{"gene":"RNF138","run_date":"2026-06-10T06:43:37","timeline":{"discoveries":[{"year":2015,"finding":"RNF138 is recruited to DNA double-strand break (DSB) sites through zinc finger domains that preferentially bind DNA with 5'- or 3'-single-stranded overhangs. RNF138 promotes DNA end resection, ATR-dependent signaling, and DSB repair by homologous recombination (HR). RNF138-dependent ubiquitylation of Ku promotes its removal from DNA breaks, thereby favoring HR over NHEJ.","method":"Recruitment assays at laser-induced damage sites, zinc finger domain binding studies, HR reporter assays, epistasis with Ku, RNF138 knockdown/knockout with defined cellular phenotypes","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional assays, domain mapping, multiple orthogonal methods (recruitment, resection, HR efficiency, survival), independently replicated in companion paper (PMID:26502057)","pmids":["26502055"],"is_preprint":false},{"year":2015,"finding":"RNF138 functions with UBE2D E2-conjugating enzymes to ubiquitylate CtIP, promoting CtIP accrual at DSB sites and stimulating early DNA end resection for homologous recombination.","method":"Systematic E2 screen, accumulation assays at DSB sites, CtIP ubiquitylation assays, HR reporter assays, epistasis with UBE2D family","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multilayered screen with mechanistic follow-up (ubiquitylation assay, recruitment, HR efficiency), independent replication alongside PMID:26502055","pmids":["26502057"],"is_preprint":false},{"year":2016,"finding":"RNF138 physically interacts with RAD51D and ubiquitinates it; the RING finger domain is required for RAD51D ubiquitination. RNF138 depletion increases RAD51D protein stability, suggesting RNF138 governs ubiquitin-proteasome-mediated degradation of RAD51D. RNF138 also enhances the RAD51D–XRCC2 interaction in a yeast three-hybrid assay and is required for RAD51 focus formation and chromosomal stability.","method":"Co-immunoprecipitation, ubiquitination assay, RING domain mutagenesis, yeast three-hybrid, RAD51 focus formation, chromosomal instability assay","journal":"DNA repair","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, in vivo ubiquitination, mutagenesis, and multiple cellular readouts in single lab","pmids":["27161866"],"is_preprint":false},{"year":2016,"finding":"RNF138 is recruited to DNA damage sites via its zinc finger domains, is phosphorylated by ATM at Ser124 (although this phosphorylation is dispensable for damage-site recruitment), and promotes RAD51D recruitment and HR efficiency.","method":"Laser micro-irradiation recruitment assays, ATM phosphorylation site identification and mutagenesis, HR reporter assay, comet assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (recruitment, mutagenesis, HR assay, comet) in single lab","pmids":["27195665"],"is_preprint":false},{"year":2017,"finding":"RNF138 co-immunoprecipitates with CaV2.1 (α1A subunit) and colocalizes at presynaptic and postsynaptic regions in neurons. RNF138 overexpression promotes polyubiquitination and accelerates proteasomal degradation of CaV2.1. Disruption of endogenous RNF138 (dominant-negative H36E mutant or shRNA) upregulates CaV2.1 protein level and stability, and rescues defective expression of EA2-associated loss-of-function CaV2.1 mutants.","method":"Co-immunoprecipitation, subcellular colocalization (immunofluorescence in neurons), ubiquitination assay, RNF138 loss-of-function (dominant-negative + shRNA), protein turnover assay","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, colocalization, ubiquitination assay, dominant-negative mutagenesis, and shRNA knockdown with multiple orthogonal readouts in single rigorous study","pmids":["28167673"],"is_preprint":false},{"year":2018,"finding":"RNF138 ubiquitinates rpS3 in irradiated glioblastoma cells, leading to rpS3 proteasomal degradation. In RNF138-deficient cells, nuclear rpS3 accumulates and interacts with DDIT3, inducing DDIT3-dependent apoptosis. Thus, RNF138-mediated ubiquitination of rpS3 suppresses radiation-induced apoptosis and confers radioresistance.","method":"Ubiquitination assay, RNF138 knockout (ΔRNF138), nuclear fractionation, rpS3 interactome analysis (Co-IP/MS), in vivo orthotopic xenograft model","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo ubiquitination, KO with defined molecular and cellular phenotypes, interactome analysis; single lab","pmids":["29371697"],"is_preprint":false},{"year":2021,"finding":"ASFV pI215L recruits RNF138 and enhances the interaction between RNF138 and RNF128 (GRAIL), promoting RNF138-mediated K48-linked ubiquitination and degradation of RNF128. This reduces K63-linked polyubiquitination of TBK1 and suppresses type I IFN production, revealing RNF138 as a negative regulator of TBK1 K63-ubiquitination in the cGAS-STING pathway.","method":"Co-immunoprecipitation, ubiquitination assay (K48/K63-linked), knockdown, overexpression, IFN-β reporter assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, linkage-specific ubiquitination assays, functional IFN readout; single lab","pmids":["34759016"],"is_preprint":false},{"year":2022,"finding":"RNF138 functions in DNA end resection in G1-phase cells at complex (clustered) DSBs induced by heavy ions or α-particles. RNF138 ubiquitinates CtIP in a radiation-dependent manner to allow CtIP recruitment to DSBs in G1. RNF138 deficiency impairs DSB repair and cell survival specifically at complex DSBs.","method":"Immunofluorescence for RPA, γH2AX, CENP-F, geminin; Fucci cell-cycle reporter; clonogenic survival; RNF138 depletion in G1 cells","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple immunofluorescence markers, clonogenic survival, cell-cycle gating; single lab, single study","pmids":["36010636"],"is_preprint":false},{"year":2023,"finding":"RNF138 mediates K48-linked polyubiquitination of SMARCC1 (a core SWI/SNF complex subunit) at Lys643, leading to its proteasomal degradation. This inhibits chromatin remodeling at SWI/SNF-regulated inflammatory gene loci and fine-tunes kinetics of late inflammatory gene transcription.","method":"Functional screen, Co-immunoprecipitation, ubiquitination assay (K48-specific, site-directed mutagenesis