Affinage

RNF4

E3 ubiquitin-protein ligase RNF4 · UniProt P78317

Length
190 aa
Mass
21.3 kDa
Annotated
2026-06-10
100 papers in source corpus 52 papers cited in narrative 52 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RNF4 is a SUMO-targeted ubiquitin E3 ligase (STUbL) that couples SUMO signaling to ubiquitin-dependent proteasomal degradation, governing genome stability at sites of DNA damage, replication forks, and nuclear bodies (PMID:18408734, PMID:17762864). It recognizes poly- or multi-SUMOylated substrates through its intrinsically disordered N-terminal tandem SUMO-interaction motifs, in which SIM2/SIM3 form the high-affinity core and SIM4 adds avidity for poly-SUMO2 chains arranged antiparallel along the chain (PMID:24844634), then catalyzes ubiquitin transfer from E2 enzymes — most efficiently UbcH5 — to mark substrates with K48-linked chains (PMID:18408734, PMID:14987998). RNF4 is an obligate dimeric RING ligase: at physiological concentration it is monomeric and inactive, and binding of poly-SUMO chains induces dimerization that activates catalysis and also drives autoubiquitylation and self-degradation (PMID:24656128, PMID:31048496); dimerization positions the donor ubiquitin across the dimer interface to license transfer, and the affinity of the E2~Ub for the RING dictates whether substrates are mono- or polyubiquitinated (PMID:21857666, PMID:27678051). The canonical paradigm is arsenic-induced degradation of SUMOylated PML/PML-RARα, where RNF4 is recruited to nuclear bodies via its SIMs to ubiquitinate SUMO-modified PML and drive proteasomal clearance underlying therapeutic differentiation (PMID:18408733, PMID:20943951). At double-strand breaks RNF4 is recruited downstream of the SUMO ligases PIAS1/PIAS4 and the DSB machinery and turns over SUMOylated MDC1, RPA, and BRCA1 to enable end resection and RAD51 loading, and it builds hybrid SUMO-ubiquitin chains read by RAP80 to recruit BRCA1, thereby controlling repair pathway choice and supporting both HR and NHEJ (PMID:22661229, PMID:23211528, PMID:23197296). At replication forks RNF4 sustains fork stability and restart by degrading SUMOylated TOP2A, BLM, and chromatin-trapped factors and by enabling ATR-CHK1 signaling (PMID:35640614, PMID:34868226, PMID:38530355), and it clears SUMOylated DNA-protein crosslinks to permit faithful chromosome segregation (PMID:34346517, PMID:25205350). RNF4 substrate selection is further tuned by an arginine-rich motif that reads phosphorylated substrates such as KAP1 (PMID:24907272), and its activity is modulated by CDK2 phosphorylation and PRMT5 methylation (PMID:25948581, PMID:35622143). Beyond degradation, RNF4 acts as a transcriptional coactivator and can generate non-degradative ubiquitin chains that stabilize substrates (PMID:27653698, PMID:10713105).

Mechanistic history

Synthesis pass · year-by-year structured walk · 23 steps
  1. 2004 High

    Established that RNF4 is itself a catalytically active RING ubiquitin ligase, defining the enzymatic core before its SUMO-targeting role was known.

    Evidence In vitro autoubiquitination with a panel of E2 enzymes and RING cysteine mutagenesis

    PMID:14987998

    Open questions at the time
    • Physiological substrates not identified at this stage
    • SUMO dependence not yet appreciated
  2. 2007 High

    Linked SUMO recognition to ubiquitin conjugation, defining the STUbL concept conserved from yeast to mammals.

    Evidence In vitro ubiquitination of SUMO-containing substrates and genetic complementation of S. pombe slx8/rfp mutants

    PMID:17762864

    Open questions at the time
    • Endogenous mammalian substrates not characterized
    • Dimerization requirement not yet defined
  3. 2008 High

    Identified the first physiological STUbL substrate, PML, and connected RNF4 to arsenic therapy of acute promyelocytic leukemia.

    Evidence In vitro SUMO-dependent ubiquitination of PML, siRNA depletion, and dominant-negative RNF4 in differentiation assays (two simultaneous papers)

    PMID:18408733 PMID:18408734

    Open questions at the time
    • Whether RNF4 binds PML directly or only SUMO unresolved at this point
    • Chain topology on PML not defined
  4. 2010 High

    Resolved that RNF4 engages SUMO rather than PML directly in nuclear bodies, clarifying the recruitment mechanism.

    Evidence FRET, FRAP, and live-cell imaging of RNF4-SUMO interaction in arsenic-induced PML bodies

    PMID:20943951

    Open questions at the time
    • Kinetics of recruitment versus degradation incompletely mapped
  5. 2010 High

    Defined the catalytic logic of RNF4 as requiring RING dimerization for ubiquitin transfer.

    Evidence Biochemical dimerization and in vitro ubiquitin transfer assays with mutagenesis

    PMID:20681948

    Open questions at the time
    • Whether dimerization is constitutive or regulated not addressed here
  6. 2011 High

    Provided the structural basis for how RNF4 dimers actively catalyze ubiquitin transfer across the dimer interface.

    Evidence Crystal structure with E2~Ub, SPR binding, and interface mutagenesis

    PMID:21857666

    Open questions at the time
    • Full-length enzyme with SIMs and substrate not crystallized
    • Substrate positioning during transfer not visualized
  7. 2012 High

    Placed RNF4 in the DNA double-strand break response as a SUMO-dependent regulator of MDC1, RPA, and resection-driven repair pathway choice.

    Evidence siRNA/DT40 knockout, SILAC proteomics identifying SUMOylated MDC1, laser micro-irradiation, and survival assays (two papers)

    PMID:22661229 PMID:22661230

    Open questions at the time
    • Precise ordering of RNF4 within the SUMO/ubiquitin DSB cascade
    • Which substrate dominates the phenotype
  8. 2012 High

    Showed RNF4 builds hybrid SUMO-ubiquitin chains that serve as a recognition signal, mechanistically linking SUMO and ubiquitin signaling at breaks.

    Evidence In vitro hybrid chain synthesis, SPR with RAP80, and BRCA1 recruitment assays

    PMID:23211528

    Open questions at the time
    • In vivo abundance and topology of hybrid chains not quantified
  9. 2012 High

    Demonstrated RNF4 is required in vivo for both HR and NHEJ and for organismal genome maintenance.

    Evidence Rnf4 knockout mouse allelic series, Co-IP of SUMOylated MDC1/BRCA1, and repair reporter assays

    PMID:23197296

    Open questions at the time
    • Tissue-specific requirements only partly explored
    • Separation of HR vs NHEJ contributions
  10. 2014 High

    Established that RNF4 activation is substrate-induced — poly-SUMO chains trigger dimerization, coupling enzyme activation to the presence of its signal.

    Evidence Concentration-defined in vitro ubiquitination, AUC/SEC, and SENP6 ablation in cells

    PMID:24656128

    Open questions at the time
    • In-cell concentration and local SUMO thresholds for activation not measured
  11. 2014 High

    Defined the molecular architecture of SUMO chain recognition by the tandem SIM module.

