Affinage

RNF126

E3 ubiquitin-protein ligase RNF126 · UniProt Q9BV68

Length
311 aa
Mass
33.9 kDa
Annotated
2026-06-10
38 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RNF126 is a RING-domain E3 ubiquitin ligase central to cytosolic and membrane-protein quality control, where it is recruited via the N-terminal Ubl domain of the BAG6 chaperone to ubiquitinate juxtahydrophobic lysine residues on mislocalized proteins and direct them to the proteasome (PMID:24981174). It also reubiquitinates membrane proteins extracted by p97/VCP and captured by BAG6 (PMID:32645369), and engages substrate-loaded UBQLN1 through its UBA domain to mark unimported mitochondrial membrane precursors such as ATP5G1 for degradation (PMID:40086734), establishing a broad role in triaging aberrant hydrophobic clients. RNF126 assembles distinct ubiquitin chain types in vitro—K48 with UbcH5b and K63 with Ubc13/Uev1a—and participates in endocytic trafficking, promoting EGFR ubiquitylation and multivesicular body formation downstream of c-Cbl, and supporting retrograde sorting of the CI-MPR (PMID:23418353, PMID:24275455). In the DNA damage response it ubiquitinates Ku80 to release Ku70/80 from breaks during NHEJ (PMID:27895153) and modifies MRE11 to activate ATR-CHK1 signaling (PMID:36563124), while acting as a negative regulator positioned between RNF8 and RNF168 by ubiquitinating RNF168 and dampening H2A ubiquitination and downstream 53BP1/RAP80 focus formation (PMID:30529286, PMID:29167269). Through targeted degradation of substrates including p21, p53, PTEN, frataxin, FSP1, MIDN, and ABCD3, RNF126 regulates cell-cycle progression, metabolic reprogramming, ferroptosis resistance, and organelle homeostasis (PMID:23026136, PMID:33664240, PMID:28228265, PMID:38514855, PMID:42263131). RNF126 is itself controlled post-translationally by PARP1-mediated PARylation and CHFR-dependent degradation (PMID:34388456), and is required in vivo for spermatogenesis, with RING-domain variants in infertile men that abolish its ligase activity (PMID:39142440).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 2012 Medium

    Established RNF126 as a substrate-specific E3 ligase coupling protein binding to proteasomal turnover, first shown for the CDK inhibitor p21.

    Evidence Co-IP, in vivo ubiquitination, and siRNA stabilization with mRNA/protein distinction in cells

    PMID:23026136

    Open questions at the time
    • No ubiquitination site mapping on p21
    • Chain linkage type not defined in this study
  2. 2013 High

    Defined RNF126's intrinsic biochemistry (K48 and K63 chain specificity with distinct E2s) and a role in EGFR endocytic degradation and MVB formation downstream of c-Cbl.

    Evidence In vitro chain-type assay, reciprocal Co-IP, and siRNA with EGFR trafficking/MVB readouts

    PMID:23418353

    Open questions at the time
    • Direct EGFR ubiquitination sites not mapped
    • Relationship between zinc-finger ubiquitin binding and catalysis unresolved
  3. 2013 Medium

    Extended RNF126 function to endosomal cargo sorting, showing its RING activity is needed for CI-MPR retrograde transport.

    Evidence Stable/transient knockdown, immunofluorescence localization, and RING-mutant rescue

    PMID:24275455

    Open questions at the time
    • Direct CI-MPR ubiquitination not demonstrated
    • Molecular link between RNF126 and retromer machinery undefined
  4. 2014 High

    Identified RNF126 as the principal BAG6-dependent ligase for cytosolic quality control, resolving how mislocalized proteins are selected for degradation.

    Evidence In vitro reconstitution with purified components plus fractionation and depletion in cells

    PMID:24981174

    Open questions at the time
    • Determinants of juxtahydrophobic lysine selection not structurally defined
    • Range of physiological MLP clients incomplete
  5. 2015 Medium

    Revealed a ligase-independent function: RNF126 promotes HR by driving E2F1-dependent BRCA1 transcription.

    Evidence Co-IP, BRCA1 promoter-luciferase, ChIP, dominant-negative deletion mutant, and HR assay

    PMID:26234677

    Open questions at the time
    • Mechanism of E2F1 enhancement on the promoter unclear
    • How non-catalytic and catalytic roles are partitioned not addressed
  6. 2016 Medium

    Connected RNF126 to metabolic reprogramming through PDK degradation, increasing TCA flux under non-adherent conditions via ERK control.