of Lys643), chromatin accessibility/transcription assays, RNF138 KO/OE","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ubiquitination site mutagenesis, Co-IP, proteasome assay, chromatin remodeling readout; multiple orthogonal methods in single rigorous study","pmids":["36800290"],"is_preprint":false},{"year":2023,"finding":"RNF138 promotes ubiquitination of PTEN, which inhibits PTEN's interaction with IRF3 and thereby prevents PTEN-mediated nuclear translocation of IRF3, suppressing IFNB1 transcription and antiviral innate immunity.","method":"Overexpression and KO of RNF138, PTEN ubiquitination assay, Co-immunoprecipitation (PTEN–IRF3 interaction), IFNB1 reporter assay, IRF3 nuclear localization assay","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, nuclear translocation assay, reporter assay; single lab","pmids":["38003298"],"is_preprint":false},{"year":2024,"finding":"RNF138 is phosphorylated at T27 by CDK activity during S and G2 phases, and is constitutively ubiquitylated (partly at K158), with ubiquitylation decreasing upon genotoxic stress. Mutations T27A, K158R, and S124A all impair DNA end resection, HR efficiency, and cell survival after ionizing radiation, establishing that post-translational modifications at all three sites regulate RNF138's role in HR.","method":"Mass spectrometry/phospho-mapping, site-directed mutagenesis, HR reporter assay, resection assay, clonogenic survival, cell-cycle synchronization","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of three sites with multiple functional readouts (resection, HR, survival); single lab","pmids":["38309501"],"is_preprint":false},{"year":2024,"finding":"Pin1 (peptidyl-prolyl isomerase) acts upstream of RNF138 during ER quality control of CaV2.1: Pin1 interacts with phosphorylated Ser/Thr-Pro motifs in the CaV2.1 II-III loop and C-terminus, promotes its polyubiquitination by RNF138, and is required for dominant-negative suppression of CaV2.1 WT by EA2 missense (but not nonsense) mutants.","method":"Co-immunoprecipitation, shRNA knockdown, pharmacological Pin1 inhibition (ATRA), Pin1-insensitive CaV2.1 mutant constructs, ubiquitination assay, protein stability assay","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, mutagenesis, shRNA, pharmacological inhibition, multiple orthogonal readouts; single lab extending prior PMID:28167673","pmids":["39609819"],"is_preprint":false},{"year":2024,"finding":"RNF138 physically associates with multiple regions of Runx2 and ubiquitinates it, leading to proteasome-dependent reduction of Runx2 protein stability. Catalytically inactive RNF138 (lacking the RING domain, Δ18-58) does not destabilize Runx2, and RNF138 depletion enhances endogenous Runx2 levels and osteoblast differentiation.","method":"Co-immunoprecipitation, ubiquitination assay, RING-deletion mutagenesis (RNF138Δ18-58), overexpression/knockdown in C3H10T1/2 and primary rat calvarial osteoblasts, proteasome inhibitor assay, transactivation assay","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, in vivo ubiquitination, RING domain mutagenesis, multiple cell models; single lab","pmids":["38327035"],"is_preprint":false},{"year":2025,"finding":"RNF138 facilitates lysosomal degradation of APC (a component of the β-catenin destruction complex), thereby stabilizing β-catenin and enhancing its nuclear localization to activate Wnt/β-catenin target genes during myoblast differentiation. Rnf138-deficient mice show delayed skeletal muscle regeneration after cardiotoxin injury.","method":"Gene knockdown/knockout in C2C12 and in vivo mouse model, multi-omics (transcriptomics + proteomics), protein turnover assay for APC, immunofluorescence for colocalization and β-catenin localization","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model, multi-omics, protein turnover assay, immunofluorescence; single lab","pmids":["40225576"],"is_preprint":false}],"current_model":"RNF138 is a RING-finger E3 ubiquitin ligase that is recruited to DNA double-strand breaks via its zinc finger domains (with preference for ssDNA overhangs), where it ubiquitylates Ku (promoting its displacement), CtIP (promoting its DSB recruitment), and RAD51D to drive DNA end resection and homologous recombination; its activity at DSBs is regulated by CDK phosphorylation at T27, ATM phosphorylation at S124, and auto-ubiquitylation at K158. Beyond DNA repair, RNF138 ubiquitylates diverse substrates including rpS3, SMARCC1, Runx2, PTEN, RNF128, and CaV2.1 to regulate radiation resistance, inflammatory gene transcription, osteoblast differentiation, antiviral innate immune signaling, and neuronal calcium channel homeostasis respectively; it also promotes Wnt/β-catenin signaling during myogenesis by targeting APC for lysosomal degradation."},"narrative":{"mechanistic_narrative":"RNF138 is a RING-finger E3 ubiquitin ligase best characterized as a regulator of DNA double-strand break (DSB) repair, where it directs the choice between homologous recombination (HR) and non-homologous end joining [PMID:26502055]. It is recruited to break sites through zinc-finger domains that preferentially bind DNA carrying single-stranded overhangs, and once there it ubiquitylates the Ku heterodimer to promote its eviction, thereby favoring HR over NHEJ [PMID:26502055]. Working with UBE2D-family E2 enzymes, RNF138 also ubiquitylates CtIP to drive its accumulation at breaks and stimulate early end resection, including at complex clustered DSBs in G1-phase cells [PMID:26502057, PMID:36010636]. It additionally engages RAD51D, governing its ubiquitin-proteasome turnover, the RAD51D-XRCC2 interaction, RAD51 focus formation, and chromosomal stability [PMID:27161866]. RNF138's repair activity is gated by post-translational modification: CDK phosphorylation at T27, ATM phosphorylation at S124, and constitutive auto-ubiquitylation at K158 are each required for resection, HR efficiency, and radioresistance [PMID:27195665, PMID:38309501]. Beyond DNA repair, RNF138 acts as a broadly deployed degradative ligase, ubiquitylating substrates that include the SWI/SNF subunit SMARCC1 to tune late inflammatory gene transcription [PMID:36800290], Runx2 to restrain osteoblast differentiation [PMID:38327035], the