{"gene":"RNF126","run_date":"2026-06-10T06:43:37","timeline":{"discoveries":[{"year":2014,"finding":"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.","method":"In vitro reconstitution with purified components, fractionation studies, RNF126 depletion in cells with client stabilization readout","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified components plus cell-based depletion experiments, multiple orthogonal methods in a single rigorous study","pmids":["24981174"],"is_preprint":false},{"year":2020,"finding":"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.","method":"In vitro reconstitution with purified factors, RNF126 depletion in cells with stabilization of extracted intermediates as readout","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with purified components plus cell-based depletion, multiple orthogonal methods","pmids":["32645369"],"is_preprint":false},{"year":2013,"finding":"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.","method":"In vitro ubiquitin chain assay, co-immunoprecipitation, siRNA knockdown with EGFR trafficking and MVB formation readouts","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro chain-type assay plus reciprocal Co-IP and loss-of-function cell phenotypes, multiple orthogonal methods","pmids":["23418353"],"is_preprint":false},{"year":2017,"finding":"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.","method":"RNF126 knockdown, E3/E2 identification by biochemical assay, ubiquitylation-site mutagenesis of Ku80, chromatin fractionation after DSB induction","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct ubiquitylation assay with E2 identification, site-directed mutagenesis, and loss-of-function chromatin release phenotype","pmids":["27895153"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Co-immunoprecipitation, in vivo ubiquitination assay, siRNA knockdown with protein stability assay, E3 ligase activity-dependent overexpression","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus in vivo ubiquitination assay and mRNA/protein distinction, single lab but multiple orthogonal methods","pmids":["23026136"],"is_preprint":false},{"year":2016,"finding":"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.","method":"RNF126 depletion and PDK1 overexpression with metabolic flux measurements, colony formation and in vivo tumorigenicity assays; ERK pathway inhibition","journal":"Cell discovery","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — loss-of-function plus metabolic flux readout and epistasis with ERK pathway, single lab","pmids":["27462466"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Co-immunoprecipitation, in vitro and in vivo ubiquitination assay, siRNA knockdown in FRDA patient-derived cells","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, in vitro and in vivo ubiquitination assays, catalytic-dead control, patient-derived cells","pmids":["28228265"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Co-immunoprecipitation, site-specific ubiquitination mapping, DNA exonuclease activity assay, ATR/CHK1 phosphorylation readout, RNF126 depletion in cells and mice","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination site mapping, functional enzymatic assay, in vivo model; single lab","pmids":["36563124"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Co-immunoprecipitation, BRCA1 promoter-luciferase transactivation assay, ChIP for E2F1 on BRCA1 promoter, dominant-negative mutant analysis, HR repair assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, ChIP, promoter assay, dominant-negative), single lab","pmids":["26234677"],"is_preprint":false},{"year":2018,"finding":"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.","method":"UV laser micro-irradiation, co-immunoprecipitation, catalytic-dead mutant RNF126, focus formation assays, H2A ubiquitination assay","journal":"Genomics, proteomics & bioinformatics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — catalytic-dead mutant control plus Co-IP and multiple focus formation readouts, single lab","pmids":["30529286"],"is_preprint":false},{"year":2017,"finding":"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.","method":"RNF126 overexpression, iRIF focus formation assays, H2A ubiquitination assay, NHEJ reporter assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple focus-formation assays plus ubiquitination and NHEJ assays establish pathway position; single lab","pmids":["29167269"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Stable and transient RNF126 knockdown, immunofluorescence microscopy for CI-MPR localization, RING domain mutant rescue experiment","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — loss-of-function plus RING domain mutant rescue, single lab, multiple readouts","pmids":["24275455"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation, PAR modification assay, CHFR recruitment assay, ATR-CHK1 activation readout upon RNF126 depletion","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus modification assay and functional signaling readout, single lab","pmids":["34388456"],"is_preprint":false},{"year":2021,"finding":"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.","method":"GST pulldown, co-immunoprecipitation, cycloheximide stability assay, ubiquitination detection, flow cytometry for G2/M, immunofluorescence for cyclin B1/CDK1 localization","journal":"International journal of radiation oncology, biology, physics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — GST pulldown plus Co-IP, stability assay, and cell-cycle functional readout; single lab","pmids":["34563636"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation, K63-linked ubiquitination assay, OTUB1 deubiquitinase activity assay, site-specific ubiquitination at Cys91","journal":"Bioscience, biotechnology, and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus chain-type ubiquitination assay and DUB activity readout, single lab","pmids":["34643674"],"is_preprint":false},{"year":2021,"finding":"RNF126 interacts with and ubiquitinates PTEN, targeting it for proteasomal degradation via polyubiquitination. PTEN binds the C-terminal RING domain-containing region of RNF126.","method":"Co-immunoprecipitation, in vivo ubiquitination assay, domain-mapping of RNF126-PTEN interaction, rescue by PTEN knockdown","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus in vivo ubiquitination assay and domain mapping, single lab","pmids":["33664240"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Co-immunoprecipitation, in vitro ubiquitination assay, proteasome inhibitor (MG132) rescue, mRNA/protein distinction","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus ubiquitination assay and MG132 rescue, single lab","pmids":["33149608"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Co-immunoprecipitation, ubiquitination site mapping (4KR-2), FSP1 subcellular fractionation/localization, CoQ/CoQH2 ratio measurement, in vitro and in vivo ferroptosis assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination site mapping, subcellular localization assay, and metabolic readout; single lab","pmids":["38514855"],"is_preprint":false},{"year":2025,"finding":"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.","method":"In vitro reconstitution of ternary complex, in vitro ubiquitination assay, RNF126 depletion with ATP5G1 stability readout","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution plus ternary complex formation and cell-based loss-of-function; single lab but multiple orthogonal methods","pmids":["40086734"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Rnf126 knockout mouse model, histological analysis of testes, HR repair assay, E3 ligase activity assay of RING domain variants","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO phenotype plus E3 ligase activity assay of disease-relevant mutants; single lab","pmids":["39142440"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Genetic lineage tracing, Rnf126 conditional knockout, electron microscopy of flagella, co-immunoprecipitation for BAG6 interaction","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — in vivo KO with structural readout plus Co-IP for BAG6; single lab","pmids":["40410177"],"is_preprint":false},{"year":2025,"finding":"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.","method":"RNF126 depletion and RING domain mutant complementation, anchorage-independent growth assay, NF-κB reporter, in vivo peritoneal colonization model","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — RING domain-dependent rescue plus in vivo colonization; single lab","pmids":["41465608"],"is_preprint":false},{"year":2026,"finding":"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.","method":"Co-immunoprecipitation, mass spectrometry-based ubiquitination site mapping, proteasome inhibitor rescue, RNF126 depletion/overexpression with MIDN stability readout","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus MS-based site mapping and functional pathway readout; single lab","pmids":["41496599"],"is_preprint":false},{"year":2026,"finding":"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.","method":"RNF126 genetic ablation, ABCD3 ubiquitination assay, pexophagy readout, peroxisome functional assays, HIF-2α/RNF126 pathway analysis, in vivo xenograft","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ubiquitination of ABCD3, genetic ablation with organelle and metabolic readouts, in vivo model; single lab","pmids":["42263131"],"is_preprint":false},{"year":2026,"finding":"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.","method":"Proteomic analysis of irradiated late mitotic cells, ATM-dependency experiments, functional assays for 53BP1/RPA2 focus formation and DSB resolution after RNF126/BRAP depletion","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics plus ATM dependency and functional focus/survival assays; single lab","pmids":["41996237"],"is_preprint":false},{"year":2026,"finding":"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.","method":"Co-immunoprecipitation, mass spectrometry, site-specific ubiquitination (K116), SIRT5 desuccinylation assay, METTL17 stability assay","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus MS identification, site-specific modification, and cross-PTM coordination; single lab","pmids":["42021405"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Co-immunoprecipitation, half-life/stability assay, western blot, nanoparticle tracking of exosomes, immunofluorescence, in vivo xenograft","journal":"Apoptosis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, Co-IP and stability assay for PTEN ubiquitination mechanism, exosome mechanistic claim less rigorously established","pmids":["35717659"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Co-immunoprecipitation, proteomics, rescue experiments with MBNL1 knockdown","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and proteomic identification with functional rescue, single lab, no direct ubiquitination assay shown","pmids":["40615482"],"is_preprint":false},{"year":2022,"finding":"RNF126 interacts with LKB1 and ubiquitinates LKB1, promoting its proteasomal degradation and thereby activating stem-cell-like properties, migration, and angiogenesis in hepatocellular carcinoma.","method":"Co-immunoprecipitation, ubiquitination assay, RNF126 overexpression/knockdown, in vivo xenograft model","journal":"Human cell","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP plus ubiquitination assay, single lab, no site-specific or in vitro reconstitution evidence","pmids":["36068398"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Co-immunoprecipitation, K63 ubiquitination assay, mTORC1 activity readout upon RNF126 silencing","journal":"Cellular signalling","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and chain-type ubiquitination assay, single lab, mechanistic link to GATOR2 not fully established","pmids":["40907628"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Co-immunoprecipitation, cycloheximide stability assay, lipid accumulation (Nile red), in vivo xenograft","journal":"Biochemical genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and stability assay, single lab, no direct ubiquitination site mapping","pmids":["40251363"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Western blotting, GSK3 inhibitor treatment in vivo and in vitro, phosphorylation site analysis, RNF126 expression assay downstream of HSF1 phosphorylation","journal":"Journal of cellular physiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — western blot-based pathway analysis, pharmacological inhibition, single lab, no direct ubiquitination of IGF-IIR by RNF126 demonstrated in this paper","pmids":["28383811"],"is_preprint":false}],"current_model":"RNF126 is a RING-domain E3 ubiquitin ligase that operates at multiple cellular compartments: it is recruited to the BAG6 chaperone complex (via BAG6's N-terminal Ubl domain) to ubiquitinate juxtahydrophobic lysine residues on cytosolic mislocalized and p97-extracted membrane proteins, directing them to the proteasome; it ubiquitinates DNA repair factors (Ku80 at DSBs via UBE2D3, MRE11 at K339/K480 to promote ATR-CHK1 signaling, and RNF168 to negatively regulate the DDR between RNF8 and RNF168); it degrades diverse substrates including p21, p53, PTEN, frataxin, LKB1, PDKs, FSP1, METTL17, MIDN, and ABCD3 to regulate cell-cycle progression, DNA repair, metabolic reprogramming, and organelle homeostasis; and it is itself regulated post-translationally by PARP1-mediated PARylation and subsequent CHFR-mediated degradation."