    Evidence NMR, SAXS, ITC, and HADDOCK docking of the tetra-SUMO2-SIM complex

    PMID:24844634

    Open questions at the time
    • Coupling of SIM engagement to RING activation not structurally resolved
  12. 2014 Medium

    Revealed a second substrate-recognition mode in which an arginine-rich motif reads phosphorylated substrates alongside the SIM reading SUMO.

    Evidence ARM/SIM mutagenesis, Co-IP, BiFC, and ubiquitination of KAP1

    PMID:24907272

    Open questions at the time
    • Generality of ARM-dependent phospho-recognition across substrates
    • Structural basis of ARM-phosphosite contact
  13. 2014 High

    Showed RNF4 can directly target nucleosomal histones via a DNA-binding motif in its RING, extending its action to chromatin at dysfunctional telomeres.

    Evidence In vitro nucleosome ubiquitination, SAXS, mutagenesis, and telomere dysfunction rescue

    PMID:24714598

    Open questions at the time
    • Genome-wide extent of nucleosome ubiquitination unknown
  14. 2014 Medium

    Connected RNF4 to chromosome segregation fidelity beyond repair, implicating it in the spindle assembly checkpoint and ploidy maintenance.

    Evidence DT40 RNF4 knockout with cytogenetics and live-cell imaging of segregation

    PMID:25205350

    Open questions at the time
    • Relevant mitotic SUMO substrate not identified
    • Mechanism of checkpoint defect unclear
  15. 2015 Medium

    Identified upstream regulation of RNF4 by CDK2 phosphorylation that tunes its S-phase repair activity.

    Evidence In vitro kinase assays, phospho-site mutagenesis, and HR reporter assays

    PMID:25948581

    Open questions at the time
    • In vivo stoichiometry of phosphorylation not established
    • Mechanism of activity enhancement unresolved
  16. 2016 High

    Defined how E2 identity determines chain output, explaining mono- versus polyubiquitination of SUMO substrates.

    Evidence In vitro ubiquitination with E2 affinity mutants (RAD6B vs UBCH5B)

    PMID:27678051

    Open questions at the time
    • Which E2 dominates at which substrates in cells not defined
  17. 2016 Medium

    Expanded RNF4 function to non-degradative outcomes, showing it can stabilize phospho-dependent oncogenic transcription factors via the ARM.

    Evidence Co-IP, ubiquitination, reporter assays, and ARM mutagenesis for beta-catenin/Myc/c-Jun/N-ICD

    PMID:27653698

    Open questions at the time
    • Chain topology of stabilizing ubiquitin not defined
    • Reconciliation with degradative role context-dependent
  18. 2019 Medium

    Generalized the obligate-dimer model, explaining why dimeric RINGs lack the activity-limiting tryptophan of monomeric RINGs.

    Evidence In vitro reconstitution with a tryptophan-insertion mutant rescuing monomeric RNF4

    PMID:31048496

    Open questions at the time
    • In-cell relevance of engineered monomer activity not tested
  19. 2019 Medium

    Demonstrated the RING domain can be chemically hijacked, validating RNF4 as a recruitable ligase for targeted protein degradation.

    Evidence Covalent ligand (CCW 28-3) targeting C132/C135 in a JQ1-linked degrader against BRD4

    PMID:31059647

    Open questions at the time
    • Selectivity and broader substrate scope of covalent recruiter not established
  20. 2021 Medium

    Defined RNF4 as a replication-independent salvage pathway for clearing SUMOylated DNA-protein crosslinks required for faithful mitosis.

    Evidence Cell-based DPC quantification, RNF4 depletion/knockout, and segregation assays with epistasis

    PMID:34346517

    Open questions at the time
    • Relative contribution versus replication-coupled DPC repair in vivo
    • Downstream protease/p97 coupling only partly defined
  21. 2022 Medium

    Placed RNF4 in replication fork dynamics by showing it limits fork reversal through SUMOylated TOP2A turnover.

    Evidence DNA fiber, PLA, Co-IP, and ubiquitination assays linking RNF4 to the ZATT-TOP2A-PICH axis

    PMID:35640614

    Open questions at the time
    • Direct demonstration of TOP2A degradation kinetics at forks limited
  22. 2024 High

    Showed RNF4 is required for normal replication and ATR-CHK1 signaling, with hyper-SUMOylated SMC5/6 accumulation driving failure and tumor-suppressive consequences.

    Evidence Conditional knockout mouse, iPOND, DNA fiber, PLA, and RAD51 epistasis

    PMID:38530355

    Open questions at the time
    • Which SUMO substrate dominates the replication phenotype not fully resolved
  23. 2024 High

    Identified a complementary SUMO1-selective STUbL, TOPORS, that is synthetic lethal with RNF4, defining the broader STUbL network for clearing SUMOylated chromatin proteins.

    Evidence Genome-scale screens, in vitro ubiquitination, p97/VCP coupling, and viability assays

    PMID:38649616

    Open questions at the time
    • Division of labor between RNF4 and TOPORS at individual substrates not fully mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RNF4 substrate selectivity, chain topology, and degradative versus non-degradative or stabilizing outcomes are integrated across the many reported substrates and regulatory inputs remains unresolved.
  • No unified model linking SIM/ARM occupancy to chain type and substrate fate
  • In-cell hierarchy among DSB, fork, DPC, and transcriptional roles undefined
  • Quantitative rules governing which substrate is targeted under a given signal lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 5 GO:0140096 catalytic activity, acting on a protein 4 GO:0016874 ligase activity 3 GO:0140110 transcription regulator activity 3 GO:0098772 molecular function regulator activity 2 GO:0003677 DNA binding 1
Localization
GO:0000228 nuclear chromosome 4 GO:0005634 nucleus 4 GO:0005654 nucleoplasm 3
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-69306 DNA Replication 4 R-HSA-73894 DNA Repair 4 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1640170 Cell Cycle 1
Partners
MDC1PIAS1PIAS4PMLRAP80RPA1TOPORSUBE2D1

