Affinage

RNF20

E3 ubiquitin-protein ligase BRE1A · UniProt Q5VTR2

Length
975 aa
Mass
113.7 kDa
Annotated
2026-04-28
71 papers in source corpus 43 papers cited in narrative 43 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RNF20 is a RING-type E3 ubiquitin ligase that, as a heterodimer with RNF40, catalyzes histone H2B lysine 120 monoubiquitination (H2Bub1)—a chromatin mark central to transcription elongation, mRNA splicing, DNA double-strand break repair, replication fork protection, and cell differentiation. The RNF20/RNF40 complex is recruited to chromatin by context-specific adaptors including WAC (linking it to RNA Pol II), RPA (at centromeres and DNA damage sites), FACT (at DSBs and hypoxia response elements), p53, HIF-1, and Fbxl19 (at CpG islands); H2Bub1 stimulates downstream H3K4 and H3K79 methylation, recruits SNF2h chromatin remodelers at DSBs and centromeres, and is read by the spliceosome component PRPF8 to couple transcription with mRNA processing (PMID:21329877, PMID:37155876, PMID:24357716, PMID:31152661, PMID:38517892, PMID:28453857). Beyond histone modification, RNF20 ubiquitinates non-histone substrates—Eg5 (mitotic kinesin stabilization), LSD1 (K29-linked, CDK9-dependent stabilization suppressing endogenous retrovirus expression), NCoR1 (proteasomal degradation enabling PPARγ-driven adipogenesis), STAT3, AP-2α, and ZSCAN4—and possesses a ligase-independent recombination mediator function that directly facilitates Rad51 filament assembly on ssDNA (PMID:27557628, PMID:38315842, PMID:31604693, PMID:37230987, PMID:24374663). RNF20 stability and activity are regulated by Smurf2-mediated proteasomal degradation, ferritinophagy-dependent lysosomal degradation, SARS-CoV-2 Mpro cleavage at Gln521, ATR-mediated phosphorylation during replication stress, and allosteric stimulation by H2B S112 GlcNAcylation acting on the E2 enzyme RAD6A (PMID:22231558, PMID:37976359, PMID:34452991, PMID:40495033, PMID:41495224).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2010 Medium

    Initial chromatin studies revealed that RNF20 occupies gene loci and maintains H2Bub1 and H3K4me3, but that H2Bub1 can repress as well as activate inducible transcription, establishing RNF20 as a context-dependent transcriptional regulator rather than a simple activator.

    Evidence ChIP and RNAi depletion at the IRF1 locus showing unexpected transcriptional derepression upon RNF20 loss

    PMID:20825659

    Open questions at the time
    • Single locus studied; genome-wide scope of repressive versus activating H2Bub1 effects unknown
    • Mechanism of repression (Pol II CTD cycling hypothesis) not directly tested
  2. 2011 High

    Multiple studies converged to define RNF20 as the principal H2B K120 ubiquitin ligase operating in both transcription and DNA repair: WAC was identified as the adaptor bridging RNF20/RNF40 to elongating RNA Pol II, CDC73/parafibromin was shown to maintain H2Bub1 levels, and RNF20 was demonstrated to be essential for DSB-induced chromatin remodeling (via SNF2h), DNA end resection, RAD51/BRCA1 recruitment, and homologous recombination.

    Evidence Co-IP/domain mapping for WAC and CDC73, ChIP at DSBs, HR repair assays, H2B K120R mutant, radiation sensitivity

    PMID:21329877 PMID:21362548 PMID:22021426 PMID:22155569

    Open questions at the time
    • Structural basis of WAC-RNF20 interaction unresolved at atomic level
    • Whether CDC73 mutations cause disease through H2Bub1 loss versus other mechanisms unclear
  3. 2012 High

    RNF20 was established as a regulated enzyme whose levels are controlled by Smurf2-mediated proteasomal degradation, whose activity is opposed by USP44 deubiquitinase, and whose loss causes R-loop accumulation and genomic instability—linking H2Bub1 to both differentiation (ESC exit) and genome integrity.

    Evidence Smurf2 KO mouse model, USP44 depletion during ESC differentiation, R-loop detection and cytogenetics upon RNF20 depletion

    PMID:22231558 PMID:22354749 PMID:22681888

    Open questions at the time
    • How Smurf2 itself is regulated at DSBs not determined
    • Whether R-loops are a direct consequence of H2Bub1 loss or secondary to transcription-replication conflicts unclear
  4. 2013 High

    The chromatin adaptor FACT was identified as a DSB-specific recruiter of RNF20 (distinct from transcription-associated recruitment via PAF1), and RNF20 was shown to be co-opted by MLL-fusion oncoproteins to amplify Dot1l-dependent H3K79 methylation at leukemogenic target genes, revealing RNF20's role in both repair and oncogenesis.

    Evidence RING domain mutagenesis abolishing FACT interaction, PAF1-independence at DSBs, ChIP-seq/RNA-seq in MLL-fusion leukemia models, in vivo mouse leukemia

    PMID:23412334 PMID:24357716

    Open questions at the time
    • How FACT is recruited to DSBs independently of PAF1 not fully resolved
    • Whether pharmacological targeting of RNF20 in MLL leukemia is feasible unknown
  5. 2013 Medium

    RNF20's substrate range was expanded beyond histones: it ubiquitinates AP-2α for proteasomal degradation, and adenovirus E1A was found to hijack RNF20 as a scaffold for viral transcription while blocking H2Bub1 to suppress interferon responses, establishing RNF20 as a target of viral immune evasion.

    Evidence Co-IP, ubiquitination assay for AP-2α; Co-IP and transcription reporter for E1A-RNF20 interaction

    PMID:23785282 PMID:24374663

    Open questions at the time
    • Ubiquitin chain type on AP-2α not characterized
    • Whether E1A-RNF20 interaction is conserved across adenovirus serotypes not tested
    • Single-lab findings for each substrate
  6. 2014 High

    Arsenite was shown to directly bind RING finger cysteine residues of RNF20/RNF40, establishing the RING domain as a druggable interface and revealing a chemical mechanism for environmental carcinogenesis through H2Bub1 loss and DNA repair impairment.