neuronal calcium channel CaV2.1 during ER quality control [PMID:28167673, PMID:39609819], rpS3 to suppress radiation-induced apoptosis [PMID:29371697], and PTEN and RNF128 to dampen antiviral innate immune signaling [PMID:34759016, PMID:38003298]. It further promotes Wnt/β-catenin signaling during myogenesis by routing APC for lysosomal degradation, with loss impairing skeletal muscle regeneration [PMID:40225576].","teleology":[{"year":2015,"claim":"Established RNF138 as a damage-recruited E3 ligase that controls DSB repair pathway choice, answering how Ku is displaced to license HR.","evidence":"Laser-damage recruitment, zinc-finger binding studies, HR reporter assays, and Ku epistasis with RNF138 knockdown/knockout","pmids":["26502055"],"confidence":"High","gaps":["Direct demonstration of Ku ubiquitylation sites not resolved","Stoichiometry of Ku eviction versus resection not defined"]},{"year":2015,"claim":"Identified the E2 partner and a key substrate, showing RNF138 ubiquitylates CtIP with UBE2D enzymes to drive early end resection.","evidence":"Systematic E2 screen, CtIP ubiquitylation and DSB-accumulation assays, HR reporter assays","pmids":["26502057"],"confidence":"High","gaps":["CtIP ubiquitylation linkage type and acceptor sites not mapped","Whether CtIP ubiquitylation is degradative or non-degradative unclear"]},{"year":2016,"claim":"Extended the HR substrate repertoire to RAD51D, linking RNF138 to RAD51 loading and chromosomal stability.","evidence":"Co-IP, in vivo ubiquitination, RING mutagenesis, yeast three-hybrid, RAD51 focus and chromosomal instability assays","pmids":["27161866"],"confidence":"Medium","gaps":["Single-lab; RAD51D ubiquitination sites not mapped","Reconciliation of degradative RAD51D turnover with positive HR role not addressed"]},{"year":2016,"claim":"Began defining upstream regulation by identifying ATM phosphorylation of RNF138 at S124, distinguishing recruitment from activity.","evidence":"Laser micro-irradiation recruitment, ATM phospho-site mutagenesis, HR reporter and comet assays","pmids":["27195665"],"confidence":"Medium","gaps":["Functional consequence of S124 phosphorylation on catalytic activity not fully resolved here","Single-lab study"]},{"year":2017,"claim":"Demonstrated a non-repair role: RNF138 controls neuronal CaV2.1 calcium channel abundance via proteasomal degradation.","evidence":"Co-IP, neuronal colocalization, ubiquitination assay, dominant-negative H36E and shRNA with turnover readouts","pmids":["28167673"],"confidence":"High","gaps":["CaV2.1 ubiquitination acceptor sites not mapped","In vivo neuronal phenotype of RNF138 loss not established"]},{"year":2018,"claim":"Linked RNF138 to radioresistance through rpS3 degradation, defining an anti-apoptotic axis in glioblastoma.","evidence":"Ubiquitination assay, RNF138 KO, nuclear fractionation, rpS3 interactome (Co-IP/MS), orthotopic xenograft","pmids":["29371697"],"confidence":"Medium","gaps":["Relationship between this cytoplasmic/nuclear rpS3 axis and DSB-repair function unclear","Single-lab"]},{"year":2021,"claim":"Placed RNF138 in innate immune control as a negative regulator of TBK1 signaling, hijacked by a viral protein.","evidence":"Co-IP, K48/K63 linkage-specific ubiquitination assays, IFN-β reporter with ASFV pI215L","pmids":["34759016"],"confidence":"Medium","gaps":["Endogenous (virus-independent) role of the RNF138–RNF128 axis not established","Single-lab"]},{"year":2022,"claim":"Showed RNF138 enables CtIP-dependent resection even in G1 at complex clustered DSBs, expanding its cell-cycle window.","evidence":"RPA/γH2AX/CENP-F immunofluorescence, Fucci cell-cycle gating, clonogenic survival after heavy-ion/α-particle damage","pmids":["36010636"],"confidence":"Medium","gaps":["Mechanism restricting this to complex lesions not defined","Single-lab"]},{"year":2023,"claim":"Defined a chromatin/transcriptional role: RNF138 degrades SWI/SNF subunit SMARCC1 to tune inflammatory gene kinetics.","evidence":"Functional screen, Co-IP, K48-specific ubiquitination with Lys643 mutagenesis, chromatin accessibility/transcription assays","pmids":["36800290"],"confidence":"High","gaps":["Signal that triggers SMARCC1 targeting not identified","Breadth of affected SWI/SNF-regulated loci not fully mapped"]},{"year":2023,"claim":"Identified PTEN as a substrate whose ubiquitination blocks PTEN-driven IRF3 nuclear translocation, reinforcing immunosuppressive function.","evidence":"RNF138 OE/KO, PTEN ubiquitination assay, PTEN–IRF3 Co-IP, IFNB1 reporter and IRF3 localization assays","pmids":["38003298"],"confidence":"Medium","gaps":["PTEN ubiquitination sites and linkage type not defined","Single-lab"]},{"year":2024,"claim":"Resolved the post-translational regulatory code of RNF138 in HR, showing T27, S124, and K158 modifications are each functionally required.","evidence":"Phospho-mapping by MS, site-directed mutagenesis (T27A/K158R/S124A), resection/HR/clonogenic assays with cell-cycle synchronization","pmids":["38309501"],"confidence":"Medium","gaps":["Mechanism by which each modification alters catalysis or recruitment not detailed","Single-lab"]},{"year":2024,"claim":"Defined an upstream isomerase partner, Pin1, that primes phosphorylated CaV2.1 for RNF138-mediated degradation in ER quality control.","evidence":"Co-IP, shRNA, Pin1 pharmacological inhibition, Pin1-insensitive CaV2.1 mutants, ubiquitination and stability assays","pmids":["39609819"],"confidence":"Medium","gaps":["Whether Pin1 regulates RNF138 substrates beyond CaV2.1 unknown","Single-lab"]},{"year":2024,"claim":"Established RNF138 as a negative regulator of osteoblast differentiation via degradation of the transcription factor Runx2.","evidence":"Co-IP, in vivo ubiquitination, RING-deletion mutagenesis, knockdown/overexpression in osteoblast models, transactivation assay","pmids":["38327035"],"confidence":"Medium","gaps":["In vivo skeletal phenotype not addressed","Single-lab"]},{"year":2025,"claim":"Connected RNF138 to Wnt/β-catenin signaling and tissue regeneration by routing APC for lysosomal degradation in myogenesis.","evidence":"C2C12 knockdown/knockout, Rnf138 KO mouse with cardiotoxin injury, multi-omics, APC turnover and β-catenin