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2012,"claim":"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","pmids":["23026136"],"confidence":"Medium","gaps":["No ubiquitination site mapping on p21","Chain linkage type not defined in this study"]},{"year":2013,"claim":"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","pmids":["23418353"],"confidence":"High","gaps":["Direct EGFR ubiquitination sites not mapped","Relationship between zinc-finger ubiquitin binding and catalysis unresolved"]},{"year":2013,"claim":"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","pmids":["24275455"],"confidence":"Medium","gaps":["Direct CI-MPR ubiquitination not demonstrated","Molecular link between RNF126 and retromer machinery undefined"]},{"year":2014,"claim":"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","pmids":["24981174"],"confidence":"High","gaps":["Determinants of juxtahydrophobic lysine selection not structurally defined","Range of physiological MLP clients incomplete"]},{"year":2015,"claim":"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","pmids":["26234677"],"confidence":"Medium","gaps":["Mechanism of E2F1 enhancement on the promoter unclear","How non-catalytic and catalytic roles are partitioned not addressed"]},{"year":2016,"claim":"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","pmids":["27462466"],"confidence":"Medium","gaps":["PDK ubiquitination sites not mapped","Which PDK isoforms are direct substrates not fully resolved"]},{"year":2017,"claim":"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","pmids":["27895153","29167269"],"confidence":"High","gaps":["Apparent dual pro- and anti-repair roles not reconciled mechanistically","Temporal regulation of these opposing activities unclear"]},{"year":2017,"claim":"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","pmids":["28228265"],"confidence":"Medium","gaps":["Frataxin ubiquitination sites not mapped","Physiological trigger regulating frataxin turnover unknown"]},{"year":2020,"claim":"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","pmids":["32645369"],"confidence":"High","gaps":["Handoff from p97 to BAG6/RNF126 not structurally defined","Substrate scope beyond model proteins limited"]},{"year":2020,"claim":"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","pmids":["33149608"],"confidence":"Medium","gaps":["p53 ubiquitination sites not mapped","Context-dependence relative to MDM2 not addressed"]},{"year":2021,"claim":"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","pmids":["34388456"],"confidence":"Medium","gaps":["PARylation sites on RNF126 not mapped","Quantitative coupling of RNF126 turnover to DDR kinetics unclear"]},{"year":2021,"claim":"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","pmids":["33664240","34643674","34563636"],"confidence":"Medium","gaps":["Substrate selection determinants across these targets not unified","In vitro reconstitution lacking for most substrates"]},{"year":2022,"claim":"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","pmids":["36563124"],"confidence":"Medium","gaps":["How ubiquitination mechanistically stimulates MRE11 nuclease unclear","Relationship to RNF126's RNF168-suppressive role unresolved"]},{"year":2024,"claim":"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","pmids":["38514855"],"confidence":"Medium","gaps":["Chemistry of non-lysine FSP1 ubiquitination not detailed","Whether modification drives degradation or relocalization not fully separated"]},{"year":2024,"claim":"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","pmids":["39142440"],"confidence":"Medium","gaps":["Causative substrate(s) in germ cells not identified","Direct human genetic causation requires larger cohorts"]},{"year":2025,"claim":"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","pmids":["40086734"],"confidence":"High","gaps":["Breadth of UBQLN1-dependent mitochondrial substrates unknown","Coordination with BAG6 pathway not delineated"]},{"year":2025,"claim":"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","pmids":["40410177"],"confidence":"Medium","gaps":["Direct flagellar substrates undefined","Whether MMAF reflects QC failure or another mechanism unclear"]},{"year":2026,"claim":"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","pmids":["41496599"],"confidence":"Medium","gaps":["Mechanism of non-lysine ubiquitin attachment not biochemically reconstituted","Hierarchy of downstream EGR1/PTEN/p53 effects unresolved"]},{"year":2026,"claim":"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","pmids":["42263131"],"confidence":"Medium","gaps":["ABCD3 ubiquitination sites not mapped","Mechanism linking ABCD3 modification to selective autophagy unclear"]},{"year":2026,"claim":"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","pmids":["42021405"],"confidence":"Medium","gaps":["Functional consequence of METTL17 turnover not fully characterized","Whether desuccinylation directly alters RNF126 recognition not shown"]},{"year":2026,"claim":"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","pmids":["41996237"],"confidence":"Medium","gaps":["Substrate ubiquitinated during late-mitotic repair unknown","Functional relationship with BRAP not mechanistically defined"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of substrate recognition","Determinants of canonical vs non-lysine ubiquitination undefined","Integration of multi-compartment functions not unified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,3,7]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,2,6,18]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[8]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1,18]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,7,9]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[2,11]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[3,9,10]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,18]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[3,7,9,10]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,13]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[5,17,23]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[23]}],"complexes":["BAG6 complex","MRN