    Evidence In vitro arsenite binding assay to RING domain, cellular H2Bub1 loss, impaired BRCA1/RAD51 recruitment

    PMID:25170678

    Open questions at the time
    • Whether arsenic concentrations used reflect physiological exposure levels not fully addressed
    • Selectivity of arsenite for RNF20 versus other RING E3 ligases not compared
  7. 2016 High

    The structural basis of E3 activity was revealed by crystal structures of the RNF20 RING domain with Ube2B~Ub conjugate, and the non-histone substrate Eg5 was identified as an RNF20/RNF40 target whose ubiquitination is required for mitotic spindle assembly, while loss of H2Bub1 was linked to NF-κB-driven inflammation and colorectal cancer.

    Evidence X-ray crystallography and mutagenesis of RING-E2 interface; Co-IP and ubiquitination assay for Eg5 with spindle phenotypes; ChIP and mouse haploinsufficiency model for NF-κB target regulation

    PMID:26854224 PMID:27557628 PMID:27569044

    Open questions at the time
    • Whether Eg5 ubiquitination is mono- or polyubiquitination and the specific lysine(s) not mapped
    • How H2Bub1 loss shifts NF-κB dimer composition mechanistically not resolved
  8. 2017 Medium

    Fbxl19 was identified as a CpG-island-directed recruiter of RNF20 to gene promoters in ES cells, and RNF20 was shown to suppress renal cell carcinoma through SREBP1c inhibition, broadening the repertoire of chromatin recruitment mechanisms and tumor-suppressive outputs.

    Evidence Co-IP and genome-wide ChIP-seq for Fbxl19-RNF20; xenograft models and pharmacological SREBP1 inhibition for tumor suppression

    PMID:28453857 PMID:28827316

    Open questions at the time
    • Direct ubiquitination of SREBP1c by RNF20 not demonstrated
    • Single-lab ChIP-seq for Fbxl19; independent validation needed
  9. 2019 High

    Multiple non-histone substrates and adaptor mechanisms were defined: p53 recruits RNF20/RNF40 to p21/PUMA loci where H2Bub1 is read by spliceosome subunit PRPF8 for mRNA maturation; eEF1BδL is monoubiquitinated by RNF20/RAD6 to recruit p-TEFb for heat shock gene transcription; and RNF20 promotes adipogenesis by degrading NCoR1 to activate PPARγ. Additionally, RNF20/RNF40 was shown essential for both HR and NHEJ (class switch recombination) in B cells under ATM/ATR control.

    Evidence In vitro reconstituted ubiquitination for eEF1BδL; affinity purification revealing PRPF8; adipocyte-conditional KO mice; conditional KO B cells with CSR assays

    PMID:30649429 PMID:30692271 PMID:31152661 PMID:31604693

    Open questions at the time
    • Whether PRPF8-H2Bub1 interaction is general or gene-specific not resolved genome-wide
    • ATR versus ATM individual contributions to H2Bub induction not separated cleanly
  10. 2021 High

    SARS-CoV-2 Mpro was shown to cleave RNF20 at Gln521, stabilizing SREBP1 and enhancing viral replication, establishing RNF20 as an antiviral factor; independently, unbiased in vivo CRISPR screens identified RNF20/RNF40 as required for cardiomyocyte maturation, and intestine-specific deletion revealed RNF20 controls VDR expression to prevent spontaneous colitis.

    Evidence Protease cleavage assay with catalytic mutant control; somatic CRISPR screen in mouse heart; intestinal conditional KO with ChIP-seq for VDR

    PMID:34088983 PMID:34290256 PMID:34452991

    Open questions at the time
    • Whether Mpro cleavage occurs at endogenous viral loads not demonstrated
    • Whether cardiomyocyte maturation defect is H2Bub1-dependent or involves non-histone substrates unclear
  11. 2023 High

    A ligase-independent function was discovered: RNF20/Bre1 directly binds Rad51, facilitates Rad51-ssDNA filament assembly and strand exchange, and counteracts anti-recombinases Srs2/FBH1, acting as a bona fide recombination mediator additive to BRCA2; simultaneously, RPA was identified as a recruiter of RNF20 to centromeric R-loops and DSBs, enabling Aurora B activation and chromosome segregation fidelity.

    Evidence In vitro reconstitution of Rad51 filament assembly/strand exchange; Co-IP and domain mapping for RPA-RNF20; genetic epistasis

    PMID:37155876 PMID:37230987

    Open questions at the time
    • Which domain of RNF20 mediates Rad51 binding not mapped
    • Whether RPA-dependent RNF20 centromeric function is conserved in human meiosis unknown
  12. 2023 High

    Tissue-specific conditional knockouts demonstrated RNF20's essential roles in spermatogenesis (via Cldn11 transcription elongation), myogenesis (where ferritinophagy-mediated RNF20 degradation impairs MyoD/MyoG expression), and viral biology (KSHV RTA interaction for lytic reactivation).

    Evidence Sertoli cell-specific KO with ChIP for Cldn11; iron deficiency model with NCOA4 KO for ferritinophagy; proteomics and Co-IP for KSHV RTA

    PMID:37024990 PMID:37888983 PMID:37976359

    Open questions at the time
    • Whether ferritinophagy-RNF20 axis is relevant to iron deficiency anemia-associated myopathies in humans unknown
    • KSHV RTA-RNF20 interaction: single lab, mechanism of exploitation unclear
  13. 2024 High

    CDK9-dependent K29-linked ubiquitination of LSD1 by RNF20 was identified as a mechanism suppressing endogenous retrovirus expression and interferon responses, creating epigenetic immunosuppression reversible by anti-PD-1 therapy; RNF20 was also shown to regulate Pol II promoter-proximal pausing at endothelial genes and to control angiogenesis through Notch1 interaction; depot-specific adipose substrates (GABPα in BAT, NCoR1 in iWAT) were defined; and RNF20 haploinsufficiency was linked to HIF1α-mediated metabolic rewiring independent of H2Bub1.