    Evidence Depletion/overexpression with metabolic flux, colony, and tumorigenicity assays plus ERK inhibition

    PMID:27462466

    Open questions at the time
    • PDK ubiquitination sites not mapped
    • Which PDK isoforms are direct substrates not fully resolved
  7. 2017 High

    Multiple studies positioned RNF126 in the DNA damage response: as a Ku80 ubiquitinator enabling NHEJ completion, and as a negative regulator between RNF8 and RNF168.

    Evidence Knockdown/overexpression, E2 identification, site mutagenesis, chromatin fractionation, and iRIF focus assays

    PMID:27895153 PMID:29167269

    Open questions at the time
    • Apparent dual pro- and anti-repair roles not reconciled mechanistically
    • Temporal regulation of these opposing activities unclear
  8. 2017 Medium

    Identified frataxin as a direct RNF126 substrate, linking the ligase to Friedreich ataxia-relevant protein levels.

    Evidence Reciprocal Co-IP, in vitro and in vivo ubiquitination with catalytic-dead control, in FRDA patient cells

    PMID:28228265

    Open questions at the time
    • Frataxin ubiquitination sites not mapped
    • Physiological trigger regulating frataxin turnover unknown
  9. 2020 High

    Showed RNF126 reubiquitinates p97/VCP-extracted membrane proteins captured by BAG6, integrating it into post-extraction membrane-protein degradation.

    Evidence In vitro reconstitution with purified factors plus depletion with stabilization of extracted intermediates

    PMID:32645369

    Open questions at the time
    • Handoff from p97 to BAG6/RNF126 not structurally defined
    • Substrate scope beyond model proteins limited
  10. 2020 Medium

    Demonstrated RNF126-mediated p53 degradation in p53-wildtype colorectal cancer cells via a triple complex with p21.

    Evidence Co-IP, in vitro ubiquitination, MG132 rescue, mRNA/protein distinction

    PMID:33149608

    Open questions at the time
    • p53 ubiquitination sites not mapped
    • Context-dependence relative to MDM2 not addressed
  11. 2021 Medium

    Established post-translational control of RNF126 itself: PARP1 PARylates RNF126, recruiting CHFR for its degradation, with RNF126 required for ATR-CHK1 activation.

    Evidence Co-IP, PAR modification assay, CHFR recruitment, and ATR-CHK1 readout upon depletion

    PMID:34388456

    Open questions at the time
    • PARylation sites on RNF126 not mapped
    • Quantitative coupling of RNF126 turnover to DDR kinetics unclear
  12. 2021 Medium

    Expanded RNF126's substrate range to PTEN, TRAF3/OTUB1, and 14-3-3σ, linking it to PI3K/AKT, antiviral signaling, and G2 arrest maintenance.

    Evidence Co-IP/GST pulldown, in vivo/chain-type ubiquitination, DUB activity assay, stability assay, and cell-cycle/localization readouts

    PMID:33664240 PMID:34563636 PMID:34643674

    Open questions at the time
    • Substrate selection determinants across these targets not unified
    • In vitro reconstitution lacking for most substrates
  13. 2022 Medium

    Showed RNF126 ubiquitinates MRE11 at K339/K480 to enhance exonuclease activity and activate ATR-CHK1 signaling, providing site-resolved DDR substrate detail.

    Evidence Co-IP, site mapping, exonuclease and ATR/CHK1 phosphorylation assays, depletion in cells and mice

    PMID:36563124

    Open questions at the time
    • How ubiquitination mechanistically stimulates MRE11 nuclease unclear
    • Relationship to RNF126's RNF168-suppressive role unresolved
  14. 2024 Medium

    Identified RNF126 as an anti-ferroptotic ligase modifying FSP1 at non-lysine residues to control its plasma membrane localization and CoQ redox state.

    Evidence Co-IP, 4KR-2 site mapping, FSP1 fractionation, CoQ/CoQH2 measurement, and in vitro/in vivo ferroptosis assays

    PMID:38514855

    Open questions at the time
    • Chemistry of non-lysine FSP1 ubiquitination not detailed
    • Whether modification drives degradation or relocalization not fully separated
  15. 2024 Medium

    Demonstrated an in vivo requirement for RNF126 in spermatogenesis, with infertility-associated RING variants that abolish ligase activity.