complex"],"partners":["BAG6","UBQLN1","MRE11","RNF168","PTEN","E2F1","PARP1","CHFR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BV68","full_name":"E3 ubiquitin-protein ligase RNF126","aliases":["RING finger protein 126"],"length_aa":311,"mass_kda":33.9,"function":"E3 ubiquitin-protein ligase that mediates ubiquitination oF target proteins (PubMed:23277564, PubMed:24275455, PubMed:24981174, PubMed:36563124). Depending on the associated E2 ligase, mediates 'Lys-27'-, 'Lys-29'-, 'Lys-48'- and/or 'Lys-63'-linked polyubiquitination of substrates (PubMed:36563124). Part of a BAG6-dependent quality control process ensuring that proteins of the secretory pathway that are mislocalized to the cytosol are degraded by the proteasome. Probably acts by providing the ubiquitin ligase activity associated with the BAG6 complex and be responsible for ubiquitination of the hydrophobic mislocalized proteins and their targeting to the proteasome (PubMed:24981174, PubMed:29042515). May also play a role in the endosomal recycling of IGF2R, the cation-independent mannose-6-phosphate receptor (PubMed:24275455). May play a role in the endosomal sorting and degradation of several membrane receptors including EGFR, FLT3, MET and CXCR4, by mediating their ubiquitination (PubMed:23418353). By ubiquitinating CDKN1A/p21 and targeting it for degradation, may also promote cell proliferation (PubMed:23026136). May monoubiquitinate AICDA (PubMed:23277564). Acts as a regulator of DNA repair by mediating 'Lys-27'- and 'Lys-29'-linked polyubiquitination of MRE11, thereby promoting the exonuclease activity of MRE11 (PubMed:36563124)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9BV68/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RNF126","classification":"Not Classified","n_dependent_lines":15,"n_total_lines":1208,"dependency_fraction":0.012417218543046357},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"BAG6","stoichiometry":4.0},{"gene":"GET4","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/search/RNF126","total_profiled":1310},"omim":[{"mim_id":"615177","title":"RING FINGER PROTEIN 126; RNF126","url":"https://www.omim.org/entry/615177"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RNF126"},"hgnc":{"alias_symbol":["FLJ20552"],"prev_symbol":[]},"alphafold":{"accession":"Q9BV68","domains":[{"cath_id":"-","chopping":"9-39","consensus_level":"high","plddt":85.731,"start":9,"end":39},{"cath_id":"3.30.40.10","chopping":"202-261","consensus_level":"high","plddt":78.7965,"start":202,"end":261}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BV68","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BV68-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BV68-F1-predicted_aligned_error_v6.png","plddt_mean":61.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RNF126","jax_strain_url":"https://www.jax.org/strain/search?query=RNF126"},"sequence":{"accession":"Q9BV68","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BV68.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BV68/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BV68"}},"corpus_meta":[{"pmid":"24981174","id":"PMC_24981174","title":"Cytosolic 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Nonhomologous End Joining-Mediated DNA Repair.","date":"2017","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/27895153","citation_count":54,"is_preprint":false},{"pmid":"23418353","id":"PMC_23418353","title":"The E3 ubiquitin ligases RNF126 and Rabring7 regulate endosomal sorting of the epidermal growth factor receptor.","date":"2013","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/23418353","citation_count":50,"is_preprint":false},{"pmid":"33664240","id":"PMC_33664240","title":"E3 ubiquitin ligase RNF126 affects bladder cancer progression through regulation of PTEN stability.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33664240","citation_count":48,"is_preprint":false},{"pmid":"27462466","id":"PMC_27462466","title":"The ERK signaling target RNF126 regulates anoikis resistance in cancer cells by changing the mitochondrial metabolic flux.","date":"2016","source":"Cell 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physics","url":"https://pubmed.ncbi.nlm.nih.gov/34563636","citation_count":7,"is_preprint":false},{"pmid":"39142440","id":"PMC_39142440","title":"An essential role of the E3 ubiquitin ligase RNF126 in ensuring meiosis I completion during spermatogenesis.","date":"2024","source":"Journal of advanced research","url":"https://pubmed.ncbi.nlm.nih.gov/39142440","citation_count":6,"is_preprint":false},{"pmid":"36068398","id":"PMC_36068398","title":"RNF126 contributes to stem cell-like properties and metastasis in hepatocellular carcinoma through ubiquitination and degradation of LKB1.","date":"2022","source":"Human cell","url":"https://pubmed.ncbi.nlm.nih.gov/36068398","citation_count":5,"is_preprint":false},{"pmid":"41465608","id":"PMC_41465608","title":"Ring-Finger Protein 126 (RNF126) Promotes Anoikis Resistance and Peritoneal Colonization in Ovarian Cancer.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41465608","citation_count":3,"is_preprint":false},{"pmid":"38728911","id":"PMC_38728911","title":"Design, synthesis and biological evaluation of new RNF126-based p300/CBP degraders.","date":"2024","source":"Bioorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38728911","citation_count":3,"is_preprint":false},{"pmid":"40410177","id":"PMC_40410177","title":"Absence of Rnf126 causes male infertility with multiple morphological abnormalities of the sperm flagella.","date":"2025","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/40410177","citation_count":3,"is_preprint":false},{"pmid":"34643674","id":"PMC_34643674","title":"RNF126 is a positive regulator of TRAF3 ubiquitination.","date":"2021","source":"Bioscience, biotechnology, and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34643674","citation_count":3,"is_preprint":false},{"pmid":"40615482","id":"PMC_40615482","title":"Ring-finger protein RNF126 promotes prostate cancer progression via regulation of MBNL1.