Evidence

Reading pass · 52 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 RNF4 is a poly-SUMO-specific E3 ubiquitin ligase that recognizes poly-SUMO-modified proteins via its SUMO interaction motifs (SIMs) and ubiquitinates them, targeting them for proteasomal degradation. RNF4 was shown to ubiquitinate PML in a SUMO-dependent fashion in vitro, and RNF4 depletion caused accumulation of mixed polyubiquitinated poly-SUMO chains and prevented arsenic-induced PML degradation. In vitro ubiquitination assay, RNF4 depletion (siRNA), proteasome inhibition, cell-based degradation assays Nature cell biology High 18408734
2008 Arsenic-induced PML SUMOylation triggers Lys48-linked polyubiquitination and proteasome-dependent degradation of PML/PML-RARα. RNF4 (human orthologue of yeast SUMO-dependent E3 ubiquitin ligase) is recruited to SUMOylated PML on nuclear bodies along with ubiquitin and proteasomes. A dominant-negative RNF4 impaired arsenic-induced differentiation, directly implicating PML-RARα catabolism in therapeutic response. Co-immunoprecipitation, dominant-negative RNF4 expression, cell differentiation assays, immunofluorescence Nature cell biology High 18408733
2007 Mammalian RNF4 is an active ubiquitin E3 ligase that complements S. pombe rfp1/rfp2 and slx8 mutants. Both RNF4 and the Rfp-Slx8 complex specifically ubiquitylate artificial SUMO-containing substrates in vitro in a SUMO binding-dependent manner, establishing the conserved function of SIM-containing RING-finger proteins in linking SUMO-interaction with ubiquitin conjugation. In vitro ubiquitination assay, genetic complementation in S. pombe, SUMO-binding assays The EMBO journal High 17762864
2011 RNF4 functions as a dimeric RING E3 ligase. It binds ubiquitin-charged UbcH5a tightly but free UbcH5a weakly. Structural docking revealed that with E2 bound to one RNF4 monomer, the thioester-linked ubiquitin reaches across the dimer to engage the other monomer via the Ile44 hydrophobic patch interacting with a conserved tyrosine at the dimer interface. Mutation of these residues abolished ubiquitylation activity, demonstrating that RNF4 dimers actively facilitate ubiquitin transfer rather than acting as inert scaffolds. Crystal structure, in vitro ubiquitination assay, site-directed mutagenesis, surface plasmon resonance binding assays Nature structural & molecular biology High 21857666
2010 RING domain dimerization is essential for RNF4 ubiquitin ligase activity. The RING domain of RNF4 forms a stable dimer, and dimerization is required for ubiquitin transfer; dimerization regulates the stability of the E2~ubiquitin thioester bond. Biochemical dimerization assays, in vitro ubiquitin transfer assays, mutagenesis The Biochemical journal High 20681948
2012 Human RNF4 is recruited to DNA double-strand breaks (DSBs) in a manner requiring its SIM domains and the SUMO E3 ligases PIAS1/PIAS4, as well as DSB-responsive proteins. RNF4 regulates ubiquitin adduct formation at DSBs and promotes turnover of SUMOylated MDC1 and RPA at damage sites. RNF4 depletion causes defective replacement of RPA by BRCA2/RAD51, persistent γH2AX, and hypersensitivity to DSB-inducing agents. PSMD4 (proteasome component) is recruited to damage sites in an RNF4-dependent manner and binds MDC1 and RPA1. siRNA depletion, laser micro-irradiation/immunofluorescence, SILAC proteomics, Co-IP, clonogenic survival assays Genes & development High 22661229
2012 RNF4 plays a critical role in DSB repair; its recruitment requires RING and SIM domains and factors including NBS1, MDC1, RNF8, 53BP1, and BRCA1. SILAC proteomics revealed MDC1 is SUMO-modified after ionizing radiation, which then recruits RNF4 to mediate ubiquitylation. Absence of RNF4 causes defective CtIP-dependent end resection and reduced RPA/Rad51 loading onto ssDNA. siRNA knockdown, homologous gene deletion (chicken DT40), SILAC proteomics, immunofluorescence, DNA damage sensitivity assays Genes & development High 22661230
2012 RNF4 synthesizes hybrid SUMO-ubiquitin chains at DSBs that are recognized by RAP80 (which contains both ubiquitin-interacting motifs and a SUMO-interacting motif). RAP80 binds hybrid SUMO-ubiquitin chains with nanomolar affinity and this is required for BRCA1 recruitment to DSBs, connecting SUMO and ubiquitin signaling in DSB recognition. In vitro chain synthesis, surface plasmon resonance binding, immunofluorescence, siRNA depletion, Co-IP Science signaling High 23211528
2014 RNF4 RING domain dimerization is substrate-induced: at physiological concentrations RNF4 is predominantly monomeric and inactive. Binding of poly-SUMO chains induces RNF4 dimerization, activating its E3 ligase activity, leading to both substrate ubiquitylation and RNF4 autoubiquitylation (causing its own degradation). Ablating SENP6 (a SUMO protease) causes SUMO chain accumulation and ubiquitin-mediated proteolysis of RNF4. In vitro ubiquitination assays at defined concentrations, SENP6 ablation, analytical ultracentrifugation/size exclusion chromatography, cell-based assays Molecular cell High 24656128
2014 RNF4 contains a nucleosome-targeting motif within its RING domain that can bind DNA, enabling selective ubiquitination of nucleosomal histones. This nucleosome-targeting activity is required for repair of TRF2-depleted dysfunctional telomeres by 53BP1-mediated NHEJ. In vitro nucleosome binding/ubiquitination assays, mutagenesis, small-angle X-ray scattering (SAXS), cell-based telomere dysfunction assays EMBO reports High 24714598
2010 Arsenic induces rapid PML redistribution into nuclear bodies where it undergoes SUMO modification. RNF4 is subsequently recruited into these bodies in a SUMO-dependent manner (requiring its SIM domains). FRET studies show RNF4 interacts with SUMO in PML bodies but not directly with PML itself. RNF4 is responsible for ubiquitylation of SUMO-modified PML and its proteasomal degradation. Live-cell imaging, FRAP, FRET, immunofluorescence, siRNA depletion Molecular biology of the cell High 20943951
2004 RNF4/SNURF possesses intrinsic ubiquitin E3 ligase activity, catalyzing its own ubiquitination in vitro in an E2-selective manner (active with UbcH5A/B, HHR6B, E2-25K, MmUbc7, UbcH13 but not others). Mutation of conserved cysteine residues in the RING finger domain abolishes ubiquitination in vitro and in cells. In vitro ubiquitination assay with multiple E2 enzymes, RING domain mutagenesis, cell-based ubiquitination FEBS letters High 14987998