    Evidence Knockout mouse testis histology, HR repair assay, and E3 activity assay of E261A/D253N variants

    PMID:39142440

    Open questions at the time
    • Causative substrate(s) in germ cells not identified
    • Direct human genetic causation requires larger cohorts
  16. 2025 High

    Showed RNF126 ubiquitinates UBQLN1-bound unimported mitochondrial precursors, extending its QC role to a UBQLN1-dependent pathway.

    Evidence In vitro ternary complex reconstitution, in vitro ubiquitination, and depletion with ATP5G1 stability readout

    PMID:40086734

    Open questions at the time
    • Breadth of UBQLN1-dependent mitochondrial substrates unknown
    • Coordination with BAG6 pathway not delineated
  17. 2025 Medium

    Linked RNF126 to germ-cell BAG6 interaction and flagellar morphogenesis, with deletion causing MMAF and germ cell apoptosis.

    Evidence Lineage tracing, conditional knockout, flagellar EM, and BAG6 Co-IP

    PMID:40410177

    Open questions at the time
    • Direct flagellar substrates undefined
    • Whether MMAF reflects QC failure or another mechanism unclear
  18. 2026 Medium

    Defined an RNF126-MIDN axis using non-canonical Cys/Ser/Thr ubiquitination of midnolin to control EGR1, PTEN, and p53 levels.

    Evidence Co-IP, MS-based site mapping, proteasome rescue, and depletion/overexpression stability readouts

    PMID:41496599

    Open questions at the time
    • Mechanism of non-lysine ubiquitin attachment not biochemically reconstituted
    • Hierarchy of downstream EGR1/PTEN/p53 effects unresolved
  19. 2026 Medium

    Connected RNF126 to hypoxia-driven pexophagy via HIF-2α-induced expression and ABCD3 ubiquitination, ablating VLCFA β-oxidation.

    Evidence Genetic ablation, ABCD3 ubiquitination, pexophagy and peroxisome function assays, and xenograft

    PMID:42263131

    Open questions at the time
    • ABCD3 ubiquitination sites not mapped
    • Mechanism linking ABCD3 modification to selective autophagy unclear
  20. 2026 Medium

    Showed cross-PTM coordination whereby SIRT5 desuccinylation of METTL17 licenses RNF126-mediated ubiquitination at K116 and degradation.

    Evidence Co-IP, MS, site-specific K116 ubiquitination, and SIRT5 desuccinylation/stability assays

    PMID:42021405

    Open questions at the time
    • Functional consequence of METTL17 turnover not fully characterized
    • Whether desuccinylation directly alters RNF126 recognition not shown
  21. 2026 Medium

    Identified an ATM-dependent role for RNF126 (with BRAP) in repair of late-mitotic DNA damage, broadening its DDR function across cell-cycle stages.

    Evidence Proteomics of irradiated late-mitotic cells, ATM-dependency tests, and 53BP1/RPA2 focus and survival assays after depletion

    PMID:41996237

    Open questions at the time
    • Substrate ubiquitinated during late-mitotic repair unknown
    • Functional relationship with BRAP not mechanistically defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RNF126 selects among its very large and chemically diverse substrate set—and how its catalytic versus non-catalytic, pro- versus anti-repair, and pro- versus anti-degradative roles are spatially and temporally partitioned—remains unresolved.
  • No structural model of substrate recognition
  • Determinants of canonical vs non-lysine ubiquitination undefined
  • Integration of multi-compartment functions not unified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 4 GO:0140096 catalytic activity, acting on a protein 3 GO:0140110 transcription regulator activity 1
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 3 GO:0005829 cytosol 3 GO:0005768 endosome 2
Pathway
R-HSA-73894 DNA Repair 4 R-HSA-1430728 Metabolism 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-1640170 Cell Cycle 2 R-HSA-9612973 Autophagy 1
Partners
BAG6CHFRE2F1MRE11PARP1PTENRNF168UBQLN1
Complex memberships
BAG6 complexMRN complex