localization assays","pmids":["40225576"],"confidence":"Medium","gaps":["Mechanism of lysosomal versus proteasomal substrate routing unclear","Direct APC ubiquitination not fully resolved"]},{"year":null,"claim":"How a single zinc-finger/RING ligase coordinates its DSB-repair role with its many degradative substrates across distinct compartments, and what determines substrate and degradation-route selection, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking nuclear DNA-repair activity to cytoplasmic/ER and signaling substrates","Determinants of proteasomal versus lysosomal targeting not defined","Ubiquitin linkage and acceptor sites unmapped for most substrates"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,1,2,4,8,12]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2,4,5,8,9,12]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,5,8]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0,1,2,7,10]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,4,5,8,12,13]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[13]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[8]}],"complexes":[],"partners":["CTIP","RAD51D","XRCC2","CACNA1A","SMARCC1","RUNX2","PTEN","APC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WVD3","full_name":"E3 ubiquitin-protein ligase RNF138","aliases":["Nemo-like kinase-associated RING finger protein","NLK-associated RING finger protein","hNARF","RING finger protein 138","RING-type E3 ubiquitin transferase RNF138"],"length_aa":245,"mass_kda":28.2,"function":"E3 ubiquitin-protein ligase involved in DNA damage response by promoting DNA resection and homologous recombination (PubMed:26502055, PubMed:26502057). Recruited to sites of double-strand breaks following DNA damage and specifically promotes double-strand break repair via homologous recombination (PubMed:26502055, PubMed:26502057). Two different, non-exclusive, mechanisms have been proposed. According to a report, regulates the choice of double-strand break repair by favoring homologous recombination over non-homologous end joining (NHEJ): acts by mediating ubiquitination of XRCC5/Ku80, leading to remove the Ku complex from DNA breaks, thereby promoting homologous recombination (PubMed:26502055). According to another report, cooperates with UBE2Ds E2 ubiquitin ligases (UBE2D1, UBE2D2, UBE2D3 or UBE2D4) to promote homologous recombination by mediating ubiquitination of RBBP8/CtIP (PubMed:26502057). Together with NLK, involved in the ubiquitination and degradation of TCF/LEF (PubMed:16714285). Also exhibits auto-ubiquitination activity in combination with UBE2K (PubMed:16714285). May act as a negative regulator in the Wnt/beta-catenin-mediated signaling pathway (PubMed:16714285)","subcellular_location":"Chromosome","url":"https://www.uniprot.org/uniprotkb/Q8WVD3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RNF138","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RNF138","total_profiled":1310},"omim":[{"mim_id":"620036","title":"IMMEDIATE-EARLY RESPONSE GENE 2; IER2","url":"https://www.omim.org/entry/620036"},{"mim_id":"616319","title":"RING FINGER PROTEIN 138; RNF138","url":"https://www.omim.org/entry/616319"},{"mim_id":"616260","title":"TENORIO SYNDROME; TNORS","url":"https://www.omim.org/entry/616260"},{"mim_id":"610432","title":"RING FINGER PROTEIN 125; RNF125","url":"https://www.omim.org/entry/610432"},{"mim_id":"609476","title":"NEMO-LIKE KINASE; NLK","url":"https://www.omim.org/entry/609476"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":90.6},{"tissue":"testis","ntpm":113.0}],"url":"https://www.proteinatlas.org/search/RNF138"},"hgnc":{"alias_symbol":["STRIN","NARF"],"prev_symbol":[]},"alphafold":{"accession":"Q8WVD3","domains":[{"cath_id":"3.30.40.10","chopping":"12-81","consensus_level":"high","plddt":92.8661,"start":12,"end":81},{"cath_id":"-","chopping":"152-240","consensus_level":"medium","plddt":84.4336,"start":152,"end":240}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WVD3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WVD3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WVD3-F1-predicted_aligned_error_v6.png","plddt_mean":78.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RNF138","jax_strain_url":"https://www.jax.org/strain/search?query=RNF138"},"sequence":{"accession":"Q8WVD3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WVD3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WVD3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WVD3"}},"corpus_meta":[{"pmid":"26502055","id":"PMC_26502055","title":"The RNF138 E3 ligase displaces Ku to promote DNA end resection and regulate DNA repair pathway choice.","date":"2015","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/26502055","citation_count":122,"is_preprint":false},{"pmid":"26502057","id":"PMC_26502057","title":"Systematic E2 screening reveals a UBE2D-RNF138-CtIP axis promoting DNA repair.","date":"2015","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/26502057","citation_count":97,"is_preprint":false},{"pmid":"34759016","id":"PMC_34759016","title":"African Swine Fever Virus pI215L Negatively Regulates cGAS-STING Signaling Pathway through Recruiting RNF138 to Inhibit K63-Linked Ubiquitination of TBK1.","date":"2021","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/34759016","citation_count":74,"is_preprint":false},{"pmid":"29371697","id":"PMC_29371697","title":"RNF138-mediated ubiquitination of rpS3 is required for resistance of glioblastoma cells to radiation-induced apoptosis.","date":"2018","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29371697","citation_count":52,"is_preprint":false},{"pmid":"36800290","id":"PMC_36800290","title":"RNF138 inhibits late inflammatory gene transcription through degradation of SMARCC1 of the SWI/SNF complex.