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40615482","citation_count":2,"is_preprint":false},{"pmid":"40086734","id":"PMC_40086734","title":"The E3 ubiquitin ligase RNF126 facilitates quality control of unimported mitochondrial membrane proteins.","date":"2025","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40086734","citation_count":2,"is_preprint":false},{"pmid":"37760968","id":"PMC_37760968","title":"RNF126, 168 and CUL1: The Potential Utilization of Multi-Functional E3 Ubiquitin Ligases in Genome Maintenance for Cancer Therapy.","date":"2023","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/37760968","citation_count":2,"is_preprint":false},{"pmid":"41496599","id":"PMC_41496599","title":"RNF126 writes a non-canonical ubiquitin code on midnolin to tune protein stability.","date":"2026","source":"Acta biochimica et biophysica 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America","url":"https://pubmed.ncbi.nlm.nih.gov/42263131","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19735,"output_tokens":8145,"usd":0.09069,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17397,"output_tokens":6071,"usd":0.11938,"stage2_stop_reason":"end_turn"},"total_usd":0.21007,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro reconstitution with purified components, fractionation studies, RNF126 depletion in cells with client stabilization readout\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified components plus cell-based depletion experiments, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"24981174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro reconstitution with purified factors, RNF126 depletion in cells with stabilization of extracted intermediates as readout\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with purified components plus cell-based depletion, multiple orthogonal methods\",\n      \"pmids\": [\"32645369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro ubiquitin chain assay, co-immunoprecipitation, siRNA knockdown with EGFR trafficking and MVB formation readouts\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro chain-type assay plus reciprocal Co-IP and loss-of-function cell phenotypes, multiple orthogonal methods\",\n      \"pmids\": [\"23418353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"RNF126 knockdown, E3/E2 identification by biochemical assay, ubiquitylation-site mutagenesis of Ku80, chromatin fractionation after DSB induction\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct ubiquitylation assay with E2 identification, site-directed mutagenesis, and loss-of-function chromatin release phenotype\",\n      \"pmids\": [\"27895153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay, siRNA knockdown with protein stability assay, E3 ligase activity-dependent overexpression\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus in vivo ubiquitination assay and mRNA/protein distinction, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"23026136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"RNF126 depletion and PDK1 overexpression with metabolic flux measurements, colony formation and in vivo tumorigenicity assays; ERK pathway inhibition\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — loss-of-function plus metabolic flux readout and epistasis with ERK pathway, single lab\",\n      \"pmids\": [\"27462466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, in vitro and in vivo ubiquitination assay, siRNA knockdown in FRDA patient-derived cells\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, in vitro and in vivo ubiquitination assays, catalytic-dead control, patient-derived cells\",\n      \"pmids\": [\"28228265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, site-specific ubiquitination mapping, DNA exonuclease activity assay, ATR/CHK1 phosphorylation readout, RNF126 depletion in cells and mice\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination site mapping, functional enzymatic assay, in vivo model; single lab\",\n      \"pmids\": [\"36563124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, BRCA1 promoter-luciferase transactivation assay, ChIP for E2F1 on BRCA1 promoter, dominant-negative mutant analysis, HR repair assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, ChIP, promoter assay, dominant-negative), single lab\",\n      \"pmids\": [\"26234677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"UV laser micro-irradiation, co-immunoprecipitation, catalytic-dead mutant RNF126, focus formation assays, H2A ubiquitination assay\",\n      \"journal\": \"Genomics, proteomics & bioinformatics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — catalytic-dead mutant control plus Co-IP and multiple focus formation readouts, single lab\",\n      \"pmids\": [\"30529286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"RNF126 overexpression, iRIF focus formation assays, H2A ubiquitination assay, NHEJ reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple focus-formation assays plus ubiquitination and NHEJ assays establish pathway position; single lab\",\n      \"pmids\": [\"29167269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Stable and transient RNF126 knockdown, immunofluorescence microscopy for CI-MPR localization, RING domain mutant rescue experiment\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — loss-of-function plus RING domain mutant rescue, single lab, multiple readouts\",\n      \"pmids\": [\"24275455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, PAR modification assay, CHFR recruitment assay, ATR-CHK1 activation readout upon RNF126 depletion\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus modification assay and functional signaling readout, single lab\",\n      \"pmids\": [\"34388456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"GST pulldown, co-immunoprecipitation, cycloheximide stability assay, ubiquitination detection, flow cytometry for G2/M, immunofluorescence for cyclin B1/CDK1 localization\",\n      \"journal\": \"International journal of radiation oncology, biology, physics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — GST pulldown plus Co-IP, stability assay, and cell-cycle functional readout; single lab\",\n      \"pmids\": [\"34563636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, K63-linked ubiquitination assay, OTUB1 deubiquitinase activity assay, site-specific ubiquitination at Cys91\",\n      \"journal\": \"Bioscience, biotechnology, and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus chain-type ubiquitination assay and DUB activity readout, single lab\",\n      \"pmids\": [\"34643674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RNF126 interacts with and ubiquitinates PTEN, targeting it for proteasomal degradation via polyubiquitination. PTEN binds the C-terminal RING domain-containing region of RNF126.