2013 RNF4 and PLK1 mediate replication fork collapse in ATR-deficient cells. Suppression of RNF4 (or AURKA/PLK1) rescues DNA replication reinitiation in ATR-deleted cells and substantially suppresses DSB accumulation. RNF4 repression correlates with persistence of SUMOylated chromatin-bound factors. Fork collapse also depends on the endonuclease scaffold SLX4, suggesting RNF4 acts upstream to enable SLX4-dependent cleavage. Genetic depletion (siRNA/shRNA), DNA fiber assays, γH2AX measurement, epistasis analysis Genes & development Medium 24142876
2012 RNF4 is required for both homologous recombination and NHEJ repair in vivo. Rnf4 knockout mice show persistent radiation-induced DNA damage and signaling. RNF4 targets SUMOylated MDC1 and SUMOylated BRCA1, and is required for Rad51 loading at DNA damage sites. Rnf4 deficiency leads to age-dependent impairment in spermatogenesis. Gene targeting in mice (allelic series), immunofluorescence, Co-IP, HR/NHEJ reporter assays, genotoxic sensitivity assays Cell death and differentiation High 23197296
2015 CDK2 phosphorylates RNF4 at T26 and T112, enhancing its E3 ligase activity. This phosphorylation is important for MDC1 degradation and proper homologous recombination repair during S phase. Mutation of the RNF4 phosphorylation sites results in MDC1 stabilization and compromised HR. In vitro kinase assay, phospho-site mutagenesis, HR reporter assays, immunofluorescence Nucleic acids research Medium 25948581
2014 RNF4 uses a bimodular substrate recognition mechanism: its SIM domain recognizes SUMOylated substrates, and an evolutionarily conserved arginine-rich motif (ARM) serves as an additional recognition module for phosphorylated substrates. For KAP1, RNF4 ARM recognizes pSer824, while SIM recognizes Lys676 SUMOylation; both are required for efficient RNF4-mediated ubiquitination and degradation of KAP1. Arginines R73 and R74 in the ARM are essential. Mutagenesis, Co-IP, bimolecular fluorescence complementation (BiFC), ubiquitination assays, computational modeling The Journal of biological chemistry Medium 24907272
2014 The RNF4 SIM domain is intrinsically disordered; SIM2 and SIM3 constitute the primary SUMO-binding module with high affinity, while SIM4 contributes to poly-SUMO2 chain binding avidity. SAXS data indicate the tetra-SUMO2-RNF4-SIMs complex adopts an ordered structure. HADDOCK modeling shows tandem SIMs bind antiparallel to the tetra-SUMO2 chain in a superhelical arrangement. NMR, SAXS, isothermal titration calorimetry, HADDOCK docking, mutagenesis The Biochemical journal High 24844634
2016 RNF4 ubiquitylation stabilizes short-lived oncogenic transcription factors (β-catenin, Myc, c-Jun, N-ICD) rather than targeting them for degradation. This stabilization requires substrate phosphorylation (not SUMOylation) and RNF4's arginine-rich motif (ARM) domain. RNF4 generates unusual polyubiquitin chains and docks to chromatin to enhance transcriptional activity of these factors. Overexpression/knockdown, Co-IP, ubiquitination assays, reporter gene assays, domain mutagenesis Cell reports Medium 27653698
2009 RNF4 and VHL control levels of SUMOylated HIF-2alpha. SUMOylation of HIF-2alpha at K394 reduces its transcriptional activity, and the SUMO-conjugated form is targeted for proteasomal degradation by RNF4 (acting as a SUMO-targeted ubiquitin ligase). Mutational analysis of SUMOylation sites, proteasome inhibition, RNF4 knockdown/overexpression, transcriptional reporter assays Nucleic acids research Medium 20026589
2010 RNF4 plays a key role in active DNA demethylation. RNF4 interacts with and requires the base excision repair enzymes TDG and APE1 for active demethylation, enhancing enzymatic activities that repair DNA G:T mismatches generated from methylcytosine deamination. Rnf4 deficiency is embryonic lethal with higher genomic DNA methylation. Functional genomics screen, cell-based methylation reporter assay, Co-IP with TDG/APE1, Rnf4 knockout mice Proceedings of the National Academy of Sciences of the United States of America Medium 20696907
2015 c-Myc is SUMOylated (at 10 identified acceptor lysines identified by mass spectrometry) and SUMOylated c-Myc is subsequently ubiquitylated and degraded by the proteasome. RNF4 knockdown enhances SUMOylated c-Myc levels, indicating RNF4 can recognize multi-SUMOylated (not only poly-SUMOylated) proteins as substrates. PIAS1 mediates c-Myc SUMOylation; SENP7 depletion increases it. siRNA knockdown, mass spectrometry identification of SUMO sites, proteasome inhibition, ubiquitination assays Cell cycle Medium 25895136
2015 RNF4-mediated polyubiquitination controls the Fanconi anemia/BRCA pathway. Loss of FAAP20 binding to FANCA exposes a SUMOylation site (K921), leading to UBC9-mediated SUMOylation, RNF4-mediated polyubiquitination, and proteasomal degradation of FANCA. RNF4 is epistatic to FA/BRCA pathway genes, and RNF4-deficient cells show interstrand cross-linker hypersensitivity. Patient mutation analysis, SUMOylation site mutagenesis, Co-IP, ubiquitination assays, epistasis genetics, cross-linker sensitivity assays The Journal of clinical investigation Medium 25751062
2011 The HTLV-1 oncoprotein Tax is a substrate for RNF4 both in vivo and in vitro. The RNF4-binding site maps adjacent to Tax ubiquitin/SUMO modification sites K280/K284. RNF4-mediated ubiquitination of Tax causes its relocalization from nucleus to cytoplasm, which is associated with increased NF-κB activity and decreased CREB-mediated activity. RNF4 RING domain activity is required for this effect. In vitro ubiquitination assay, Co-IP, immunofluorescence, domain mapping, RING mutant analysis, reporter gene assays, siRNA Blood Medium 22106342
2017 Ataxin-3 (a deubiquitylating enzyme) counteracts RNF4 activity at DSBs by negatively regulating ubiquitylation of the RNF4 substrate MDC1. Ataxin-3 is recruited to DSBs in a SUMOylation-dependent fashion and is directly stimulated by SUMO in vitro, defining SUMO-dependent DUB activity toward MDC1. Loss of ataxin-3 decreases MDC1 chromatin dwell time, which is reversed by co-depletion of RNF4. siRNA depletion, in vitro DUB assay, immunofluorescence, epistasis (co-depletion), FRAP The EMBO journal Medium 28275011
2021 RNF4 defines a major pathway for proteasomal clearance of SUMOylated DNA-protein crosslinks (DPCs) in a replication-independent manner. SUMO-RNF4-dependent DPC resolution acts as a salvage mechanism after DNA replication. Absence of the SUMO-RNF4 pathway causes mitotic entry with high DPC loads, leading to defective chromosome segregation and cell death. Cell-based DPC quantification, RNF4 depletion/knockout, chromosome segregation assays, epistasis with replication-dependent repair The EMBO journal Medium 34346517