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/36800290","citation_count":21,"is_preprint":false},{"pmid":"30260263","id":"PMC_30260263","title":"RNF138 confers cisplatin resistance in gastric cancer cells via activating Chk1 signaling pathway.","date":"2018","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/30260263","citation_count":20,"is_preprint":false},{"pmid":"28518149","id":"PMC_28518149","title":"Rnf138 deficiency promotes apoptosis of spermatogonia in juvenile male mice.","date":"2017","source":"Cell death & 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(Amsterdam)","url":"https://pubmed.ncbi.nlm.nih.gov/22155992","citation_count":17,"is_preprint":false},{"pmid":"33907817","id":"PMC_33907817","title":"Silencing microRNA‑29b‑3p expression protects human trabecular meshwork cells against oxidative injury via upregulation of RNF138 to activate the ERK pathway.","date":"2021","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33907817","citation_count":15,"is_preprint":false},{"pmid":"27195665","id":"PMC_27195665","title":"Ubiquitylation of Rad51d Mediated by E3 Ligase Rnf138 Promotes the Homologous Recombination Repair Pathway.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27195665","citation_count":12,"is_preprint":false},{"pmid":"26515018","id":"PMC_26515018","title":"RNF138 joins the HR team.","date":"2015","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/26515018","citation_count":8,"is_preprint":false},{"pmid":"28167673","id":"PMC_28167673","title":"Ubiquitin Ligase RNF138 Promotes Episodic Ataxia Type 2-Associated Aberrant Degradation of Human Cav2.1 (P/Q-Type) Calcium Channels.","date":"2017","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/28167673","citation_count":7,"is_preprint":false},{"pmid":"38327035","id":"PMC_38327035","title":"RING finger E3 ligase, RNF138 inhibits osteoblast differentiation by negatively regulating Runx2 protein turnover.","date":"2024","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/38327035","citation_count":5,"is_preprint":false},{"pmid":"36010636","id":"PMC_36010636","title":"The Ubiquitin Ligase RNF138 Cooperates with CtIP to Stimulate Resection of Complex DNA Double-Strand Breaks in Human G1-Phase Cells.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36010636","citation_count":5,"is_preprint":false},{"pmid":"38309501","id":"PMC_38309501","title":"The role of RNF138 in DNA end resection is regulated by ubiquitylation and CDK phosphorylation.","date":"2024","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38309501","citation_count":4,"is_preprint":false},{"pmid":"38003298","id":"PMC_38003298","title":"RNF138 Downregulates Antiviral Innate Immunity by Inhibiting IRF3 Activation.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38003298","citation_count":4,"is_preprint":false},{"pmid":"39789198","id":"PMC_39789198","title":"RNF138 contributes to cisplatin resistance in nasopharyngeal carcinoma cells.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39789198","citation_count":2,"is_preprint":false},{"pmid":"40225576","id":"PMC_40225576","title":"RNF138 regulates skeletal muscle differentiation via the Wnt/β-catenin signaling pathway.","date":"2025","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/40225576","citation_count":1,"is_preprint":false},{"pmid":"39609819","id":"PMC_39609819","title":"Pin1 promotes human CaV2.1 channel polyubiquitination by RNF138: pathophysiological implication for episodic ataxia type 2.","date":"2024","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/39609819","citation_count":1,"is_preprint":false},{"pmid":"35616168","id":"PMC_35616168","title":"[Corrigendum] Downregulation of RNF138 inhibits cellular proliferation, migration, invasion and EMT in glioma cells via suppression of the Erk signaling pathway.","date":"2022","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/35616168","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.08.22.24311857","title":"Insulin Resistance Risk in Normal BMI Individuals: Investigating the Role of Genetic Polymorphisms in RNF138, ABCA1, and ESRRG-GPATCH2 Genes - A Case-Control Study in the Indian Population","date":"2024-08-22","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.22.24311857","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13660,"output_tokens":3961,"usd":0.050197,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11672,"output_tokens":4430,"usd":0.084555,"stage2_stop_reason":"end_turn"},"total_usd":0.134752,"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\": 2015,\n      \"finding\": \"RNF138 is recruited to DNA double-strand break (DSB) sites through zinc finger domains that preferentially bind DNA with 5'- or 3'-single-stranded overhangs. RNF138 promotes DNA end resection, ATR-dependent signaling, and DSB repair by homologous recombination (HR). RNF138-dependent ubiquitylation of Ku promotes its removal from DNA breaks, thereby favoring HR over NHEJ.\",\n      \"method\": \"Recruitment assays at laser-induced damage sites, zinc finger domain binding studies, HR reporter assays, epistasis with Ku, RNF138 knockdown/knockout with defined cellular phenotypes\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional assays, domain mapping, multiple orthogonal methods (recruitment, resection, HR efficiency, survival), independently replicated in companion paper (PMID:26502057)\",\n      \"pmids\": [\"26502055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RNF138 functions with UBE2D E2-conjugating enzymes to ubiquitylate CtIP, promoting CtIP accrual at DSB sites and stimulating early DNA end resection for homologous recombination.\",\n      \"method\": \"Systematic E2 screen, accumulation assays at DSB sites, CtIP ubiquitylation assays, HR reporter assays, epistasis with UBE2D family\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multilayered screen with mechanistic follow-up (ubiquitylation assay, recruitment, HR efficiency), independent replication alongside PMID:26502055\",\n      \"pmids\": [\"26502057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RNF138 physically interacts with RAD51D and ubiquitinates it; the RING finger domain is required for RAD51D ubiquitination. RNF138 depletion increases RAD51D protein stability, suggesting RNF138 governs ubiquitin-proteasome-mediated degradation of RAD51D. RNF138 also enhances the RAD51D–XRCC2 interaction in a yeast three-hybrid assay and is required for RAD51 focus formation and chromosomal stability.