    Evidence K29-specific ubiquitination assay with CDK9 inhibition; PRO-seq/GRO-seq for Pol II pausing; depot-specific adipose KO mice; mouse haploinsufficiency model with ChIP-seq

    PMID:38296968 PMID:38315842 PMID:39322771 PMID:40436847

    Open questions at the time
    • Whether K29-linked LSD1 ubiquitination is unique to RNF20 or shared with other E3 ligases not tested
    • Structural basis of Notch1-RNF20 interaction unknown
    • H2Bub1-independent mechanisms at HIF1α remain poorly characterized molecularly
  14. 2025 High

    RNF20 was established as a replication fork protector: it localizes to replicating sites, promotes H2Bub there, facilitates RAD51/RAD51C loading at stalled forks, and prevents MRE11/DNA2-dependent fork degradation—functions requiring both RING domain catalytic activity and ATR-mediated phosphorylation.

    Evidence DNA fiber assay with RING and phospho-deficient mutants, epistasis to fork remodelers, chromatin relaxation rescue

    PMID:40495033

    Open questions at the time
    • ATR phosphorylation site(s) on RNF20 not mapped
    • Whether fork protection involves non-histone substrates not addressed
  15. 2026 High

    Cryo-EM structures of the full RNF20/RNF40-RAD6A-nucleosome complex revealed that H2B S112 GlcNAcylation allosterically stimulates ubiquitin transfer by contacting RAD6A (not the E3), enhancing K120 nucleophilicity; crystal structures of Bre1-Lge1 and AlphaFold models of the RNF20/RNF40-WAC complex defined the extensive adaptor interfaces essential for H2Bub1 in vivo.

    Evidence Cryo-EM with chemically synthesized GlcNAc-nucleosomes and kinetics; X-ray crystallography of Bre1-Lge1 with in vitro/in vivo mutagenesis

    PMID:41495224 PMID:41533567

    Open questions at the time
    • Whether GlcNAcylation-mediated stimulation occurs at all genomic loci or specific chromatin contexts unknown
    • Full-length RNF20/RNF40 structure on nucleosome not yet determined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: how RNF20 selects between histone and diverse non-histone substrates in different cellular contexts; the structural basis for ligase-independent Rad51 mediator activity; whether RNF20 mutations cause Mendelian disease in humans; and how ATR phosphorylation sites regulate RNF20 activity at replication forks versus DSBs.
  • No substrate-selection mechanism resolved
  • No full-length structure of human RNF20/RNF40 heterodimer
  • No Mendelian disease association established by direct genetic evidence

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 12 GO:0042393 histone binding 5 GO:0060090 molecular adaptor activity 2
Localization
GO:0005694 chromosome 6 GO:0005634 nucleus 5
Pathway
R-HSA-4839726 Chromatin organization 7 R-HSA-392499 Metabolism of proteins 6 R-HSA-73894 DNA Repair 6 R-HSA-74160 Gene expression (Transcription) 6 R-HSA-1266738 Developmental Biology 4 R-HSA-1640170 Cell Cycle 2 R-HSA-8953854 Metabolism of RNA 2
Partners
FACTNOTCH1RAD51RAD6ARNF40RPASMURF2WAC
Complex memberships
RNF20/RNF40 heterodimerRNF20/RNF40-RAD6A (hBre1-hRAD6) E3-E2 complex