2024 TOPORS functions as a SUMO1-selective STUbL that complements RNF4 in generating ubiquitin modifications on SUMOylated targets including DPCs and PML, stimulating p97/VCP recruitment and proteasomal degradation. Combined loss of TOPORS and RNF4 is synthetic lethal due to defective clearance of SUMOylated chromatin proteins, cell cycle arrest, and apoptosis. Genome-scale genetic screens, in vitro ubiquitination assays, Co-IP, cell viability assays, mass spectrometry Nature structural & molecular biology High 38649616
2015 USP11 (ubiquitin-specific protease 11) deubiquitinates hybrid SUMO-ubiquitin chains to counteract RNF4. USP11 was identified as a functional interactor of RNF4 by proteomics. USP11 stabilizes SUMO-enriched nuclear bodies and counteracts RNF4 to inhibit nuclear body dissolution in response to DNA damage. Proteomics (interactor identification), in vitro DUB assay on SUMO-ubiquitin hybrid chains, immunofluorescence, siRNA depletion The Journal of biological chemistry Medium 25969536
2000 RNF4 physically interacts with the BTB/POZ-AT hook-zinc finger protein PATZ via a region in PATZ containing an AT-hook domain. This interaction was confirmed by affinity chromatography and Co-IP. PATZ and RNF4 colocalize in nuclear bodies. RNF4 acts as a transcriptional activator; PATZ acts as a repressor; co-expression switches RNF4-mediated activation to repression. RNF4 also associates with HMGI(Y). Yeast two-hybrid, affinity chromatography, Co-IP, immunofluorescence/confocal microscopy, cotransfection reporter assays The Journal of biological chemistry Medium 10713105
2004 RNF4 acts as a coactivator of NF-Y-mediated transcription at the GTP cyclohydrolase I (GCH) promoter CCAAT box. RNF4 does not bind the CCAAT box directly but physically associates with the NF-Y complex (shown by immunoprecipitation). RNF4-mediated activation requires endogenous NF-Y. Promoter deletion/mutagenesis analysis, co-transfection reporter assay, dominant-negative NF-Y, Co-IP Molecular pharmacology Medium 15496512
2003 RNF4 interacts with the TRPS1 transcription factor. The RNF4-binding region within RNF4 maps to amino acids 6-65, and the TRPS1-binding region maps to aa 985-1184. Complex formation was verified by Co-IP from transfected and native mammalian cells. Endogenous RNF4 and TRPS1 colocalize in nuclear structures. RNF4 inhibits the transcriptional repression function of TRPS1. Yeast two-hybrid, Co-IP from native cells, confocal microscopy, reporter gene assay The Journal of biological chemistry Medium 12885770
2004 SUMO-1 promotes association of RNF4/SNURF with PML nuclear bodies. RNF4 efficiently binds SUMO-1 in a noncovalent fashion and is also covalently modified by SUMO-1. Ectopic SUMO-1 enhances PML-RNF4 interaction. PML3 overexpression abolishes RNF4 coactivation function, paralleling its ability to recruit RNF4 into nuclear bodies. Biochemical SUMO-binding assay, Co-IP, immunofluorescence, reporter gene assay Experimental cell research Medium 15707587
2013 RNF4 targets SUMO-2-conjugated EBV Rta for ubiquitination. RNF4 directly interacts with Rta (GST pulldown and Co-IP). RNF4 SIM domain mutants fail to ubiquitinate Rta. Lys mutations abrogating SUMO-3 conjugation to Rta decrease RNF4-mediated ubiquitination. RNF4 knockdown enhances Rta expression and promotes EBV lytic replication. GST pulldown, Co-IP, in vitro ubiquitination assay, SIM domain mutagenesis, RNF4 knockdown The Journal of biological chemistry Medium 23504328
2022 RNF4 controls the extent of replication fork reversal by targeting SUMOylated TOP2A for ubiquitination and degradation at stalled forks. RNF4 downregulation leads to aberrant activation of the ZATT-TOP2A-PICH complex, excessive fork reversal, and elevated fork collapse frequencies. siRNA depletion, DNA fiber assays, proximity ligation assay, Co-IP, ubiquitination assays Nucleic acids research Medium 35640614
2021 RNF4 recognizes and ubiquitylates SUMOylated BLM helicase, promoting its proteasome-mediated turnover at damaged replication forks. RNF4 depletion inhibits firing of new DNA replication origins required for restart after prolonged replication stress. Co-depletion of BLM rescues the origin firing defect caused by RNF4 depletion. DNA fiber assays, siRNA depletion, epistasis (co-depletion), Co-IP, ubiquitination assays Frontiers in genetics Medium 34868226
2023 SLX4 dimerization and SUMO-SIM interactions drive assembly of SLX4 nuclear condensates that compartmentalize the SUMO-RNF4 signaling pathway. SENP6 and RNF4 regulate assembly and disassembly of SLX4 condensates, respectively. SLX4 condensation per se triggers selective protein SUMOylation and ubiquitination, inducing ubiquitylation/chromatin extraction of topoisomerase 1 DNA-protein crosslinks. Super-resolution microscopy, condensate assays, Co-IP, SENP6/RNF4 depletion, ubiquitination assays Molecular cell Medium 37059091
2014 RNF4 depletion in chicken DT40 RNF4-/- cells causes a partial defect in spindle assembly checkpoint, premature sister chromatid dissociation, and markedly increased lagging chromosomes at anaphase, resulting in gradual whole chromosome loss over 6 weeks. This establishes a role for RNF4 in chromosome segregation and maintenance of genomic integrity. Gene targeting (DT40 knockout), cell cycle checkpoint analysis, cytogenetics, live-cell imaging of chromosome segregation Genes to cells Medium 25205350
2015 RNF4 negatively regulates NF-κB signaling by downregulating TAB2 via a lysosomal pathway. RNF4 interacts with the TAK1-TAB2-TAB3 complex (but not TAB1). RNF4 overexpression impairs NF-κB activation in a dose-dependent manner; RNF4 knockdown potentiates NF-κB activation and impairs endogenous TAB2 degradation. siRNA screen, Co-IP, overexpression/knockdown reporter assays, TAB2 degradation assays FEBS letters Medium 26299341
2017 RNF4-mediated SUMOylation-dependent ubiquitination of FXR is controlled by casein kinase 2 (CK2): CK2 phosphorylates FXR at Ser327, enabling PIAS1-mediated SUMO2 conjugation at Lys325 via a non-canonical pSuM motif, which then promotes RNF4-dependent polyubiquitination and proteasomal degradation of FXR. This SUMOylation-dependent ubiquitination is required for maximal FXR transcriptional activity. Mutagenesis of SUMO site/phospho-site, Co-IP, ubiquitination assays, CK2 kinase assays, reporter gene assays Journal of molecular cell biology Medium 28201649