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 RNF126 is the primary Bag6-dependent E3 ubiquitin ligase for cytosolic quality control of mislocalized proteins (MLPs). RNF126 is recruited to the N-terminal Ubl domain of Bag6 and preferentially ubiquitinates juxtahydrophobic lysine residues on Bag6-associated clients. Bag6-dependent ubiquitination was reconstituted with purified components in vitro. In vitro reconstitution with purified components, fractionation studies, RNF126 depletion in cells with client stabilization readout Molecular cell High 24981174
2020 RNF126 catalyzes reubiquitination of p97/VCP-extracted membrane proteins. RNF126 interacts with BAG6, which captures p97-liberated substrates; RNF126 depletion diminishes ubiquitination of extracted membrane proteins and slows their proteasomal turnover. The reubiquitination of a p97-extracted misfolded multispanning membrane protein was reconstituted with purified factors. In vitro reconstitution with purified factors, RNF126 depletion in cells with stabilization of extracted intermediates as readout Molecular cell High 32645369
2013 RNF126 specifies K48-linked ubiquitin chains with UbcH5b and K63-linked chains with Ubc13/Uev1a in vitro. RNF126 and related Rabring7 associate with EGFR through a ubiquitin-binding zinc finger domain, promote EGFR ubiquitylation, and function downstream of c-Cbl. Depletion of RNF126 causes EGFR retention in a late endocytic compartment, inefficient EGFR degradation, destabilization of ESCRT-II, and reduced multivesicular body formation after EGF stimulation. In vitro ubiquitin chain assay, co-immunoprecipitation, siRNA knockdown with EGFR trafficking and MVB formation readouts Journal of cell science High 23418353
2017 RNF126 ubiquitylates Ku80 at DSBs using UBE2D3 as the E2 enzyme, promoting dissociation of Ku70/80 from DNA and completion of NHEJ repair. Knockdown of RNF126 prevented Ku70/80 dissociation from DSBs and inhibited break repair. Mutation of Ku80 ubiquitylation site lysines to arginine delayed Ku70/80 release from chromatin. RNF126 knockdown, E3/E2 identification by biochemical assay, ubiquitylation-site mutagenesis of Ku80, chromatin fractionation after DSB induction Molecular and cellular biology High 27895153
2012 RNF126 interacts with and ubiquitinates the CDK inhibitor p21(Cip), targeting it for proteasomal degradation. RNF126 overexpression increased p21 ubiquitination in an E3 ligase activity-dependent manner; RNF126 knockdown stabilized p21 protein without altering its mRNA. Co-immunoprecipitation, in vivo ubiquitination assay, siRNA knockdown with protein stability assay, E3 ligase activity-dependent overexpression Cancer research Medium 23026136
2016 RNF126 acts as an E3 ubiquitin ligase for pyruvate dehydrogenase kinases (PDKs), promoting their proteasomal degradation. Decreased PDK levels allow pyruvate dehydrogenase to convert pyruvate to acetyl-CoA, increasing TCA cycle flux. RNF126 expression is controlled by the ERK signaling pathway under non-adherent conditions. RNF126 depletion and PDK1 overexpression with metabolic flux measurements, colony formation and in vivo tumorigenicity assays; ERK pathway inhibition Cell discovery Medium 27462466
2017 RNF126 directly ubiquitinates frataxin (FXN), targeting it for proteasomal degradation. RNF126 interacts with frataxin and promotes its ubiquitination in a catalytic activity-dependent manner both in vivo and in vitro. RNF126 depletion causes frataxin accumulation in cells from Friedreich ataxia patients. Co-immunoprecipitation, in vitro and in vivo ubiquitination assay, siRNA knockdown in FRDA patient-derived cells Cell reports Medium 28228265