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 RNF20 localizes to DNA double-strand breaks (DSBs) independently of H2AX and is required for DSB-induced H2B ubiquitination, H3K4 methylation at DSBs, and recruitment of chromatin-remodeling factor SNF2h; depletion of RNF20 or expression of H2B K120R compromises DNA end resection, RAD51 and BRCA1 recruitment, and homologous recombination repair (HRR), and this function can be partially bypassed by forced chromatin relaxation. siRNA depletion, H2B K120R mutant expression, γ-H2AX foci, ChIP, HR repair assay, radiation sensitivity Molecular cell High 21362548
2011 WAC interacts with RNF20/RNF40 through its C-terminal coiled-coil region, recruits the complex to RNA polymerase II via its N-terminal WW domain during active transcription, and promotes RNF20/RNF40 E3 ligase activity for H2B ubiquitination; WAC depletion abolishes H2Bub. Protein affinity purification, Co-IP, domain mapping, knockdown, ChIP Molecular cell High 21329877
2012 RNF20-mediated H2B monoubiquitylation (H2Bub1) increases during embryonic stem cell (ESC) differentiation and is required for transcriptional induction of relatively long genes; USP44 deubiquitinase negatively regulates H2Bub1 and its downregulation during differentiation contributes to increased H2Bub1. Knockdown/depletion, qRT-PCR, RNA-seq, ChIP, western blot Molecular cell High 22681888
2012 Smurf2 (HECT-domain E3 ligase) targets RNF20 for proteasomal degradation, thereby regulating RNF20-dependent H2B monoubiquitination and H3K4/H3K79 trimethylation; Smurf2 and RNF20 co-localize at γ-H2AX foci at DSBs. Genetic ablation (mouse model), western blot, immunofluorescence co-localization, ChIP Nature medicine High 22231558
2012 RNF20/RNF40 deficiency leads to formation of aberrant R-loops (RNA:DNA hybrids) at replication forks, causing replication-associated DSBs, specific genomic rearrangements, and chromosomal instability. Bre1/RNF20 depletion, DNA fiber assay, cytogenetics, R-loop detection Cancer research High 22354749
2011 CDC73 (parafibromin) interacts with RNF20 and RNF40 (identified by yeast two-hybrid), and CDC73 is required for maintenance of H2B K120 monoubiquitination; pathogenic CDC73 mutations reduce H2Bub1 in parathyroid tumors. Yeast two-hybrid, Co-IP, domain mapping, siRNA knockdown, western blot, tumor samples Human molecular genetics High 22021426
2013 Histone chaperone FACT (SUPT16H subunit) directly binds RNF20 in vivo; mutation at the RING-finger domain of RNF20 abolishes this interaction; FACT is required for RNF20 recruitment to DSBs and subsequent H2B ubiquitylation and SNF2h accumulation, enabling homologous recombination repair. PAF1 (a known transcriptional mediator of FACT-RNF20 association) is dispensable for DNA-damage-induced RNF20-FACT interaction. Co-IP, RING domain mutagenesis, siRNA depletion, laser-induced DSB imaging, γ-H2AX, HR assay Journal of cell science High 24357716
2013 RNF20 is required for MLL-fusion-mediated leukemogenesis; Rnf20 knockdown reduces H2B ubiquitination enriched in MLL-fusion target gene bodies, reduces local H3K79 methylation by Dot1l at Hoxa9 and Meis1, and suppresses MLL-fusion target gene expression, indicating co-transcriptional RNF20 recruitment amplifies Dot1l-mediated H3K79me at oncogenic targets. shRNA knockdown, ChIP-seq, RNA-seq, in vivo mouse leukemia model Proceedings of the National Academy of Sciences of the United States of America High 23412334
2013 Human adenovirus E1A protein binds RNF20 (hBre1) and repurposes it from a ubiquitin ligase to a scaffold that recruits hPaf1 to activate viral early gene transcription, while simultaneously blocking H2B monoubiquitination to suppress the interferon response. Co-IP, reporter assay, knockdown, ChIP PLoS pathogens Medium 23785282
2014 Arsenite binds directly to the RING finger domain cysteine residues of RNF20 and RNF40 in vitro and in cells, inhibiting H2B ubiquitination and impairing BRCA1/RAD51 recruitment to DSBs and DNA repair. In vitro binding assay, cell-based H2Bub1 assay, laser-induced DSB recruitment, comet assay Journal of the American Chemical Society High 25170678
2016 RNF20/RNF40 complex monoubiquitinates and stabilizes the mitotic kinesin motor protein Eg5, interacting with it during mitosis; loss of RNF20/RNF40 causes spindle assembly defects, cell cycle arrest, and apoptosis. Co-IP, ubiquitination assay, siRNA depletion, immunofluorescence, in vivo tumor models Nature communications High 27557628
2016 Downregulation of RNF20 and H2Bub1 favors recruitment of p65-containing NF-κB dimers over repressive p50 homodimers and decreases H3K9me3 on a subset of NF-κB target genes, augmenting their transcription and promoting inflammation-associated colorectal cancer. siRNA knockdown, ChIP, NF-κB reporter, mouse genetic model (RNF20+/- mice), human patient samples Cell reports High 26854224
2016 Crystal structure of the RNF20 RING domain reveals it forms a homodimer that specifically interacts with the Ube2B~Ub conjugate; heterodimer of RNF20 and RNF40 RING domains is active; mutagenesis of E3-E2 and E3-ubiquitin interfaces identifies key contacts required for Ube2B~Ub interaction. X-ray crystallography, mutagenesis, in vitro ubiquitin transfer assay Journal of molecular biology High 27569044
2017 RNF20 suppresses tumorigenesis in clear cell renal cell carcinoma by inhibiting SREBP1c, which regulates cell cycle progression through PTTG1; RNF20 overexpression represses lipogenesis and cell proliferation. Overexpression, knockdown, western blot, xenograft tumor models, pharmacological SREBP1 inhibition Molecular and cellular biology Medium 28827316
2011 RNF20 and RNF40 physically and functionally interact with the androgen receptor (AR) and modulate AR-dependent transcription; ChIP shows androgen induction of FKBP51 and PSA is accompanied by dynamic increase in H2Bub1 within transcribed regions. Co-IP, reporter assay, ChIP, siRNA depletion Molecular and cellular endocrinology Medium 22155569