2022 DNA damage-induced sumoylation of Sp1 at Lys16 (requiring prior ATM-dependent phosphorylation) enables its recognition and ubiquitination by RNF4. Additionally, Cyclin A/CDK2-mediated phosphorylation of Sp1 at Ser59 upon S-phase entry is required for RNF4 recognition, ubiquitination, and degradation of Sp1. Sp1 degradation removes 53BP1 from DSBs in S phase, allowing BRCA1 recruitment and HR. Mutagenesis, Co-IP, ubiquitination assays, HR reporter, siRNA, PARP inhibitor sensitivity DNA repair Medium 35124373
2022 PRMT5 methylates RNF4 at Arg164, which attenuates the interaction between PML-RARα and RNF4, stabilizing PML-RARα. Arsenic trioxide treatment triggers dissociation of PRMT5 from PML nuclear bodies, reducing RNF4 methylation and promoting RNF4-mediated PML-RARα ubiquitination and degradation. Co-IP, methylation assays, mutagenesis (Arg164), ubiquitination assays, cell differentiation assays Cellular and molecular life sciences Medium 35622143
2020 RNF4 binds, ubiquitinates, and stabilizes phosphorylated eIF2α (p-eIF2α) but not ATF4 or CHOP. This stabilization of p-eIF2α by RNF4 is required for melanoma tumorigenesis and therapy resistance. RNF4 and p-eIF2α establish a positive feed-forward loop. Co-IP, ubiquitination assays, overexpression/knockdown, xenograft models The Journal of investigative dermatology Medium 32360601
2016 RNF4-mediated ubiquitination of SUMOylated NDRG2 at K333 (SUMO1 site) promotes NDRG2 proteasomal degradation in lung adenocarcinoma cells. SUMO1 modification of NDRG2 is required for its tumor suppressor function. SUMOylation site mutagenesis, ubiquitination assays, RNF4 knockdown, cell proliferation/tumor growth assays Oncotarget Low 27072586
2019 A covalent ligand (CCW 28-3) was identified that reacts with zinc-coordinating cysteines C132 and C135 in the RNF4 RING domain. Incorporation of this covalent RNF4 recruiter into a bifunctional degrader (linked to JQ1) causes BRD4 degradation in a proteasome- and RNF4-dependent manner, demonstrating that covalent modification of the RING domain can recruit RNF4 to non-SUMO substrates. ABPP-based covalent ligand screening, mass spectrometry site identification, degradation assays with proteasome inhibitors and RNF4 knockdown ACS chemical biology Medium 31059647
2016 A post-translational modification cascade involving HDAC9-mediated deacetylation of Nkx3.2 triggers PIASy-mediated sumoylation and subsequent RNF4-mediated SUMO-targeted ubiquitination, controlling Nkx3.2 protein stability and chondrocyte hypertrophic maturation. Overexpression, knockdown, Co-IP, ubiquitination assays, reporter gene assays, cell differentiation assays Cellular signalling Low 27312341
2021 RASSF1A acts as a scaffold required for RNF4/SNURF to target the NOTCH effector HES1 for ubiquitination and degradation. Loss of RASSF1A prevents RNF4-mediated HES1 degradation. Co-IP, ubiquitination assays, siRNA knockdown, reporter gene assays EMBO reports Low 34897944
2024 PIAS4-mediated SUMOylation of chromatin-trapped WRN helicase triggers RNF4-dependent ubiquitination and proteasomal degradation of WRN, requiring p97/VCP for chromatin extraction. This PIAS4-RNF4 axis controls WRN spatiotemporal dynamics in cancer cells. Single-molecule tracking, phenotypic screen, siRNA/inhibitor-based PIAS4/RNF4 depletion, proteasome assays, Co-IP Nature communications Medium 39025847
2016 E2-RING interaction affinity governs whether RNF4 mediates mono- or polyubiquitination of polySUMO substrates. RAD6B (low affinity for RNF4 RING) monoubiquitinates SUMO chains, while UBCH5B (high affinity) polyubiquitinates them. Mutating RAD6B RING-binding surface to resemble UBCH5B converts it to a polyubiquitinating E2 with RNF4. In vitro ubiquitination assays, E2 mutagenesis, binding affinity measurements Journal of molecular biology High 27678051
2019 RNF4 is an obligate dimeric RING E3 ligase. Introduction of a tryptophan residue into the RNF4 RING domain rescues activity of inactive monomeric RNF4 mutants. Dimeric RINGs lack the conserved tryptophan (present in monomeric RINGs) to prevent hyperactivity; dimerization compensates for weak E2~Ub binding in these E3 ligases. In vitro ubiquitination assays, mutagenesis, E2 binding studies, comparative analysis The Biochemical journal Medium 31048496
2017 EBV miR-BHRF1-1 targets RNF4 for post-transcriptional downregulation, leading to accumulation of SUMO2/3 conjugates during productive EBV infection. Reconstitution of RNF4 in miR-BHRF1-1-expressing cells reduces viral protein levels and impairs virus release, demonstrating that viral suppression of RNF4 promotes SUMO conjugate accumulation required for efficient EBV replication. miR-BHRF1-1 sponge/miRNA-resistant RNF4 reconstitution, SUMO-conjugate analysis, viral replication assays PLoS pathogens Medium 28414785
2020 RNF4-mediated SUMOylated PARIS ubiquitination and proteasomal degradation relieves PARIS-mediated transcriptional repression of PGC-1α. PIASy inhibits RNF4-mediated ubiquitination of PARIS and blocks relief of PARIS repression. SUMO3+RNF4 co-expression relieves PARIS-mediated repression in reporter assays. Co-IP, ubiquitination assays, reporter gene assays, siRNA Biochemical and biophysical research communications Low 32197837
2019 SUMOylation of PIM1 at K169 (within a consensus SUMOylation motif in the active site) promotes ubiquitin-mediated degradation via RNF4 recruitment. E171A mutation abolishes SUMOylation, significantly increases PIM1 half-life, and markedly reduces ubiquitylation. SUMOylated PIM1 shows enhanced protein kinase activity in vitro. In vitro SUMOylation and kinase assays, mutagenesis (E171A, K169), half-life measurement, Co-IP Scientific reports Medium 28620180
2024 RNF4 is required for normal DNA replication and ATR-CHK1 signaling of replication stress. RNF4 deletion causes failure of replication fork stability factors (Fanconi anemia proteins, PIF1, RECQL5) to accumulate at replication forks. In RNF4-deficient cells, hyper-SUMOylated SMC5/6 complex members accumulate on chromatin and contribute to replication failure via a RAD51-dependent mechanism. RNF4 deletion suppresses Myc-driven tumorigenesis. Conditional knockout mouse model (B cell lineage), DNA fiber assays, iPOND chromatin enrichment, proximity ligation assay, RAD51 epistasis The Journal of clinical investigation High 38530355