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, RING domain mutagenesis, yeast three-hybrid, RAD51 focus formation, chromosomal instability assay\",\n      \"journal\": \"DNA repair\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, in vivo ubiquitination, mutagenesis, and multiple cellular readouts in single lab\",\n      \"pmids\": [\"27161866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"RNF138 is recruited to DNA damage sites via its zinc finger domains, is phosphorylated by ATM at Ser124 (although this phosphorylation is dispensable for damage-site recruitment), and promotes RAD51D recruitment and HR efficiency.\",\n      \"method\": \"Laser micro-irradiation recruitment assays, ATM phosphorylation site identification and mutagenesis, HR reporter assay, comet assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (recruitment, mutagenesis, HR assay, comet) in single lab\",\n      \"pmids\": [\"27195665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RNF138 co-immunoprecipitates with CaV2.1 (α1A subunit) and colocalizes at presynaptic and postsynaptic regions in neurons. RNF138 overexpression promotes polyubiquitination and accelerates proteasomal degradation of CaV2.1. Disruption of endogenous RNF138 (dominant-negative H36E mutant or shRNA) upregulates CaV2.1 protein level and stability, and rescues defective expression of EA2-associated loss-of-function CaV2.1 mutants.\",\n      \"method\": \"Co-immunoprecipitation, subcellular colocalization (immunofluorescence in neurons), ubiquitination assay, RNF138 loss-of-function (dominant-negative + shRNA), protein turnover assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, colocalization, ubiquitination assay, dominant-negative mutagenesis, and shRNA knockdown with multiple orthogonal readouts in single rigorous study\",\n      \"pmids\": [\"28167673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RNF138 ubiquitinates rpS3 in irradiated glioblastoma cells, leading to rpS3 proteasomal degradation. In RNF138-deficient cells, nuclear rpS3 accumulates and interacts with DDIT3, inducing DDIT3-dependent apoptosis. Thus, RNF138-mediated ubiquitination of rpS3 suppresses radiation-induced apoptosis and confers radioresistance.\",\n      \"method\": \"Ubiquitination assay, RNF138 knockout (ΔRNF138), nuclear fractionation, rpS3 interactome analysis (Co-IP/MS), in vivo orthotopic xenograft model\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo ubiquitination, KO with defined molecular and cellular phenotypes, interactome analysis; single lab\",\n      \"pmids\": [\"29371697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ASFV pI215L recruits RNF138 and enhances the interaction between RNF138 and RNF128 (GRAIL), promoting RNF138-mediated K48-linked ubiquitination and degradation of RNF128. This reduces K63-linked polyubiquitination of TBK1 and suppresses type I IFN production, revealing RNF138 as a negative regulator of TBK1 K63-ubiquitination in the cGAS-STING pathway.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay (K48/K63-linked), knockdown, overexpression, IFN-β reporter assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, linkage-specific ubiquitination assays, functional IFN readout; single lab\",\n      \"pmids\": [\"34759016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RNF138 functions in DNA end resection in G1-phase cells at complex (clustered) DSBs induced by heavy ions or α-particles. RNF138 ubiquitinates CtIP in a radiation-dependent manner to allow CtIP recruitment to DSBs in G1. RNF138 deficiency impairs DSB repair and cell survival specifically at complex DSBs.\",\n      \"method\": \"Immunofluorescence for RPA, γH2AX, CENP-F, geminin; Fucci cell-cycle reporter; clonogenic survival; RNF138 depletion in G1 cells\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple immunofluorescence markers, clonogenic survival, cell-cycle gating; single lab, single study\",\n      \"pmids\": [\"36010636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RNF138 mediates K48-linked polyubiquitination of SMARCC1 (a core SWI/SNF complex subunit) at Lys643, leading to its proteasomal degradation. This inhibits chromatin remodeling at SWI/SNF-regulated inflammatory gene loci and fine-tunes kinetics of late inflammatory gene transcription.\",\n      \"method\": \"Functional screen, Co-immunoprecipitation, ubiquitination assay (K48-specific, site-directed mutagenesis of Lys643), chromatin accessibility/transcription assays, RNF138 KO/OE\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ubiquitination site mutagenesis, Co-IP, proteasome assay, chromatin remodeling readout; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"36800290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RNF138 promotes ubiquitination of PTEN, which inhibits PTEN's interaction with IRF3 and thereby prevents PTEN-mediated nuclear translocation of IRF3, suppressing IFNB1 transcription and antiviral innate immunity.\",\n      \"method\": \"Overexpression and KO of RNF138, PTEN ubiquitination assay, Co-immunoprecipitation (PTEN–IRF3 interaction), IFNB1 reporter assay, IRF3 nuclear localization assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, nuclear translocation assay, reporter assay; single lab\",\n      \"pmids\": [\"38003298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RNF138 is phosphorylated at T27 by CDK activity during S and G2 phases, and is constitutively ubiquitylated (partly at K158), with ubiquitylation decreasing upon genotoxic stress. Mutations T27A, K158R, and S124A all impair DNA end resection, HR efficiency, and cell survival after ionizing radiation, establishing that post-translational modifications at all three sites regulate RNF138's role in HR.\",\n      \"method\": \"Mass spectrometry/phospho-mapping, site-directed mutagenesis, HR reporter assay, resection assay, clonogenic survival, cell-cycle synchronization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of three sites with multiple functional readouts (resection, HR, survival); single lab\",\n      \"pmids\": [\"38309501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Pin1 (peptidyl-prolyl isomerase) acts upstream of RNF138 during ER quality control of CaV2.1: Pin1 interacts with phosphorylated Ser/Thr-Pro motifs in the CaV2.1 II-III loop and C-terminus, promotes its polyubiquitination by RNF138, and is required for dominant-negative suppression of CaV2.1 WT by EA2 missense (but not nonsense) mutants.