2019 RNF20/RNF40 complex associates with p53 on chromatin; p53 mediates recruitment of RNF20/RNF40 to p21 and PUMA loci; RNF20/RNF40-dependent H2B ubiquitination (ubH2B) is recognized by the ubiquitin-binding motif of PRPF8 (a spliceosome subunit), which is required for maturation of p21 and PUMA mRNAs, linking H2Bub1 to mRNA splicing. Protein affinity purification, Co-IP, ChIP, knockdown, RT-PCR mRNA splicing assay Journal of molecular cell biology High 31152661
2019 RNF20/RNF40 in conjunction with RAD6 monoubiquitinates lysine 381 of eEF1BδL (a heat shock transcription factor); monoubiquitylated eEF1BδL increases protein accumulation and potentiates p-TEFb recruitment to heat shock-responsive gene promoters, enhancing their transcription; cooperative physical interactions among eEF1BδL, RNF20/RNF40, and HSF1 are required. In vitro ubiquitylation assay with purified factors, Co-IP, ChIP, siRNA knockdown, qRT-PCR Nucleic acids research High 30649429
2019 RNF20 promotes adipogenesis by acting as a transcriptional coactivator for PPARγ through proteasomal degradation of nuclear corepressor NCoR1; Rnf20 adipocyte-specific knockout mice show reduced fat mass and impaired PPARγ target gene expression. Conditional knockout mice, quantitative proteomics, western blot, reporter assay, adipogenesis assay Diabetes High 31604693
2013 RNF20 interacts with and promotes polyubiquitination and proteasome-dependent degradation of AP-2α transcription factor; overexpression of RNF20 inhibits AP-2α activity and rescues C/EBPα expression repressed by AP-2α. Co-IP, mass spectrometry, ubiquitination assay, overexpression, reporter assay Acta biochimica et biophysica Sinica Medium 24374663
2021 SARS-CoV-2 main protease 3Clpro cleaves RNF20 at a conserved Gln521, which prevents SREBP1 from RNF20-mediated degradation and promotes viral replication; RNAi-mediated depletion of RNF20 or RNF40 enhances viral replication, indicating antiviral activity. Bioinformatics prediction, protease cleavage assay, catalytic mutant (3ClproC145A), RNAi knockdown, viral replication assay Proceedings of the National Academy of Sciences of the United States of America High 34452991
2023 RNF20/RNF40-RAD6A (hRAD6A) ubiquitin transfer structures were captured by chemical trapping and solved by cryo-EM; RNF40 directly binds nucleosomal DNA; the interface shows conserved E3/E2/nucleosome interaction from yeast to humans; an unconventional non-hydrophobic contact in the Bre1 RING-Rad6 interface positions E2 directly above the target H2B lysine. Chemical trapping, cryo-EM structure determination, mutagenesis Molecular cell High 37633270
2023 Replication protein A (RPA) interacts with RNF20 and recruits it to mitotic centromeres in a centromeric R-loop-dependent manner and to chromosomal breaks upon DNA damage; disruption of RPA-RNF20 interaction increases mitotic lagging chromosomes and impairs BRCA1/RAD51 loading and HR repair; mechanistically, the RPA-RNF20 pathway promotes local H2Bub, H3K4 dimethylation, and SNF2H recruitment, ensuring Aurora B kinase activation at centromeres. Co-IP, domain mapping, RPA-RNF20 interaction disruption mutants, ChIP, immunofluorescence, HR assay Proceedings of the National Academy of Sciences of the United States of America High 37155876
2023 Bre1/RNF20 functions as a recombination mediator independent of its ligase activity: it interacts with Rad51, directs Rad51 to ssDNA, facilitates Rad51-ssDNA filament assembly and strand exchange in vitro, and counteracts the Srs2/FBH1 helicases that disrupt Rad51 filaments; this function is additive to Rad52 (yeast) or BRCA2 (human). In vitro Rad51 filament assembly and strand exchange reconstitution, Co-IP, genetic epistasis, cell-based HR assay Nature communications High 37230987
2018 RNF20 interacts with Snail and G9a; RNF20 and H3K9me2 are enriched on the E-cadherin promoter in a Snail-dependent manner; RNF20 knockdown reduces this enrichment, linking RNF20 to Snail-mediated epigenetic repression of E-cadherin during EMT. Co-IP, ChIP, siRNA knockdown, migration/invasion assay Frontiers in oncology Medium 33364200
2017 Fbxl19 (CxxC domain-containing protein) interacts with Rnf20 and recruits it to CpG island-containing gene promoters; Fbxl19 downregulation reduces H2Bub1 genome-wide at CpG island targets; this interaction is required for proper ES cell differentiation. Co-IP, genome-wide ChIP-seq, siRNA knockdown, differentiation assay Nucleic acids research Medium 28453857
2024 RNF20 stabilizes LSD1 via K29-linked ubiquitination in a CDK9-phosphorylation-dependent manner; this CDK9/RNF20-dependent LSD1 stabilization promotes H3K4 demethylation, suppresses endogenous retrovirus expression and interferon response, leading to epigenetic immunosuppression; loss of RNF20 sensitizes cancer cells to anti-PD-1 immunotherapy. Co-IP, ubiquitination assay (K29-specific), CDK9 inhibition, ectopic LSD1 rescue, in vivo anti-PD-1 treatment Proceedings of the National Academy of Sciences of the United States of America High 38315842
2024 HIF-1 recruits both FACT and RNF20/RNF40 to hypoxia response elements (HREs); FACT and RNF20/RNF40 stabilize HIF-1 binding at HREs and each other; hypoxia induces H2B K120 monoubiquitination at HIF-1 target genes in an HIF-1-dependent manner; FACT and RNF20/RNF40 are required for transcription initiation and elongation at HIF-1 target genes. ChIP, siRNA knockdown, RNA-seq, Co-IP Cell reports Medium 38517892
2024 RNF20 mediates RNA Polymerase II promoter-proximal pausing at highly paused endothelial cell genes; RNF20 restricts ERG-dependent Pol II pause release at these genes while binding Notch1 to promote H2Bub1 at Notch target genes; loss of Rnf20 leads to uncontrolled tip cell specification; RNF20 also orchestrates VEGFA mRNA splicing. CRISPR/Cas9 knockout, ChIP-seq, PRO-seq/GRO-seq (transcriptional pausing), RNA-seq, Co-IP with Notch1, in vivo angiogenesis assay Nature cardiovascular research High 39322771
2025 RNF20 localizes to replicating sites and promotes H2Bub there; RNF20 knockdown leads to MRE11/DNA2-dependent stalled fork degradation; RNF20 facilitates RAD51 and RAD51C loading at stalled forks; RING domain (catalytic) and ATR-mediated phosphorylation of RNF20 are essential for these replication stress responses; chromatin relaxation rescues fork protection defects in RNF20-depleted cells. DNA fiber assay, siRNA depletion, RING domain mutant, phospho-deficient mutant, Co-IP, immunofluorescence at replication forks, chromatin relaxation rescue EMBO reports High 40495033