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation. Nature cell biology 696 18408734
2008 Arsenic degrades PML or PML-RARalpha through a SUMO-triggered RNF4/ubiquitin-mediated pathway. Nature cell biology 611 18408733
2012 RNF4, a SUMO-targeted ubiquitin E3 ligase, promotes DNA double-strand break repair. Genes & development 278 22661229
2019 Covalent Ligand Screening Uncovers a RNF4 E3 Ligase Recruiter for Targeted Protein Degradation Applications. ACS chemical biology 255 31059647
2007 Conserved function of RNF4 family proteins in eukaryotes: targeting a ubiquitin ligase to SUMOylated proteins. The EMBO journal 252 17762864
2012 SUMO-targeted ubiquitin E3 ligase RNF4 is required for the response of human cells to DNA damage. Genes & development 210 22661230
2012 RNF4-dependent hybrid SUMO-ubiquitin chains are signals for RAP80 and thereby mediate the recruitment of BRCA1 to sites of DNA damage. Science signaling 154 23211528
2011 Mechanism of ubiquitylation by dimeric RING ligase RNF4. Nature structural & molecular biology 151 21857666
2007 The Slx5-Slx8 complex affects sumoylation of DNA repair proteins and negatively regulates recombination. Molecular and cellular biology 124 17591698
2016 PolySUMOylation by Siz2 and Mms21 triggers relocation of DNA breaks to nuclear pores through the Slx5/Slx8 STUbL. Genes & development 106 27056668
2012 RNF4 is required for DNA double-strand break repair in vivo. Cell death and differentiation 100 23197296
2013 RNF4 and PLK1 are required for replication fork collapse in ATR-deficient cells. Genes & development 92 24142876
2015 c-Myc is targeted to the proteasome for degradation in a SUMOylation-dependent manner, regulated by PIAS1, SENP7 and RNF4. Cell cycle (Georgetown, Tex.) 88 25895136
2008 Activation of the Slx5-Slx8 ubiquitin ligase by poly-small ubiquitin-like modifier conjugates. The Journal of biological chemistry 86 18499666
2005 Suppression of genomic instability by SLX5 and SLX8 in Saccharomyces cerevisiae. DNA repair 86 16325482
2000 A novel member of the BTB/POZ family, PATZ, associates with the RNF4 RING finger protein and acts as a transcriptional repressor. The Journal of biological chemistry 81 10713105
2009 RNF4 and VHL regulate the proteasomal degradation of SUMO-conjugated Hypoxia-Inducible Factor-2alpha. Nucleic acids research 79 20026589
2014 SUMO chain-induced dimerization activates RNF4. Molecular cell 73 24656128
2010 RING domain dimerization is essential for RNF4 function. The Biochemical journal 73 20681948
2017 Ataxin-3 consolidates the MDC1-dependent DNA double-strand break response by counteracting the SUMO-targeted ubiquitin ligase RNF4. The EMBO journal 72 28275011
2013 Distinct SUMO ligases cooperate with Esc2 and Slx5 to suppress duplication-mediated genome rearrangements. PLoS genetics 72 23935535
2010 Arsenic-induced SUMO-dependent recruitment of RNF4 into PML nuclear bodies. Molecular biology of the cell 70 20943951
2016 SUMO-Targeted Ubiquitin Ligase (STUbL) Slx5 regulates proteolysis of centromeric histone H3 variant Cse4 and prevents its mislocalization to euchromatin. Molecular biology of the cell 68 26960795
2014 ATL response to arsenic/interferon therapy is triggered by SUMO/PML/RNF4-dependent Tax degradation. Blood 65 25395419
2005 Genetic analysis connects SLX5 and SLX8 to the SUMO pathway in Saccharomyces cerevisiae. Genetics 65 16387868
2004 SUMO-1 promotes association of SNURF (RNF4) with PML nuclear bodies. Experimental cell research 63 15707587
2007 Fission yeast Rnf4 homologs are required for DNA repair. The Journal of biological chemistry 61 17502373
2021 Mechanism and function of DNA replication-independent DNA-protein crosslink repair via the SUMO-RNF4 pathway. The EMBO journal 58 34346517
2010 Identification of RING finger protein 4 (RNF4) as a modulator of DNA demethylation through a functional genomics screen. Proceedings of the National Academy of Sciences of the United States of America 58 20696907
2017 Manipulating PML SUMOylation via Silencing UBC9 and RNF4 Regulates Cardiac Fibrosis. Molecular therapy : the journal of the American Society of Gene Therapy 56 28143738
2009 Role of SUMO in RNF4-mediated promyelocytic leukemia protein (PML) degradation: sumoylation of PML and phospho-switch control of its SUMO binding domain dissected in living cells. The Journal of biological chemistry 52 19380586
2016 RNF4-Dependent Oncogene Activation by Protein Stabilization. Cell reports 49 27653698
2011 The Sumo-targeted ubiquitin ligase RNF4 regulates the localization and function of the HTLV-1 oncoprotein Tax. Blood 47 22106342
2023 Compartmentalization of the SUMO/RNF4 pathway by SLX4 drives DNA repair. Molecular cell 46 37059091
2010 Wss1 is a SUMO-dependent isopeptidase that interacts genetically with the Slx5-Slx8 SUMO-targeted ubiquitin ligase. Molecular and cellular biology 46 20516210
2016 miR-762 promotes porcine immature Sertoli cell growth via the ring finger protein 4 (RNF4) gene. Scientific reports 45 27596571
2014 RNF4 interacts with both SUMO and nucleosomes to promote the DNA damage response. EMBO reports 44 24714598
2007 Stimulation of in vitro sumoylation by Slx5-Slx8: evidence for a functional interaction with the SUMO pathway. DNA repair 44 17669696
2004 Transcriptional coregulator SNURF (RNF4) possesses ubiquitin E3 ligase activity. FEBS letters 44 14987998
2003 The RING finger protein RNF4, a co-regulator of transcription, interacts with the TRPS1 transcription factor. The Journal of biological chemistry 44 12885770
2001 RNF4 is a growth inhibitor expressed in germ cells but not in human testicular tumors. The American journal of pathology 44 11583949
2000 Interaction between the transcription factor SPBP and the positive cofactor RNF4. An interplay between protein binding zinc fingers. The Journal of biological chemistry 44 10849425
2014 An arginine-rich motif of ring finger protein 4 (RNF4) oversees the recruitment and degradation of the phosphorylated and SUMOylated Krüppel-associated box domain-associated protein 1 (KAP1)/TRIM28 protein during genotoxic stress. The Journal of biological chemistry 41 24907272
2014 PML, SUMO, and RNF4: guardians of nuclear protein quality. Molecular cell 41 24996060
2012 Requirement of PML SUMO interacting motif for RNF4- or arsenic trioxide-induced degradation of nuclear PML isoforms. PloS one 40 23028697
2003 Translational regulation of a novel testis-specific RNF4 transcript. Molecular reproduction and development 39 12874792
2016 Slx5/Slx8 Promotes Replication Stress Tolerance by Facilitating Mitotic Progression. Cell reports 36 27134171
2015 RNF4-mediated polyubiquitination regulates the Fanconi anemia/BRCA pathway. The Journal of clinical investigation 36 25751062
2015 Ubiquitin-specific Protease 11 (USP11) Deubiquitinates Hybrid Small Ubiquitin-like Modifier (SUMO)-Ubiquitin Chains to Counteract RING Finger Protein 4 (RNF4). The Journal of biological chemistry 36 25969536
2024 Concerted SUMO-targeted ubiquitin ligase activities of TOPORS and RNF4 are essential for stress management and cell proliferation. Nature structural & molecular biology 35 38649616
2009 The SUMO-targeted ubiquitin ligase subunit Slx5 resides in nuclear foci and at sites of DNA breaks. Cell cycle (Georgetown, Tex.) 35 19270524
