Affinage

RNF138

E3 ubiquitin-protein ligase RNF138 · UniProt Q8WVD3

Length
245 aa
Mass
28.2 kDa
Annotated
2026-06-10
22 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2015 High

    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

    PMID:26502055

    Open questions at the time
    • Direct demonstration of Ku ubiquitylation sites not resolved
    • Stoichiometry of Ku eviction versus resection not defined
  2. 2015 High

    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

    PMID:26502057

    Open questions at the time
    • CtIP ubiquitylation linkage type and acceptor sites not mapped
    • Whether CtIP ubiquitylation is degradative or non-degradative unclear
  3. 2016 Medium

    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

    PMID:27161866

    Open questions at the time
    • Single-lab; RAD51D ubiquitination sites not mapped
    • Reconciliation of degradative RAD51D turnover with positive HR role not addressed
  4. 2016 Medium

    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

    PMID:27195665

    Open questions at the time
    • Functional consequence of S124 phosphorylation on catalytic activity not fully resolved here
    • Single-lab study
  5. 2017 High

    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

    PMID:28167673

    Open questions at the time
    • CaV2.1 ubiquitination acceptor sites not mapped
    • In vivo neuronal phenotype of RNF138 loss not established
  6. 2018 Medium

    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

    PMID:29371697

    Open questions at the time
    • Relationship between this cytoplasmic/nuclear rpS3 axis and DSB-repair function unclear
    • Single-lab
  7. 2021 Medium

    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

    PMID:34759016

    Open questions at the time
    • Endogenous (virus-independent) role of the RNF138–RNF128 axis not established
    • Single-lab
  8. 2022 Medium

    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

    PMID:36010636

    Open questions at the time
    • Mechanism restricting this to complex lesions not defined
    • Single-lab
  9. 2023 High

    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

    PMID:36800290

    Open questions at the time
    • Signal that triggers SMARCC1 targeting not identified
    • Breadth of affected SWI/SNF-regulated loci not fully mapped
  10. 2023 Medium

    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

    PMID:38003298

    Open questions at the time
    • PTEN ubiquitination sites and linkage type not defined
    • Single-lab
  11. 2024 Medium

    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

    PMID:38309501

    Open questions at the time
    • Mechanism by which each modification alters catalysis or recruitment not detailed
    • Single-lab
  12. 2024 Medium

    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

    PMID:39609819

    Open questions at the time
    • Whether Pin1 regulates RNF138 substrates beyond CaV2.1 unknown
    • Single-lab
  13. 2024 Medium

    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

    PMID:38327035

    Open questions at the time
    • In vivo skeletal phenotype not addressed
    • Single-lab
  14. 2025 Medium

    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

    PMID:40225576

    Open questions at the time
    • Mechanism of lysosomal versus proteasomal substrate routing unclear
    • Direct APC ubiquitination not fully resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016874 ligase activity 6 GO:0003677 DNA binding 1
Localization
GO:0005634 nucleus 3 GO:0005783 endoplasmic reticulum 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-392499 Metabolism of proteins 6 R-HSA-73894 DNA Repair 5 R-HSA-168256 Immune System 2 R-HSA-162582 Signal Transduction 1 R-HSA-4839726 Chromatin organization 1
Partners
APCCACNA1ACTIPPTENRAD51DRUNX2SMARCC1XRCC2

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 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. 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 Nature cell biology High 26502055
2015 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. Systematic E2 screen, accumulation assays at DSB sites, CtIP ubiquitylation assays, HR reporter assays, epistasis with UBE2D family Nature cell biology High 26502057
2016 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. Co-immunoprecipitation, ubiquitination assay, RING domain mutagenesis, yeast three-hybrid, RAD51 focus formation, chromosomal instability assay DNA repair Medium 27161866
2016 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. Laser micro-irradiation recruitment assays, ATM phosphorylation site identification and mutagenesis, HR reporter assay, comet assay PloS one Medium 27195665
2017 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. Co-immunoprecipitation, subcellular colocalization (immunofluorescence in neurons), ubiquitination assay, RNF138 loss-of-function (dominant-negative + shRNA), protein turnover assay The Journal of neuroscience High 28167673
2018 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. Ubiquitination assay, RNF138 knockout (ΔRNF138), nuclear fractionation, rpS3 interactome analysis (Co-IP/MS), in vivo orthotopic xenograft model Experimental & molecular medicine Medium 29371697
2021 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. Co-immunoprecipitation, ubiquitination assay (K48/K63-linked), knockdown, overexpression, IFN-β reporter assay Journal of immunology Medium 34759016
2022 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. Immunofluorescence for RPA, γH2AX, CENP-F, geminin; Fucci cell-cycle reporter; clonogenic survival; RNF138 depletion in G1 cells Cells Medium 36010636
2023 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. Functional screen, Co-immunoprecipitation, ubiquitination assay (K48-specific, site-directed mutagenesis of Lys643), chromatin accessibility/transcription assays, RNF138 KO/OE Cell reports High 36800290
2023 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. Overexpression and KO of RNF138, PTEN ubiquitination assay, Co-immunoprecipitation (PTEN–IRF3 interaction), IFNB1 reporter assay, IRF3 nuclear localization assay International journal of molecular sciences Medium 38003298
2024 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. Mass spectrometry/phospho-mapping, site-directed mutagenesis, HR reporter assay, resection assay, clonogenic survival, cell-cycle synchronization The Journal of biological chemistry Medium 38309501
2024 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. Co-immunoprecipitation, shRNA knockdown, pharmacological Pin1 inhibition (ATRA), Pin1-insensitive CaV2.1 mutant constructs, ubiquitination assay, protein stability assay Cell communication and signaling Medium 39609819
2024 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. 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 of cellular physiology Medium 38327035
2025 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. 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 Theranostics Medium 40225576