2022 RNF126 physically associates with the MRE11-RAD50-NBS1 (MRN) complex and ubiquitinates MRE11 at K339 and K480, increasing MRE11 DNA exonuclease activity and subsequent RPA binding and ATR phosphorylation, thereby activating the ATR-CHK1 DDR pathway after irradiation. Co-immunoprecipitation, site-specific ubiquitination mapping, DNA exonuclease activity assay, ATR/CHK1 phosphorylation readout, RNF126 depletion in cells and mice Advanced science Medium 36563124
2015 RNF126 promotes homologous recombination by facilitating E2F1-dependent transcriptional activation of BRCA1, independent of its E3 ligase activity. RNF126 directly binds E2F1 and promotes its enrichment on the BRCA1 promoter. An RNF126 deletion mutant lacking the 11-amino-acid E2F1-interaction region acts as a dominant negative, suppressing BRCA1 expression and HR. Co-immunoprecipitation, BRCA1 promoter-luciferase transactivation assay, ChIP for E2F1 on BRCA1 promoter, dominant-negative mutant analysis, HR repair assay Oncogene Medium 26234677
2018 RNF126 is recruited to DNA damage sites in an RNF8-dependent manner. RNF126 directly ubiquitinates RNF168, and RNF126 overexpression (but not catalytically-inactive C229/232A mutant) diminishes H2AX ubiquitination and 53BP1/RAP80 focus formation, placing RNF126 as a negative regulator acting between RNF8 and RNF168. UV laser micro-irradiation, co-immunoprecipitation, catalytic-dead mutant RNF126, focus formation assays, H2A ubiquitination assay Genomics, proteomics & bioinformatics Medium 30529286
2017 RNF126 overexpression abolishes 53BP1 iRIF formation as well as RNF168, FK2, RAP80, and BRCA1 foci after ionizing radiation, while γH2AX, MDC1, and RNF8 foci are maintained, placing RNF126 between RNF8 and RNF168 in the DDR cascade. RNF126 overexpression also reduces RNF168-mediated H2A monoubiquitination at K13/15 and inhibits NHEJ. RNF126 overexpression, iRIF focus formation assays, H2A ubiquitination assay, NHEJ reporter assay The Journal of biological chemistry Medium 29167269
2013 RNF126 is required for retrograde sorting of the cation-independent mannose 6-phosphate receptor (CI-MPR). RNF126 depletion disperses CI-MPR into Rab4-positive endosomes, delays retrograde sorting, and causes lysosomal degradation of CI-MPR and missorting of cathepsin D. The RING finger domain (E3 ligase activity) is required to rescue CI-MPR levels. Stable and transient RNF126 knockdown, immunofluorescence microscopy for CI-MPR localization, RING domain mutant rescue experiment Experimental cell research Medium 24275455
2021 PARP1 interacts with and poly(ADP-ribosyl)ates RNF126, which recruits the PAR-binding E3 ligase CHFR to promote ubiquitination and degradation of RNF126. RNF126 is required for ATR-CHK1 signaling activation induced by irradiation or PARP inhibitor treatment. Co-immunoprecipitation, PAR modification assay, CHFR recruitment assay, ATR-CHK1 activation readout upon RNF126 depletion Biochemical and biophysical research communications Medium 34388456
2021 RNF126 binds 14-3-3σ and prevents ubiquitination-mediated degradation of both RNF126 and 14-3-3σ. RNF126 is required for IR-induced G2 arrest maintenance (but not rapid G2/M blockage) and for cytoplasmic sequestration of cyclin B1 and CDK1 after IR. GST pulldown, co-immunoprecipitation, cycloheximide stability assay, ubiquitination detection, flow cytometry for G2/M, immunofluorescence for cyclin B1/CDK1 localization International journal of radiation oncology, biology, physics Medium 34563636
2021 RNF126 interacts with and promotes K63-linked polyubiquitination of TRAF3, and also ubiquitinates the deubiquitinase OTUB1 at cysteine 91 (its catalytic residue), thereby reducing OTUB1 deubiquitinase activity toward TRAF3 and positively regulating the antiviral response. Co-immunoprecipitation, K63-linked ubiquitination assay, OTUB1 deubiquitinase activity assay, site-specific ubiquitination at Cys91 Bioscience, biotechnology, and biochemistry Medium 34643674