2007 The yeast Slx5-Slx8 DNA integrity complex displays ubiquitin ligase activity. Cell cycle (Georgetown, Tex.) 35 18032921
2006 Purification of the yeast Slx5-Slx8 protein complex and characterization of its DNA-binding activity. Nucleic acids research 35 17020915
2019 RNF4-A Paradigm for SUMOylation-Mediated Ubiquitination. Proteomics 33 31566917
2001 PATZ attenuates the RNF4-mediated enhancement of androgen receptor-dependent transcription. The Journal of biological chemistry 33 11719514
1998 Identification and characterization of a novel RING-finger gene (RNF4) mapping at 4p16.3. Genomics 31 9479498
2015 CDK-mediated RNF4 phosphorylation regulates homologous recombination in S-phase. Nucleic acids research 28 25948581
2013 Role of RNF4 in the ubiquitination of Rta of Epstein-Barr virus. The Journal of biological chemistry 28 23504328
2003 Down-regulation of estrogen receptor beta and transcriptional coregulator SNURF/RNF4 in testicular germ cell cancer. European urology 28 14644130
2000 Rnf4, a RING protein expressed in the developing nervous and reproductive systems, interacts with Gscl, a gene within the DiGeorge critical region. Developmental dynamics : an official publication of the American Association of Anatomists 27 10822263
2007 Slx5 promotes transcriptional silencing and is required for robust growth in the absence of Sir2. Molecular and cellular biology 26 18086879
2015 RNF4 negatively regulates NF-κB signaling by down-regulating TAB2. FEBS letters 25 26299341
2014 Structural analysis of poly-SUMO chain recognition by the RNF4-SIMs domain. The Biochemical journal 25 24844634
2008 Identification of polymorphism and association analysis with reproductive traits in the porcine RNF4 gene. Animal reproduction science 24 18358646
2016 RNF4 regulates DNA double-strand break repair in a cell cycle-dependent manner. Cell cycle (Georgetown, Tex.) 23 26766492
2019 SUMOylation by SUMO2 is implicated in the degradation of misfolded ataxin-7 via RNF4 in SCA7 models. Disease models & mechanisms 21 30559154
2014 Disruption of SUMO-targeted ubiquitin ligases Slx5-Slx8/RNF4 alters RecQ-like helicase Sgs1/BLM localization in yeast and human cells. DNA repair 21 25588990
2017 A CK2-RNF4 interplay coordinates non-canonical SUMOylation and degradation of nuclear receptor FXR. Journal of molecular cell biology 20 28201649
2022 RNF4 controls the extent of replication fork reversal to preserve genome stability. Nucleic acids research 19 35640614
2020 Knockdown of endogenous RNF4 exacerbates ischaemia-induced cardiomyocyte apoptosis in mice. Journal of cellular and molecular medicine 18 32722882
2018 Slx5-Slx8 ubiquitin ligase targets active pools of the Yen1 nuclease to limit crossover formation. Nature communications 18 30479332
2022 DNA damage-induced sumoylation of Sp1 induces its interaction with RNF4 and degradation in S phase to remove 53BP1 from DSBs and permit HR. DNA repair 17 35124373
2017 The Epstein-Barr virus miR-BHRF1-1 targets RNF4 during productive infection to promote the accumulation of SUMO conjugates and the release of infectious virus. PLoS pathogens 17 28414785
2002 Expression of the nuclear RING finger protein SNURF/RNF4 during rat testis development suggests a role in spermatid maturation. Mechanisms of development 17 12351196
2024 WRN inhibition leads to its chromatin-associated degradation via the PIAS4-RNF4-p97/VCP axis. Nature communications 16 39025847
2020 Regulation of eIF2α by RNF4 Promotes Melanoma Tumorigenesis and Therapy Resistance. The Journal of investigative dermatology 16 32360601
2016 A post-translational modification cascade employing HDAC9-PIASy-RNF4 axis regulates chondrocyte hypertrophy by modulating Nkx3.2 protein stability. Cellular signalling 16 27312341
2021 RNF4 Regulates the BLM Helicase in Recovery From Replication Fork Collapse. Frontiers in genetics 15 34868226
2014 SUMO-targeted ubiquitin ligase RNF4 plays a critical role in preventing chromosome loss. Genes to cells : devoted to molecular & cellular mechanisms 15 25205350
2021 The E3 Ubiquitin-Protein Ligase RNF4 Promotes TNF-α-Induced Cell Death Triggered by RIPK1. International journal of molecular sciences 14 34071450
2021 RASSF1A disrupts the NOTCH signaling axis via SNURF/RNF4-mediated ubiquitination of HES1. EMBO reports 14 34897944
2016 RNF4-mediated SUMOylation is essential for NDRG2 suppression of lung adenocarcinoma. Oncotarget 14 27072586
2022 RNF4~RGMb~BMP6 axis required for osteogenic differentiation and cancer cell survival. Cell death & disease 13 36153321
2020 RNF4-mediated SUMO-targeted ubiquitination relieves PARIS/ZNF746-mediated transcriptional repression. Biochemical and biophysical research communications 13 32197837
2016 Loss of ubiquitin E2 Ube2w rescues hypersensitivity of Rnf4 mutant cells to DNA damage. Scientific reports 13 27185577
2016 Stabilization of nuclear oncoproteins by RNF4 and the ubiquitin system in cancer. Molecular & cellular oncology 13 28197534
2017 A Lysine Desert Protects a Novel Domain in the Slx5-Slx8 SUMO Targeted Ub Ligase To Maintain Sumoylation Levels in Saccharomyces cerevisiae. Genetics 12 28550017
2024 RNF4 sustains Myc-driven tumorigenesis by facilitating DNA replication. The Journal of clinical investigation 11 38530355
2016 Role of E2-RING Interactions in Governing RNF4-Mediated Substrate Ubiquitination. Journal of molecular biology 11 27678051
2014 The SUMO-targeted ubiquitin ligase RNF4 localizes to etoposide-exposed mitotic chromosomes: implication for a novel DNA damage response during mitosis. Biochemical and biophysical research communications 11 24695317
2013 Physical and Genetic Interactions Between Uls1 and the Slx5-Slx8 SUMO-Targeted Ubiquitin Ligase. G3 (Bethesda, Md.) 11 23550137
2024 RNF4 mediated degradation of PDHA1 promotes colorectal cancer metabolism and metastasis. NPJ precision oncology 10 39521913
2019 Designing active RNF4 monomers by introducing a tryptophan: avidity towards E2∼Ub conjugates dictates the activity of ubiquitin RING E3 ligases. The Biochemical journal 10 31048496
2004 RNF4 is a coactivator for nuclear factor Y on GTP cyclohydrolase I proximal promoter. Molecular pharmacology 10 15496512
2023 RNF4 and USP7 cooperate in ubiquitin-regulated steps of DNA replication. Open biology 9 37607592
2022 RNF4 silencing induces cell growth arrest and DNA damage by promoting nuclear targeting of p62 in hepatocellular carcinoma. Oncogene 9 35236966
2022 PRMT5-mediated RNF4 methylation promotes therapeutic resistance of APL cells to As2O3 by stabilizing oncoprotein PML-RARα. Cellular and molecular life sciences : CMLS 9 35622143
2022 RNF4 promotes tumorigenesis, therapy resistance of cholangiocarcinoma and affects cell cycle by regulating the ubiquitination degradation of p27kip1 in the nucleus. Experimental cell research 9 35926659
2020 AR regulates porcine immature Sertoli cell growth via binding to RNF4 and miR-124a. Reproduction in domestic animals = Zuchthygiene 9 33305371
2017 A functional SUMO-motif in the active site of PIM1 promotes its degradation via RNF4, and stimulates protein kinase activity. Scientific reports 9 28620180

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