2024 RNF20 regulates oocyte acentrosomal spindle assembly by recruiting tropomyosin 3 (TPM3) to centromeres and spindle poles via its coiled-coil motif; this function is independent of RNF20's E3 ligase activity; RNF20-depleted oocytes show abnormal spindle and chromosome misalignment. Oocyte-specific depletion, immunofluorescence, Co-IP, coiled-coil domain mapping, E3 ligase dead mutant Advanced science Medium 38240347
2018 RNF20 interacts with ZSCAN4 protein; RNF20 depletion increases ZSCAN4 protein levels and stabilizes its half-life without affecting ZSCAN4 mRNA, indicating RNF20 negatively regulates ZSCAN4 protein stability via ubiquitin-proteasome degradation. Co-IP, cycloheximide chase, siRNA knockdown, K48-polyubiquitination assay Biochemical and biophysical research communications Medium 29477841
2023 Conditional knockout of Rnf20 in Sertoli cells causes H2BK120ub loss, impairs transcription elongation of Cldn11 (tight junction component), disrupts cell adhesion and seminiferous tubule organization, and leads to apoptosis of spermatogonia and spermatocytes, causing male infertility recapitulating Sertoli cell-only syndrome. Conditional knockout mouse (Amh-Cre), ChIP, RNA-seq, western blot, histology Cell & bioscience High 37024990
2021 RNF20 and RNF40 are required for cardiomyocyte maturation; in vivo CRISPR screen identifies RNF20/40 as regulators; the H2BK120 monoubiquitination epigenetic mark controls dynamic gene expression changes required for cardiomyocyte maturation. In vivo somatic CRISPR screen, conditional validation, RNA-seq, ChIP Nature communications High 34290256
2021 Intestine-specific deletion of Rnf20 or Rnf40 causes spontaneous colorectal inflammation; RNF20/RNF40 controls H3K4me3 occupancy and transcription of the Vitamin D Receptor (Vdr) gene and VDR target genes; loss of H2Bub1 promotes IBD-associated gene expression programs. Conditional knockout mice, ChIP-seq, RNA-seq, patient ChIP-seq Cell death and differentiation High 34088983
2019 RNF20 and RNF40 are required for DSB repair leading to both homologous recombination and class switch recombination (NHEJ) in mouse B cells; DSBs induce a global increase in H2Bub independent of H2AX phosphorylation; ATM and ATR jointly regulate IR-induced H2Bub. Conditional knockout B cells, class switch recombination assay, HR assay, western blot for H2Bub, γ-H2AX Molecular and cellular biology High 30692271
2023 Ferritinophagy (selective autophagy) induced by iron deficiency causes RNF20 degradation through the autophagy-lysosomal pathway; reduced RNF20 decreases H2Bub1 at promoters of myogenic markers MyoD and MyoG, inhibiting myogenic differentiation and skeletal muscle regeneration. Iron deficiency model, lysosomal inhibitor, conditional NCOA4 KO, ChIP, myogenic differentiation assay Science advances High 37976359
2024 RNF20 controls Rbx1 expression and thereby the activity of the VHL ubiquitin ligase complex and HIF1α protein levels; RNF20 haploinsufficiency results in inadequate tumor suppression via the Rnf20-H2Bub1-p53 axis and induces metabolic rewiring through HIF1α-mediated RNAPII promoter-proximal pause release (independent of H2Bub1). Mouse haploinsufficiency model, RNA-seq, ChIP-seq, western blot, metabolomics Nature communications High 40436847
2024 Upon cold stimuli in brown adipose tissue (BAT), RNF20 is rapidly downregulated allowing GABPα protein to accumulate (by controlling its stability), stimulating thermogenic gene expression; in inguinal white adipose tissue (iWAT), RNF20 is gradually upregulated upon prolonged cold and promotes beige adipogenesis via NCoR1 protein degradation to activate PPARγ (depot-specific substrates). Adipose tissue-specific KO mice, cold challenge experiments, Co-IP, protein stability assay, western blot, gene expression Nature communications High 38296968
2023 KSHV RTA protein interacts with the RNF20/RNF40 complex; this interaction is necessary for RTA-induced KSHV lytic reactivation. Proteomics, Co-IP, siRNA knockdown, lytic reactivation assay Journal of virology Medium 37888983
2026 H2B S112 GlcNAcylation allosterically stimulates RNF20/RNF40-RAD6A-mediated H2B K120 monoubiquitylation by interacting with the E2 enzyme RAD6A (not the E3 ligase); cryo-EM structure of trapped RNF20/RNF40-RAD6A-Ub-H2BS112GlcNAc nucleosome complex reveals the GlcNAc moiety enhances nucleophilicity of H2B K120; the C2 N-acetyl group and β-configuration of C1 are essential. Chemical synthesis of modified nucleosomes, cryo-EM, kinetics assays, mutagenesis, structure-activity relationship analysis Nature chemical biology High 41495224
2026 Crystal structure of the Bre1-Lge1 complex and AlphaFold model of RNF20/RNF40-WAC reveal extensive interaction interfaces; the RNF20/RNF40-WAC interaction is critical for the H2BUb1 reaction in vitro and in vivo; key electrostatic interactions at these interfaces encode binding specificity. X-ray crystallography, AlphaFold structural modeling, in vitro ubiquitination assay, in vivo functional assay Nucleic acids research High 41533567
2023 RNF20 promotes STAT3 ubiquitination and degradation; exosomal miR-let-7b-5p targets RNF20, reducing it and thereby allowing STAT3/FOXO1 axis activation and insulin resistance in skeletal muscle cells; ectopic RNF20 expression attenuates this insulin resistance. Luciferase reporter (let-7b-5p target), Co-IP, ubiquitination assay, rescue experiment with RNF20 overexpression Diabetes, metabolic syndrome and obesity Medium 37842335
2010 RNF20 (hBre1) is localized to the IRF1 gene locus in both uninduced and IFNγ-induced states; RNAi-mediated depletion of RNF20 lowers both H2Bub and H3K4me3 but unexpectedly upregulates IFNγ-induced IRF1 transcription, indicating that H2Bub can exert a repressive effect on inducible transcription at this locus, possibly by affecting RNA Pol II CTD phosphorylation cycling. ChIP, RNAi depletion, qRT-PCR Epigenetics & chromatin Medium 20825659