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 The RNF138 E3 ligase displaces Ku to promote DNA end resection and regulate DNA repair pathway choice. Nature cell biology 122 26502055
2015 Systematic E2 screening reveals a UBE2D-RNF138-CtIP axis promoting DNA repair. Nature cell biology 97 26502057
2021 African Swine Fever Virus pI215L Negatively Regulates cGAS-STING Signaling Pathway through Recruiting RNF138 to Inhibit K63-Linked Ubiquitination of TBK1. Journal of immunology (Baltimore, Md. : 1950) 74 34759016
2018 RNF138-mediated ubiquitination of rpS3 is required for resistance of glioblastoma cells to radiation-induced apoptosis. Experimental & molecular medicine 52 29371697
2023 RNF138 inhibits late inflammatory gene transcription through degradation of SMARCC1 of the SWI/SNF complex. Cell reports 21 36800290
2018 RNF138 confers cisplatin resistance in gastric cancer cells via activating Chk1 signaling pathway. Cancer biology & therapy 20 30260263
2018 Downregulation of RNF138 inhibits cellular proliferation, migration, invasion and EMT in glioma cells via suppression of the Erk signaling pathway. Oncology reports 20 30272353
2017 Rnf138 deficiency promotes apoptosis of spermatogonia in juvenile male mice. Cell death & disease 20 28518149
2016 RNF138 interacts with RAD51D and is required for DNA interstrand crosslink repair and maintaining chromosome integrity. DNA repair 17 27161866
2012 A novel gene RNF138 expressed in human gliomas and its function in the glioma cell line U251. Analytical cellular pathology (Amsterdam) 17 22155992
2021 Silencing microRNA‑29b‑3p expression protects human trabecular meshwork cells against oxidative injury via upregulation of RNF138 to activate the ERK pathway. International journal of molecular medicine 15 33907817
2016 Ubiquitylation of Rad51d Mediated by E3 Ligase Rnf138 Promotes the Homologous Recombination Repair Pathway. PloS one 12 27195665
2015 RNF138 joins the HR team. Nature cell biology 8 26515018
2017 Ubiquitin Ligase RNF138 Promotes Episodic Ataxia Type 2-Associated Aberrant Degradation of Human Cav2.1 (P/Q-Type) Calcium Channels. The Journal of neuroscience : the official journal of the Society for Neuroscience 7 28167673
2024 RING finger E3 ligase, RNF138 inhibits osteoblast differentiation by negatively regulating Runx2 protein turnover. Journal of cellular physiology 5 38327035
2022 The Ubiquitin Ligase RNF138 Cooperates with CtIP to Stimulate Resection of Complex DNA Double-Strand Breaks in Human G1-Phase Cells. Cells 5 36010636
2024 The role of RNF138 in DNA end resection is regulated by ubiquitylation and CDK phosphorylation. The Journal of biological chemistry 4 38309501
2023 RNF138 Downregulates Antiviral Innate Immunity by Inhibiting IRF3 Activation. International journal of molecular sciences 4 38003298
2025 RNF138 contributes to cisplatin resistance in nasopharyngeal carcinoma cells. Scientific reports 2 39789198
2025 RNF138 regulates skeletal muscle differentiation via the Wnt/β-catenin signaling pathway. Theranostics 1 40225576
2024 Pin1 promotes human CaV2.1 channel polyubiquitination by RNF138: pathophysiological implication for episodic ataxia type 2. Cell communication and signaling : CCS 1 39609819
2022 [Corrigendum] Downregulation of RNF138 inhibits cellular proliferation, migration, invasion and EMT in glioma cells via suppression of the Erk signaling pathway. Oncology reports 1 35616168

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