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown, pharmacological Pin1 inhibition (ATRA), Pin1-insensitive CaV2.1 mutant constructs, ubiquitination assay, protein stability assay\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, mutagenesis, shRNA, pharmacological inhibition, multiple orthogonal readouts; single lab extending prior PMID:28167673\",\n      \"pmids\": [\"39609819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RNF138 physically associates with multiple regions of Runx2 and ubiquitinates it, leading to proteasome-dependent reduction of Runx2 protein stability. Catalytically inactive RNF138 (lacking the RING domain, Δ18-58) does not destabilize Runx2, and RNF138 depletion enhances endogenous Runx2 levels and osteoblast differentiation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, RING-deletion mutagenesis (RNF138Δ18-58), overexpression/knockdown in C3H10T1/2 and primary rat calvarial osteoblasts, proteasome inhibitor assay, transactivation assay\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, in vivo ubiquitination, RING domain mutagenesis, multiple cell models; single lab\",\n      \"pmids\": [\"38327035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RNF138 facilitates lysosomal degradation of APC (a component of the β-catenin destruction complex), thereby stabilizing β-catenin and enhancing its nuclear localization to activate Wnt/β-catenin target genes during myoblast differentiation. Rnf138-deficient mice show delayed skeletal muscle regeneration after cardiotoxin injury.\",\n      \"method\": \"Gene knockdown/knockout in C2C12 and in vivo mouse model, multi-omics (transcriptomics + proteomics), protein turnover assay for APC, immunofluorescence for colocalization and β-catenin localization\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model, multi-omics, protein turnover assay, immunofluorescence; single lab\",\n      \"pmids\": [\"40225576\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RNF138 is a RING-finger E3 ubiquitin ligase that is recruited to DNA double-strand breaks via its zinc finger domains (with preference for ssDNA overhangs), where it ubiquitylates Ku (promoting its displacement), CtIP (promoting its DSB recruitment), and RAD51D to drive DNA end resection and homologous recombination; its activity at DSBs is regulated by CDK phosphorylation at T27, ATM phosphorylation at S124, and auto-ubiquitylation at K158. Beyond DNA repair, RNF138 ubiquitylates diverse substrates including rpS3, SMARCC1, Runx2, PTEN, RNF128, and CaV2.1 to regulate radiation resistance, inflammatory gene transcription, osteoblast differentiation, antiviral innate immune signaling, and neuronal calcium channel homeostasis respectively; it also promotes Wnt/β-catenin signaling during myogenesis by targeting APC for lysosomal degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RNF138 is a RING-finger E3 ubiquitin ligase best characterized as a regulator of DNA double-strand break (DSB) repair, where it directs the choice between homologous recombination (HR) and non-homologous end joining [#0]. It is recruited to break sites through zinc-finger domains that preferentially bind DNA carrying single-stranded overhangs, and once there it ubiquitylates the Ku heterodimer to promote its eviction, thereby favoring HR over NHEJ [#0]. Working with UBE2D-family E2 enzymes, RNF138 also ubiquitylates CtIP to drive its accumulation at breaks and stimulate early end resection, including at complex clustered DSBs in G1-phase cells [#1, #7]. It additionally engages RAD51D, governing its ubiquitin-proteasome turnover, the RAD51D-XRCC2 interaction, RAD51 focus formation, and chromosomal stability [#2]. RNF138's repair activity is gated by post-translational modification: CDK phosphorylation at T27, ATM phosphorylation at S124, and constitutive auto-ubiquitylation at K158 are each required for resection, HR efficiency, and radioresistance [#3, #10]. Beyond DNA repair, RNF138 acts as a broadly deployed degradative ligase, ubiquitylating substrates that include the SWI/SNF subunit SMARCC1 to tune late inflammatory gene transcription [#8], Runx2 to restrain osteoblast differentiation [#12], the neuronal calcium channel CaV2.1 during ER quality control [#4, #11], rpS3 to suppress radiation-induced apoptosis [#5], and PTEN and RNF128 to dampen antiviral innate immune signaling [#6, #9]. It further promotes Wnt/\\u03b2-catenin signaling during myogenesis by routing APC for lysosomal degradation, with loss impairing skeletal muscle regeneration [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established RNF138 as a damage-recruited E3 ligase that controls DSB repair pathway choice, answering how Ku is displaced to license HR.\",\n      \"evidence\": \"Laser-damage recruitment, zinc-finger binding studies, HR reporter assays, and Ku epistasis with RNF138 knockdown/knockout\",\n      \"pmids\": [\"26502055\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration of Ku ubiquitylation sites not resolved\", \"Stoichiometry of Ku eviction versus resection not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified the E2 partner and a key substrate, showing RNF138 ubiquitylates CtIP with UBE2D enzymes to drive early end resection.\",\n      \"evidence\": \"Systematic E2 screen, CtIP ubiquitylation and DSB-accumulation assays, HR reporter assays\",\n      \"pmids\": [\"26502057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CtIP ubiquitylation linkage type and acceptor sites not mapped\", \"Whether CtIP ubiquitylation is degradative or non-degradative unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended the HR substrate repertoire to RAD51D, linking RNF138 to RAD51 loading and chromosomal stability.\",\n      \"evidence\": \"Co-IP, in vivo ubiquitination, RING mutagenesis, yeast three-hybrid, RAD51 focus and chromosomal instability assays\",\n      \"pmids\": [\"27161866\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab; RAD51D ubiquitination sites not mapped\", \"Reconciliation of degradative RAD51D turnover with positive HR role not addressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Began defining upstream regulation by identifying ATM phosphorylation of RNF138 at S124, distinguishing recruitment from activity.