Source papers

Stage 0 corpus · 71 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Regulation of homologous recombination by RNF20-dependent H2B ubiquitination. Molecular cell 299 21362548
2012 RNF20 and USP44 regulate stem cell differentiation by modulating H2B monoubiquitylation. Molecular cell 175 22681888
2012 A tumor suppressor function of Smurf2 associated with controlling chromatin landscape and genome stability through RNF20. Nature medicine 136 22231558
2011 WAC, a functional partner of RNF20/40, regulates histone H2B ubiquitination and gene transcription. Molecular cell 132 21329877
2016 RNF20 Links Histone H2B Ubiquitylation with Inflammation and Inflammation-Associated Cancer. Cell reports 109 26854224
2012 Deficiency in mammalian histone H2B ubiquitin ligase Bre1 (Rnf20/Rnf40) leads to replication stress and chromosomal instability. Cancer research 105 22354749
2013 Histone H2B ubiquitin ligase RNF20 is required for MLL-rearranged leukemia. Proceedings of the National Academy of Sciences of the United States of America 95 23412334
2011 The tumor suppressor CDC73 interacts with the ring finger proteins RNF20 and RNF40 and is required for the maintenance of histone 2B monoubiquitination. Human molecular genetics 71 22021426
2019 E3 Ubiquitin Ligases RNF20 and RNF40 Are Required for Double-Stranded Break (DSB) Repair: Evidence for Monoubiquitination of Histone H2B Lysine 120 as a Novel Axis of DSB Signaling and Repair. Molecular and cellular biology 58 30692271
2016 Ubiquitin ligase RNF20/40 facilitates spindle assembly and promotes breast carcinogenesis through stabilizing motor protein Eg5. Nature communications 58 27557628
2021 Massively parallel in vivo CRISPR screening identifies RNF20/40 as epigenetic regulators of cardiomyocyte maturation. Nature communications 51 34290256
2013 Histone chaperone FACT regulates homologous recombination by chromatin remodeling through interaction with RNF20. Journal of cell science 51 24357716
2017 The HDAC inhibitor panobinostat (LBH589) exerts in vivo anti-leukaemic activity against MLL-rearranged acute lymphoblastic leukaemia and involves the RNF20/RNF40/WAC-H2B ubiquitination axis. Leukemia 48 28690313
2014 Arsenite binds to the RING finger domains of RNF20-RNF40 histone E3 ubiquitin ligase and inhibits DNA double-strand break repair. Journal of the American Chemical Society 47 25170678
2017 RNF20 and histone H2B ubiquitylation exert opposing effects in Basal-Like versus luminal breast cancer. Cell death and differentiation 46 28157208
2017 RNF20 Suppresses Tumorigenesis by Inhibiting the SREBP1c-PTTG1 Axis in Kidney Cancer. Molecular and cellular biology 45 28827316
2011 Histone H2B ubiquitin ligases RNF20 and RNF40 in androgen signaling and prostate cancer cell growth. Molecular and cellular endocrinology 44 22155569
2021 Protease cleavage of RNF20 facilitates coronavirus replication via stabilization of SREBP1. Proceedings of the National Academy of Sciences of the United States of America 43 34452991
2018 Role of RNF20 in cancer development and progression - a comprehensive review. Bioscience reports 37 29934362
2016 The RING finger domain E3 ubiquitin ligases BRCA1 and the RNF20/RNF40 complex in global loss of the chromatin mark histone H2B monoubiquitination (H2Bub1) in cell line models and primary high-grade serous ovarian cancer. Human molecular genetics 30 27798111
2023 Mechanistic insights into nucleosomal H2B monoubiquitylation mediated by yeast Bre1-Rad6 and its human homolog RNF20/RNF40-hRAD6A. Molecular cell 27 37633270
2010 Menin and RNF20 recruitment is associated with dynamic histone modifications that regulate signal transducer and activator of transcription 1 (STAT1)-activated transcription of the interferon regulatory factor 1 gene (IRF1). Epigenetics & chromatin 27 20825659
2016 Structure and Function of the RING Domains of RNF20 and RNF40, Dimeric E3 Ligases that Monoubiquitylate Histone H2B. Journal of molecular biology 26 27569044
2019 RNF20 Functions as a Transcriptional Coactivator for PPARγ by Promoting NCoR1 Degradation in Adipocytes. Diabetes 25 31604693
2013 Viral retasking of hBre1/RNF20 to recruit hPaf1 for transcriptional activation. PLoS pathogens 22 23785282
2023 The RPA-RNF20-SNF2H cascade promotes proper chromosome segregation and homologous recombination repair. Proceedings of the National Academy of Sciences of the United States of America 21 37155876
2020 The RNF20/40 complex regulates p53-dependent gene transcription and mRNA splicing. Journal of molecular cell biology 21 31152661
2019 RNF20/40-mediated eEF1BδL monoubiquitylation stimulates transcription of heat shock-responsive genes. Nucleic acids research 20 30649429
2014 Bre1a, a histone H2B ubiquitin ligase, regulates the cell cycle and differentiation of neural precursor cells. The Journal of neuroscience : the official journal of the Society for Neuroscience 19 24553946
2021 RNF20 and RNF40 regulate vitamin D receptor-dependent signaling in inflammatory bowel disease. Cell death and differentiation 17 34088983
2020 Rnf20 deficiency in adipocyte impairs adipose tissue development and thermogenesis. Protein & cell 17 32797353
2020 RNF20 Is Critical for Snail-Mediated E-Cadherin Repression in Human Breast Cancer. Frontiers in oncology 15 33364200
2018 Spinal RNF20-Mediated Histone H2B Monoubiquitylation Regulates mGluR5 Transcription for Neuropathic Allodynia. The Journal of neuroscience : the official journal of the Society for Neuroscience 15 30201771
2022 Endothelial cells regulated by RNF20 orchestrate the proliferation and differentiation of neural precursor cells during embryonic development. Cell reports 14 36103829