2021 RNF126 interacts with and ubiquitinates PTEN, targeting it for proteasomal degradation via polyubiquitination. PTEN binds the C-terminal RING domain-containing region of RNF126. Co-immunoprecipitation, in vivo ubiquitination assay, domain-mapping of RNF126-PTEN interaction, rescue by PTEN knockdown Cell death & disease Medium 33664240
2020 RNF126 interacts with and promotes proteasomal degradation of p53 via ubiquitination in p53-wildtype colorectal cancer cells, forming a triple complex with p53 and p21. RNF126 knockdown stabilized p53 and p21 without changing their mRNA levels. Co-immunoprecipitation, in vitro ubiquitination assay, proteasome inhibitor (MG132) rescue, mRNA/protein distinction OncoTargets and therapy Medium 33149608
2024 RNF126 acts as an anti-ferroptotic E3 ligase by interacting with FSP1 (AIFM2) and ubiquitinating FSP1 at non-lysine 4KR-2 sites. RNF126-mediated ubiquitination of FSP1 affects FSP1's plasma membrane localization; RNF126 deletion reduces membrane-localized FSP1 and increases the CoQ/CoQH2 ratio, increasing sensitivity to ferroptosis. Co-immunoprecipitation, ubiquitination site mapping (4KR-2), FSP1 subcellular fractionation/localization, CoQ/CoQH2 ratio measurement, in vitro and in vivo ferroptosis assays Oncogene Medium 38514855
2025 RNF126 interacts with substrate-engaged UBQLN1 via UBQLN1's ubiquitin-associated (UBA) domain and catalyzes ubiquitination of UBQLN1-bound unimported mitochondrial membrane protein substrates (e.g., ATP5G1). Recombinant RNF126 forms a ternary complex with UBQLN1 and ATP5G1 precursor in vitro. Without RNF126, proteasomal degradation of ATP5G1 is compromised. In vitro reconstitution of ternary complex, in vitro ubiquitination assay, RNF126 depletion with ATP5G1 stability readout The Journal of biological chemistry High 40086734
2024 RNF126 promotes spermatogenesis; its deletion causes testicular atrophy, meiotic arrest at prophase I, impaired homologous recombination repair, and increased apoptosis. RING domain missense variants (E261A and D253N) found in infertile men directly compromise RNF126 E3 ubiquitin ligase activity. Rnf126 knockout mouse model, histological analysis of testes, HR repair assay, E3 ligase activity assay of RING domain variants Journal of advanced research Medium 39142440
2025 RNF126 interacts with BAG6 in the context of sperm synthesis and germ cell development. Rnf126 deletion causes MMAF (multiple morphological abnormalities of sperm flagella) including truncated, twisted, and malformed flagella, as well as germ cell apoptosis. Genetic lineage tracing, Rnf126 conditional knockout, electron microscopy of flagella, co-immunoprecipitation for BAG6 interaction Cell death discovery Medium 40410177
2025 RNF126 promotes NF-κB activation in ovarian cancer cells under floating (anchorage-independent) conditions in a RING domain-dependent manner, contributing to anoikis resistance and peritoneal colonization. RNF126 depletion and RING domain mutant complementation, anchorage-independent growth assay, NF-κB reporter, in vivo peritoneal colonization model International journal of molecular sciences Medium 41465608
2026 RNF126 ubiquitinates midnolin (MIDN) primarily at non-canonical cysteine, serine, and threonine residues (C230, C236, S237, T239, S241) as mapped by mass spectrometry, targeting MIDN for 26S-proteasomal degradation. The RNF126-MIDN axis controls EGR1 abundance and downstream PTEN and p53 levels. Co-immunoprecipitation, mass spectrometry-based ubiquitination site mapping, proteasome inhibitor rescue, RNF126 depletion/overexpression with MIDN stability readout Acta biochimica et biophysica Sinica Medium 41496599