\",\n      \"evidence\": \"Laser micro-irradiation recruitment, ATM phospho-site mutagenesis, HR reporter and comet assays\",\n      \"pmids\": [\"27195665\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of S124 phosphorylation on catalytic activity not fully resolved here\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated a non-repair role: RNF138 controls neuronal CaV2.1 calcium channel abundance via proteasomal degradation.\",\n      \"evidence\": \"Co-IP, neuronal colocalization, ubiquitination assay, dominant-negative H36E and shRNA with turnover readouts\",\n      \"pmids\": [\"28167673\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CaV2.1 ubiquitination acceptor sites not mapped\", \"In vivo neuronal phenotype of RNF138 loss not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked RNF138 to radioresistance through rpS3 degradation, defining an anti-apoptotic axis in glioblastoma.\",\n      \"evidence\": \"Ubiquitination assay, RNF138 KO, nuclear fractionation, rpS3 interactome (Co-IP/MS), orthotopic xenograft\",\n      \"pmids\": [\"29371697\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship between this cytoplasmic/nuclear rpS3 axis and DSB-repair function unclear\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed RNF138 in innate immune control as a negative regulator of TBK1 signaling, hijacked by a viral protein.\",\n      \"evidence\": \"Co-IP, K48/K63 linkage-specific ubiquitination assays, IFN-\\u03b2 reporter with ASFV pI215L\",\n      \"pmids\": [\"34759016\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous (virus-independent) role of the RNF138\\u2013RNF128 axis not established\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed RNF138 enables CtIP-dependent resection even in G1 at complex clustered DSBs, expanding its cell-cycle window.\",\n      \"evidence\": \"RPA/\\u03b3H2AX/CENP-F immunofluorescence, Fucci cell-cycle gating, clonogenic survival after heavy-ion/\\u03b1-particle damage\",\n      \"pmids\": [\"36010636\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism restricting this to complex lesions not defined\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a chromatin/transcriptional role: RNF138 degrades SWI/SNF subunit SMARCC1 to tune inflammatory gene kinetics.\",\n      \"evidence\": \"Functional screen, Co-IP, K48-specific ubiquitination with Lys643 mutagenesis, chromatin accessibility/transcription assays\",\n      \"pmids\": [\"36800290\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal that triggers SMARCC1 targeting not identified\", \"Breadth of affected SWI/SNF-regulated loci not fully mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified PTEN as a substrate whose ubiquitination blocks PTEN-driven IRF3 nuclear translocation, reinforcing immunosuppressive function.\",\n      \"evidence\": \"RNF138 OE/KO, PTEN ubiquitination assay, PTEN\\u2013IRF3 Co-IP, IFNB1 reporter and IRF3 localization assays\",\n      \"pmids\": [\"38003298\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PTEN ubiquitination sites and linkage type not defined\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved the post-translational regulatory code of RNF138 in HR, showing T27, S124, and K158 modifications are each functionally required.\",\n      \"evidence\": \"Phospho-mapping by MS, site-directed mutagenesis (T27A/K158R/S124A), resection/HR/clonogenic assays with cell-cycle synchronization\",\n      \"pmids\": [\"38309501\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which each modification alters catalysis or recruitment not detailed\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined an upstream isomerase partner, Pin1, that primes phosphorylated CaV2.1 for RNF138-mediated degradation in ER quality control.\",\n      \"evidence\": \"Co-IP, shRNA, Pin1 pharmacological inhibition, Pin1-insensitive CaV2.1 mutants, ubiquitination and stability assays\",\n      \"pmids\": [\"39609819\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Pin1 regulates RNF138 substrates beyond CaV2.1 unknown\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established RNF138 as a negative regulator of osteoblast differentiation via degradation of the transcription factor Runx2.\",\n      \"evidence\": \"Co-IP, in vivo ubiquitination, RING-deletion mutagenesis, knockdown/overexpression in osteoblast models, transactivation assay\",\n      \"pmids\": [\"38327035\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo skeletal phenotype not addressed\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected RNF138 to Wnt/\\u03b2-catenin signaling and tissue regeneration by routing APC for lysosomal degradation in myogenesis.\",\n      \"evidence\": \"C2C12 knockdown/knockout, Rnf138 KO mouse with cardiotoxin injury, multi-omics, APC turnover and \\u03b2-catenin localization assays\",\n      \"pmids\": [\"40225576\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of lysosomal versus proteasomal substrate routing unclear\", \"Direct APC ubiquitination not fully resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single zinc-finger/RING ligase coordinates its DSB-repair role with its many degradative substrates across distinct compartments, and what determines substrate and degradation-route selection, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking nuclear DNA-repair activity to cytoplasmic/ER and signaling substrates\", \"Determinants of proteasomal versus lysosomal targeting not defined\", \"Ubiquitin linkage and acceptor sites unmapped for most substrates\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 1, 2, 4, 8, 12]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 4, 5, 8, 9, 12]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 5, 8]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 1, 2, 7, 10]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 4, 5, 8, 12, 13]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CtIP\", \"RAD51D\", \"XRCC2\", \"CACNA1A\", \"SMARCC1\", \"RUNX2\", \"PTEN\", \"APC\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}