2021 RNF20 affects porcine adipocyte differentiation via regulation of mitotic clonal expansion. Cell proliferation 13 34647359
2018 ZSCAN4 is negatively regulated by the ubiquitin-proteasome system and the E3 ubiquitin ligase RNF20. Biochemical and biophysical research communications 13 29477841
2015 RNF20-SNF2H Pathway of Chromatin Relaxation in DNA Double-Strand Break Repair. Genes 13 26184323
2013 RNF20 promotes the polyubiquitination and proteasome-dependent degradation of AP-2α protein. Acta biochimica et biophysica Sinica 13 24374663
2023 Bre1/RNF20 promotes Rad51-mediated strand exchange and antagonizes the Srs2/FBH1 helicases. Nature communications 12 37230987
2022 Epoxymicheliolide directly targets histone H2B to inhibit neuroinflammation via recruiting E3 ligase RNF20. Pharmacological research 12 35074526
2023 Iron deficiency-induced ferritinophagy impairs skeletal muscle regeneration through RNF20-mediated H2Bub1 modification. Science advances 11 37976359
2023 Pancreatic Cancer-Derived Exosomal miR-Let-7b-5p Stimulates Insulin Resistance in Skeletal Muscle Cells Through RNF20/STAT3/FOXO1 Axis Regulation. Diabetes, metabolic syndrome and obesity : targets and therapy 10 37842335
2017 Synthetic lethal targeting of RNF20 through PARP1 silencing and inhibition. Cellular oncology (Dordrecht, Netherlands) 10 28462496
2024 Hypoxia-inducible factor 1 recruits FACT and RNF20/40 to mediate histone ubiquitination and transcriptional activation of target genes. Cell reports 9 38517892
2023 KSHV RTA utilizes the host E3 ubiquitin ligase complex RNF20/40 to drive lytic reactivation. Journal of virology 9 37888983
2017 Fbxl19 recruitment to CpG islands is required for Rnf20-mediated H2B mono-ubiquitination. Nucleic acids research 9 28453857
2024 Albendazole inhibits colon cancer progression and therapy resistance by targeting ubiquitin ligase RNF20. British journal of cancer 8 38278978
2024 RNF20-mediated transcriptional pausing and VEGFA splicing orchestrate vessel growth. Nature cardiovascular research 8 39322771
2023 RNF20 is required for male fertility through regulation of H2B ubiquitination in the Sertoli cells. Cell & bioscience 8 37024990
2022 Rnf20 inhibition enhances immunotherapy by improving regulatory T cell generation. Cellular and molecular life sciences : CMLS 8 36371755
2025 RNF20-mediated H2B monoubiquitination protects stalled forks from degradation and promotes fork restart. EMBO reports 7 40495033
2024 RNF20 contributes to epigenetic immunosuppression through CDK9-dependent LSD1 stabilization. Proceedings of the National Academy of Sciences of the United States of America 7 38315842
2024 Ubiquitin ligase RNF20 coordinates sequential adipose thermogenesis with brown and beige fat-specific substrates. Nature communications 6 38296968
2025 RNF20 links the DNA damage response and metabolic rewiring in lung cancer through HIF1α. Nature communications 5 40436847
2024 RNF20 Regulates Oocyte Meiotic Spindle Assembly by Recruiting TPM3 to Centromeres and Spindle Poles. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 4 38240347
2023 RNF20 deletion causes inflammation in model of sepsis through the NLRP3 activation. Immunopharmacology and immunotoxicology 4 36650938
2023 Adipocyte Rnf20 ablation increases the fast-twitch fibers of skeletal muscle via lysophosphatidylcholine 16:0. Cellular and molecular life sciences : CMLS 4 37555936
2025 RNF20/RNF40 supports the aggressive behavior in cervical cancer by regulating a peroxisome-based anti-ferroptotic mechanism. Cell communication and signaling : CCS 3 40597205
2024 RNF20 Reduces Cell Proliferation and Warburg Effect by Promoting NLRP3 Ubiquitination in Liver Cancer. Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer 3 38608146
2012 R-loops and genomic instability in Bre1 (RNF20/40)-deficient cells. Cell cycle (Georgetown, Tex.) 3 22825248
2025 Adipocyte RNF20 Knockout Leads to Hyperinsulinemia via the H2Bub-H3K4me3-Slc2a4 Axis. Journal of cellular and molecular medicine 2 40522008
2020 Molecular Characterization, Expression Profiling, and SNP Analysis of the Porcine RNF20 Gene. Animals : an open access journal from MDPI 2 32443664
2026 Allosteric activation of RNF20/RNF40-RAD6A-mediated H2BK120 monoubiquitylation by H2BS112 GlcNAcylation. Nature chemical biology 1 41495224
2025 RNF20 dual regulation of MDA5 signaling to maintain immune homeostasis in chickens. Journal of virology 1 39998124
2023 RNF20/RNF40 ameliorates streptozotocin-induced type 1 diabetes by activating vitamin D receptors in vivo. Allergologia et immunopathologia 1 37422774
2026 Structural insights into the Bre1-Lge1 and RNF20/RNF40-WAC interactions critical for H2B ubiquitination. Nucleic acids research 0 41533567
2026 RNF20 dynamically regulates RIG-I and MDA5 transcription and degradation via nucleocytoplasmic translocation to balance antiviral signaling. PLoS pathogens 0 41712649
2026 Decoding RNF20: an epigenetic modifier and beyond. Frontiers in cell and developmental biology 0 42004469
2025 The Islet-1 Interaction Partner Rnf20 Regulates Glucose Homeostasis and Pancreatic β-Cell Identity. Diabetes 0 40743566
2025 Endothelial RNF20 suppresses endothelial-to-mesenchymal transition and safeguards physiological angiocrine signaling to prevent congenital heart disease. Nature communications 0 41145490
2025 Melittin inhibits NSCLC metastasis by targeting USP10 and promoting RNF20-mediated ubiquitination and degradation of PSMA7. Journal of translational medicine 0 41254650