpression, xenograft, wound healing/transwell assays Experimental cell research Medium 37164050
2024 RNF113A KO in HeLa cells leads to nuclear localization of NRF2 and upregulation of NRF2 target genes, elevated intracellular ROS, increased sensitivity to H2O2-induced cell death, enhanced stress granule formation under arsenite stress, and decreased glutathione levels due to reduced GLUT1 expression and lower glucose uptake. CRISPR KO, RNA sequencing, immunofluorescence, ROS measurement, cell death assays, stress granule imaging, glutathione/glucose assays Animal cells and systems Medium 38741949
2026 KDM7B/PHF8 is identified as the bona fide demethylase of RNF113A, antagonizing SMYD3-mediated methylation and thereby maintaining low levels of methylated RNF113A, limiting activation of the ALKBH3-ASCC DNA repair complex and sensitizing cancer cells to alkylating agents. Demethylase assay, Co-IP, CRISPR modulation, xenograft models, genetically engineered mouse models, chemotherapy response assays bioRxivpreprint Medium 41509214

Source papers

Stage 0 corpus · 18 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
2020 The X-linked trichothiodystrophy-causing gene RNF113A links the spliceosome to cell survival upon DNA damage. Nature communications 39 32152280
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 38 37280654
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 18 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 2 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