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay, domain-mapping of RNF126-PTEN interaction, rescue by PTEN knockdown\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus in vivo ubiquitination assay and domain mapping, single lab\",\n      \"pmids\": [\"33664240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, in vitro ubiquitination assay, proteasome inhibitor (MG132) rescue, mRNA/protein distinction\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus ubiquitination assay and MG132 rescue, single lab\",\n      \"pmids\": [\"33149608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination site mapping (4KR-2), FSP1 subcellular fractionation/localization, CoQ/CoQH2 ratio measurement, in vitro and in vivo ferroptosis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination site mapping, subcellular localization assay, and metabolic readout; single lab\",\n      \"pmids\": [\"38514855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro reconstitution of ternary complex, in vitro ubiquitination assay, RNF126 depletion with ATP5G1 stability readout\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution plus ternary complex formation and cell-based loss-of-function; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"40086734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Rnf126 knockout mouse model, histological analysis of testes, HR repair assay, E3 ligase activity assay of RING domain variants\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO phenotype plus E3 ligase activity assay of disease-relevant mutants; single lab\",\n      \"pmids\": [\"39142440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic lineage tracing, Rnf126 conditional knockout, electron microscopy of flagella, co-immunoprecipitation for BAG6 interaction\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — in vivo KO with structural readout plus Co-IP for BAG6; single lab\",\n      \"pmids\": [\"40410177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"RNF126 depletion and RING domain mutant complementation, anchorage-independent growth assay, NF-κB reporter, in vivo peritoneal colonization model\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — RING domain-dependent rescue plus in vivo colonization; single lab\",\n      \"pmids\": [\"41465608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry-based ubiquitination site mapping, proteasome inhibitor rescue, RNF126 depletion/overexpression with MIDN stability readout\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus MS-based site mapping and functional pathway readout; single lab\",\n      \"pmids\": [\"41496599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"RNF126 genetic ablation, ABCD3 ubiquitination assay, pexophagy readout, peroxisome functional assays, HIF-2α/RNF126 pathway analysis, in vivo xenograft\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ubiquitination of ABCD3, genetic ablation with organelle and metabolic readouts, in vivo model; single lab\",\n      \"pmids\": [\"42263131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"Proteomic analysis of irradiated late mitotic cells, ATM-dependency experiments, functional assays for 53BP1/RPA2 focus formation and DSB resolution after RNF126/BRAP depletion\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics plus ATM dependency and functional focus/survival assays; single lab\",\n      \"pmids\": [\"41996237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, site-specific ubiquitination (K116), SIRT5 desuccinylation assay, METTL17 stability assay\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus MS identification, site-specific modification, and cross-PTM coordination; single lab\",\n      \"pmids\": [\"42021405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, half-life/stability assay, western blot, nanoparticle tracking of exosomes, immunofluorescence, in vivo xenograft\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, Co-IP and stability assay for PTEN ubiquitination mechanism, exosome mechanistic claim less rigorously established\",\n      \"pmids\": [\"35717659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, proteomics, rescue experiments with MBNL1 knockdown\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and proteomic identification with functional rescue, single lab, no direct ubiquitination assay shown\",\n      \"pmids\": [\"40615482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RNF126 interacts with LKB1 and ubiquitinates LKB1, promoting its proteasomal degradation and thereby activating stem-cell-like properties, migration, and angiogenesis in hepatocellular carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, RNF126 overexpression/knockdown, in vivo xenograft model\",\n      \"journal\": \"Human cell\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP plus ubiquitination assay, single lab, no site-specific or in vitro reconstitution evidence\",\n      \"pmids\": [\"36068398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, K63 ubiquitination assay, mTORC1 activity readout upon RNF126 silencing\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and chain-type ubiquitination assay, single lab, mechanistic link to GATOR2 not fully established\",\n      \"pmids\": [\"40907628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, cycloheximide stability assay, lipid accumulation (Nile red), in vivo xenograft\",\n      \"journal\": \"Biochemical genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and stability assay, single lab, no direct ubiquitination site mapping\",\n      \"pmids\": [\"40251363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Western blotting, GSK3 inhibitor treatment in vivo and in vitro, phosphorylation site analysis, RNF126 expression assay downstream of HSF1 phosphorylation\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — western blot-based pathway analysis, pharmacological inhibition, single lab, no direct ubiquitination of IGF-IIR by RNF126 demonstrated in this paper\",\n      \"pmids\": [\"28383811\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RNF126 is a RING-domain E3 ubiquitin ligase that operates at multiple cellular compartments: it is recruited to the BAG6 chaperone complex (via BAG6's N-terminal Ubl domain) to ubiquitinate juxtahydrophobic lysine residues on cytosolic mislocalized and p97-extracted membrane proteins, directing them to the proteasome; it ubiquitinates DNA repair factors (Ku80 at DSBs via UBE2D3, MRE11 at K339/K480 to promote ATR-CHK1 signaling, and RNF168 to negatively regulate the DDR between RNF8 and RNF168); it degrades diverse substrates including p21, p53, PTEN, frataxin, LKB1, PDKs, FSP1, METTL17, MIDN, and ABCD3 to regulate cell-cycle progression, DNA repair, metabolic reprogramming, and organelle homeostasis; and it is itself regulated post-translationally by PARP1-mediated PARylation and