2026 Under hypoxia, HIF-2α drives RNF126 expression; RNF126 ubiquitinates the peroxisomal membrane transporter ABCD3, triggering selective peroxisome autophagy (pexophagy) and depleting peroxisomes, which ablates very-long-chain fatty acid β-oxidation and hepatocyte differentiation features. RNF126 genetic ablation, ABCD3 ubiquitination assay, pexophagy readout, peroxisome functional assays, HIF-2α/RNF126 pathway analysis, in vivo xenograft Proceedings of the National Academy of Sciences of the United States of America Medium 42263131
2026 RNF126 and BRAP selectively accumulate in an ATM-dependent manner in cells irradiated in late mitosis (anaphase/telophase). Both E3 ligases are required for damage-induced 53BP1 and RPA2 focus formation, resolution of DNA lesions, and cell survival after late mitotic damage. Proteomic analysis of irradiated late mitotic cells, ATM-dependency experiments, functional assays for 53BP1/RPA2 focus formation and DSB resolution after RNF126/BRAP depletion Cell reports Medium 41996237
2026 SIRT5 acts as a desuccinylase for METTL17 at Lys274, and this desuccinylation facilitates RNF126-mediated ubiquitination of METTL17 at K116, leading to its proteasomal degradation. RNF126 interacts with METTL17 as shown by mass spectrometry and co-immunoprecipitation. Co-immunoprecipitation, mass spectrometry, site-specific ubiquitination (K116), SIRT5 desuccinylation assay, METTL17 stability assay Cell & bioscience Medium 42021405
2022 RNF126 interacts with PTEN in nasopharyngeal carcinoma cells and promotes its ubiquitination and degradation, activating the PI3K/AKT pathway; RNF126 is also packaged into tumor-derived exosomes that deliver PTEN-degrading activity to recipient cells. Co-immunoprecipitation, half-life/stability assay, western blot, nanoparticle tracking of exosomes, immunofluorescence, in vivo xenograft Apoptosis Low 35717659
2025 RNF126 binds MBNL1 directly (shown by IP and Co-IP) and targets it for degradation, with MBNL1 acting as a downstream effector of RNF126-mediated PI3K/AKT, MEK/ERK, and EMT pathway activation in prostate cancer. Co-immunoprecipitation, proteomics, rescue experiments with MBNL1 knockdown Scientific reports Low 40615482
2022 RNF126 interacts with LKB1 and ubiquitinates LKB1, promoting its proteasomal degradation and thereby activating stem-cell-like properties, migration, and angiogenesis in hepatocellular carcinoma. Co-immunoprecipitation, ubiquitination assay, RNF126 overexpression/knockdown, in vivo xenograft model Human cell Low 36068398
2025 RNF126 promotes K63-linked ubiquitination of ILF3 in HEK293T cells; RNF126 silencing attenuates the interaction between ILF3 and the GATOR2 complex, thereby positively regulating amino acid-sensing mTORC1 signaling. Co-immunoprecipitation, K63 ubiquitination assay, mTORC1 activity readout upon RNF126 silencing Cellular signalling Low 40907628
2025 RNF126 promotes ubiquitination and degradation of ACAP2 in ovarian cancer; ACAP2 was identified as a ubiquitination substrate of RNF126 by co-immunoprecipitation, and RNF126-mediated ACAP2 degradation reprograms lipid metabolism. Co-immunoprecipitation, cycloheximide stability assay, lipid accumulation (Nile red), in vivo xenograft Biochemical genetics Low 40251363
2017 ANG II activates ERK/GSK3 to phosphorylate HSF1 (S307 by ERK, then S303 by GSK3), leading to downregulation of RNF126 expression; reduced RNF126 stabilizes its substrate IGF-IIR, promoting cardiomyocyte hypertrophy. Western blotting, GSK3 inhibitor treatment in vivo and in vitro, phosphorylation site analysis, RNF126 expression assay downstream of HSF1 phosphorylation Journal of cellular physiology Low 28383811