subsequent CHFR-mediated degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0]. It also reubiquitinates membrane proteins extracted by p97/VCP and captured by BAG6 [#1], and engages substrate-loaded UBQLN1 through its UBA domain to mark unimported mitochondrial membrane precursors such as ATP5G1 for degradation [#18], establishing a broad role in triaging aberrant hydrophobic clients. RNF126 assembles distinct ubiquitin chain types in vitro\\u2014K48 with UbcH5b and K63 with Ubc13/Uev1a\\u2014and participates in endocytic trafficking, promoting EGFR ubiquitylation and multivesicular body formation downstream of c-Cbl, and supporting retrograde sorting of the CI-MPR [#2, #11]. In the DNA damage response it ubiquitinates Ku80 to release Ku70/80 from breaks during NHEJ [#3] and modifies MRE11 to activate ATR-CHK1 signaling [#7], while acting as a negative regulator positioned between RNF8 and RNF168 by ubiquitinating RNF168 and dampening H2A ubiquitination and downstream 53BP1/RAP80 focus formation [#9, #10]. 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 [#4, #15, #6, #17, #23]. RNF126 is itself controlled post-translationally by PARP1-mediated PARylation and CHFR-dependent degradation [#12], and is required in vivo for spermatogenesis, with RING-domain variants in infertile men that abolish its ligase activity [#19].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established RNF126 as a substrate-specific E3 ligase coupling protein binding to proteasomal turnover, first shown for the CDK inhibitor p21.\",\n      \"evidence\": \"Co-IP, in vivo ubiquitination, and siRNA stabilization with mRNA/protein distinction in cells\",\n      \"pmids\": [\"23026136\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No ubiquitination site mapping on p21\", \"Chain linkage type not defined in this study\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro chain-type assay, reciprocal Co-IP, and siRNA with EGFR trafficking/MVB readouts\",\n      \"pmids\": [\"23418353\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct EGFR ubiquitination sites not mapped\", \"Relationship between zinc-finger ubiquitin binding and catalysis unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended RNF126 function to endosomal cargo sorting, showing its RING activity is needed for CI-MPR retrograde transport.\",\n      \"evidence\": \"Stable/transient knockdown, immunofluorescence localization, and RING-mutant rescue\",\n      \"pmids\": [\"24275455\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CI-MPR ubiquitination not demonstrated\", \"Molecular link between RNF126 and retromer machinery undefined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified RNF126 as the principal BAG6-dependent ligase for cytosolic quality control, resolving how mislocalized proteins are selected for degradation.\",\n      \"evidence\": \"In vitro reconstitution with purified components plus fractionation and depletion in cells\",\n      \"pmids\": [\"24981174\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of juxtahydrophobic lysine selection not structurally defined\", \"Range of physiological MLP clients incomplete\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed a ligase-independent function: RNF126 promotes HR by driving E2F1-dependent BRCA1 transcription.\",\n      \"evidence\": \"Co-IP, BRCA1 promoter-luciferase, ChIP, dominant-negative deletion mutant, and HR assay\",\n      \"pmids\": [\"26234677\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of E2F1 enhancement on the promoter unclear\", \"How non-catalytic and catalytic roles are partitioned not addressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected RNF126 to metabolic reprogramming through PDK degradation, increasing TCA flux under non-adherent conditions via ERK control.\",\n      \"evidence\": \"Depletion/overexpression with metabolic flux, colony, and tumorigenicity assays plus ERK inhibition\",\n      \"pmids\": [\"27462466\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PDK ubiquitination sites not mapped\", \"Which PDK isoforms are direct substrates not fully resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"Knockdown/overexpression, E2 identification, site mutagenesis, chromatin fractionation, and iRIF focus assays\",\n      \"pmids\": [\"27895153\", \"29167269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Apparent dual pro- and anti-repair roles not reconciled mechanistically\", \"Temporal regulation of these opposing activities unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified frataxin as a direct RNF126 substrate, linking the ligase to Friedreich ataxia-relevant protein levels.\",\n      \"evidence\": \"Reciprocal Co-IP, in vitro and in vivo ubiquitination with catalytic-dead control, in FRDA patient cells\",\n      \"pmids\": [\"28228265\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Frataxin ubiquitination sites not mapped\", \"Physiological trigger regulating frataxin turnover unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed RNF126 reubiquitinates p97/VCP-extracted membrane proteins captured by BAG6, integrating it into post-extraction membrane-protein degradation.\",\n      \"evidence\": \"In vitro reconstitution with purified factors plus depletion with stabilization of extracted intermediates\",\n      \"pmids\": [\"32645369\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Handoff from p97 to BAG6/RNF126 not structurally defined\", \"Substrate scope beyond model proteins limited\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated RNF126-mediated p53 degradation in p53-wildtype colorectal cancer cells via a triple complex with p21.\",\n      \"evidence\": \"Co-IP, in vitro ubiquitination, MG132 rescue, mRNA/protein distinction\",\n      \"pmids\": [\"33149608\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"p53 ubiquitination sites not mapped\", \"Context-dependence relative to MDM2 not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established post-translational control of RNF126 itself: PARP1 PARylates RNF126, recruiting CHFR for its degradation, with RNF126 required for ATR-CHK1 activation.\",\n      \"evidence\": \"Co-IP, PAR modification assay, CHFR recruitment, and ATR-CHK1 readout upon depletion\",\n      \"pmids\": [\"34388456\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PARylation sites on RNF126 not mapped\", \"Quantitative coupling of RNF126 turnover to DDR kinetics unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Expanded RNF126's substrate range to PTEN, TRAF3/OTUB1, and 14-3-3\\u03c3, linking it to PI3K/AKT, antiviral signaling, and G2 arrest maintenance.\",\n      \"evidence\": \"Co-IP/GST pulldown, in vivo/chain-type ubiquitination, DUB activity assay, stability assay, and cell-cycle/localization readouts\",\n      \"pmids\": [\"33664240\", \"34643674\", \"34563636\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Substrate selection determinants across these targets not unified\", \"In vitro reconstitution lacking for most substrates\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed RNF126 ubiquitinates MRE11 at K339/K480 to enhance exonuclease activity and activate ATR-CHK1 signaling, providing site-resolved DDR substrate detail.\",\n      \"evidence\": \"Co-IP, site mapping, exonuclease and ATR/CHK1 phosphorylation assays, depletion in cells and mice\",\n      \"pmids\": [\"36563124\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How ubiquitination mechanistically stimulates MRE11 nuclease unclear\", \"Relationship to RNF126's RNF168-suppressive role unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified RNF126 as an anti-ferroptotic ligase modifying FSP1 at non-lysine residues to control its plasma membrane localization and CoQ redox state.\",\n      \"evidence\": \"Co-IP, 4KR-2 site mapping, FSP1 fractionation, CoQ/CoQH2 measurement, and in vitro/in vivo ferroptosis assays\",\n      \"pmids\": [\"38514855\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Chemistry of non-lysine FSP1 ubiquitination not detailed\", \"Whether modification drives degradation or relocalization not fully separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated an in vivo requirement for RNF126 in spermatogenesis, with infertility-associated RING variants that abolish ligase activity.\",\n      \"evidence\": \"Knockout mouse testis histology, HR repair assay, and E3 activity assay of E261A/D253N variants\",\n      \"pmids\": [\"39142440\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causative substrate(s) in germ cells not identified\", \"Direct human genetic causation requires larger cohorts\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed RNF126 ubiquitinates UBQLN1-bound unimported mitochondrial precursors, extending its QC role to a UBQLN1-dependent pathway.\",\n      \"evidence\": \"In vitro ternary complex reconstitution, in vitro ubiquitination, and depletion with ATP5G1 stability readout\",\n      \"pmids\": [\"40086734\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Breadth of UBQLN1-dependent mitochondrial substrates unknown\", \"Coordination with BAG6 pathway not delineated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked RNF126 to germ-cell BAG6 interaction and flagellar morphogenesis, with deletion causing MMAF and germ cell apoptosis.\",\n      \"evidence\": \"Lineage tracing, conditional knockout, flagellar EM, and BAG6 Co-IP\",\n      \"pmids\": [\"40410177\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct flagellar substrates undefined\", \"Whether MMAF reflects QC failure or another mechanism unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined an RNF126-MIDN axis using non-canonical Cys/Ser/Thr ubiquitination of midnolin to control EGR1, PTEN, and p53 levels.\",\n      \"evidence\": \"Co-IP, MS-based site mapping, proteasome rescue, and depletion/overexpression stability readouts\",\n      \"pmids\": [\"41496599\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of non-lysine ubiquitin attachment not biochemically reconstituted\", \"Hierarchy of downstream EGR1/PTEN/p53 effects unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected RNF126 to hypoxia-driven pexophagy via HIF-2\\u03b1-induced expression and ABCD3 ubiquitination, ablating VLCFA \\u03b2-oxidation.\",\n      \"evidence\": \"Genetic ablation, ABCD3 ubiquitination, pexophagy and peroxisome function assays, and xenograft\",\n      \"pmids\": [\"42263131\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ABCD3 ubiquitination sites not mapped\", \"Mechanism linking ABCD3 modification to selective autophagy unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed cross-PTM coordination whereby SIRT5 desuccinylation of METTL17 licenses RNF126-mediated ubiquitination at K116 and degradation.\",\n      \"evidence\": \"Co-IP, MS, site-specific K116 ubiquitination, and SIRT5 desuccinylation/stability assays\",\n      \"pmids\": [\"42021405\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of METTL17 turnover not fully characterized\", \"Whether desuccinylation directly alters RNF126 recognition not shown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified an ATM-dependent role for RNF126 (with BRAP) in repair of late-mitotic DNA damage, broadening its DDR function across cell-cycle stages.\",\n      \"evidence\": \"Proteomics of irradiated late-mitotic cells, ATM-dependency tests, and 53BP1/RPA2 focus and survival assays after depletion\",\n      \"pmids\": [\"41996237\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Substrate ubiquitinated during late-mitotic repair unknown\", \"Functional relationship with BRAP not mechanistically defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RNF126 selects among its very large and chemically diverse substrate set\\u2014and how its catalytic versus non-catalytic, pro- versus anti-repair, and pro- versus anti-degradative roles are spatially and temporally partitioned\\u2014remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of substrate recognition\", \"Determinants of canonical vs non-lysine ubiquitination undefined\", \"Integration of multi-compartment functions not unified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0061630\", \"supporting_discovery_ids\": [0, 2, 18]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 3, 7]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 2, 6, 18]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1, 18]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 7, 9]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [2, 11]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [3, 9, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 18]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [3, 7, 9, 10]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 13]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [5, 17, 23]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [23]}\n    ],\n    \"complexes\": [\n      \"BAG6 complex\",\n      \"MRN complex\"\n    ],\n    \"partners\": [\n      \"BAG6\",\n      \"UBQLN1\",\n      \"MRE11\",\n      \"RNF168\",\n      \"PTEN\",\n      \"E2F1\",\n      \"PARP1\",\n      \"CHFR\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}