Source papers

Stage 0 corpus · 38 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Cytosolic quality control of mislocalized proteins requires RNF126 recruitment to Bag6. Molecular cell 153 24981174
2012 E3 ubiquitin ligase RNF126 promotes cancer cell proliferation by targeting the tumor suppressor p21 for ubiquitin-mediated degradation. Cancer research 66 23026136
2022 RNF126-Mediated MRE11 Ubiquitination Activates the DNA Damage Response and Confers Resistance of Triple-Negative Breast Cancer to Radiotherapy. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 63 36563124
2017 Ubiquitylation of Ku80 by RNF126 Promotes Completion of Nonhomologous End Joining-Mediated DNA Repair. Molecular and cellular biology 54 27895153
2013 The E3 ubiquitin ligases RNF126 and Rabring7 regulate endosomal sorting of the epidermal growth factor receptor. Journal of cell science 50 23418353
2021 E3 ubiquitin ligase RNF126 affects bladder cancer progression through regulation of PTEN stability. Cell death & disease 48 33664240
2016 The ERK signaling target RNF126 regulates anoikis resistance in cancer cells by changing the mitochondrial metabolic flux. Cell discovery 48 27462466
2015 RNF126 promotes homologous recombination via regulation of E2F1-mediated BRCA1 expression. Oncogene 47 26234677
2020 RNF126-Mediated Reubiquitination Is Required for Proteasomal Degradation of p97-Extracted Membrane Proteins. Molecular cell 46 32645369
2017 E3 Ligase RNF126 Directly Ubiquitinates Frataxin, Promoting Its Degradation: Identification of a Potential Therapeutic Target for Friedreich Ataxia. Cell reports 38 28228265
2017 HSF1 phosphorylation by ERK/GSK3 suppresses RNF126 to sustain IGF-IIR expression for hypertension-induced cardiomyocyte hypertrophy. Journal of cellular physiology 32 28383811
2022 Tumor cell-derived exosome RNF126 affects the immune microenvironment and promotes nasopharyngeal carcinoma progression by regulating PTEN ubiquitination. Apoptosis : an international journal on programmed cell death 28 35717659
2024 RNF126-mediated ubiquitination of FSP1 affects its subcellular localization and ferroptosis. Oncogene 22 38514855
2018 RNF126 Quenches RNF168 Function in the DNA Damage Response. Genomics, proteomics & bioinformatics 21 30529286
2016 E3 Ubiquitin ligase RNF126 regulates the progression of tongue cancer. Cancer medicine 21 27227488
2020 Roles of RNF126 and BCA2 E3 ubiquitin ligases in DNA damage repair signaling and targeted cancer therapy. Pharmacological research 20 32147403
2020 Overexpression of RNF126 Promotes the Development of Colorectal Cancer via Enhancing p53 Ubiquitination and Degradation. OncoTargets and therapy 15 33149608
2013 The ubiquitin ligase RNF126 regulates the retrograde sorting of the cation-independent mannose 6-phosphate receptor. Experimental cell research 15 24275455
2017 Ring finger protein 126 (RNF126) suppresses ionizing radiation-induced p53-binding protein 1 (53BP1) focus formation. The Journal of biological chemistry 14 29167269
2024 ZNF263 cooperates with ZNF31 to promote the drug resistance and EMT of pancreatic cancer through transactivating RNF126. Journal of cellular physiology 9 38515383
2021 CHFR-mediated degradation of RNF126 confers sensitivity to PARP inhibitors in triple-negative breast cancer cells. Biochemical and biophysical research communications 8 34388456
2021 A Novel Role for RNF126 in the Promotion of G2 Arrest via Interaction With 14-3-3σ. International journal of radiation oncology, biology, physics 7 34563636
2024 An essential role of the E3 ubiquitin ligase RNF126 in ensuring meiosis I completion during spermatogenesis. Journal of advanced research 6 39142440
2022 RNF126 contributes to stem cell-like properties and metastasis in hepatocellular carcinoma through ubiquitination and degradation of LKB1. Human cell 5 36068398
2025 Absence of Rnf126 causes male infertility with multiple morphological abnormalities of the sperm flagella. Cell death discovery 3 40410177
2025 Ring-Finger Protein 126 (RNF126) Promotes Anoikis Resistance and Peritoneal Colonization in Ovarian Cancer. International journal of molecular sciences 3 41465608
2024 Design, synthesis and biological evaluation of new RNF126-based p300/CBP degraders. Bioorganic chemistry 3 38728911
2021 RNF126 is a positive regulator of TRAF3 ubiquitination. Bioscience, biotechnology, and biochemistry 3 34643674
2026 RNF126 writes a non-canonical ubiquitin code on midnolin to tune protein stability. Acta biochimica et biophysica Sinica 2 41496599
2025 The E3 ubiquitin ligase RNF126 facilitates quality control of unimported mitochondrial membrane proteins. The Journal of biological chemistry 2 40086734
2025 Ring-finger protein RNF126 promotes prostate cancer progression via regulation of MBNL1. Scientific reports 2 40615482
2023 RNF126, 168 and CUL1: The Potential Utilization of Multi-Functional E3 Ubiquitin Ligases in Genome Maintenance for Cancer Therapy. Biomedicines 2 37760968
2026 An Optimized RNF126-Targeting Covalent Handle for Molecular Glue Degraders. bioRxiv : the preprint server for biology 1 41867716
2025 RNF126 Promotes Ovarian Cancer Progression by Reprogramming Lipid Metabolism Through Degradation of ACAP2. Biochemical genetics 1 40251363
2025 RNF126 suppresses amino acid-mediated mTORC1 signaling pathway by ubiquitinating ILF3 in HEK293T cells. Cellular signalling 1 40907628
2026 RNF126 and BRAP safeguard genome integrity after DNA damage in late mitosis. Cell reports 0 41996237
2026 SIRT5-RNF126 coordinated regulation of METTL17 stability controls mitochondrial function and glioma progression. Cell & bioscience 0 42021405
2026 RNF126 is a peroxisomal fate switch enabling redifferentiation therapy in hepatocellular carcinoma. Proceedings of the National Academy of Sciences of the United States of America 0 42263131

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