Affinage

RNF2

E3 ubiquitin-protein ligase RING2 · UniProt Q99496

Length
336 aa
Mass
37.7 kDa
Annotated
2026-06-10
100 papers in source corpus 41 papers cited in narrative 42 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/8 claims corpus-supported (88%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RNF2 (RING1B) is the catalytic RING-finger E3 ubiquitin ligase of Polycomb Repressive Complex 1 that monoubiquitinates histone H2A at lysine 119 to enforce chromatin-based transcriptional repression essential for development and stem-cell identity (PMID:16710298, PMID:16714294, PMID:12589020). Its ligase activity depends on heterodimerization with BMI1, whose RING domain is embraced by the Ring1B N-terminal arm; the catalytic residues lie in Ring1B, BMI1 acts allosterically, and the heterodimer recruits the E2 UbcH5c and engages nucleosomal substrate through both a heterodimer-specific basic DNA-binding surface and the nucleosome acidic patch (PMID:16710298, PMID:16714294, PMID:21772249, PMID:24603765). Activity is further gated by atypical self-generated K6/K27/K48 mixed polyubiquitin chains that are required for H2A ligase function, and the same lysines are competitively modified by E6-AP/UBE3A as K48 chains that drive proteasomal degradation, while USP7 deubiquitinates and stabilizes Ring1B — establishing a ubiquitin-based switch between activation and turnover (PMID:17157253, PMID:20351251, PMID:20800574). The Ring1B C-terminal ubiquitin-like domain provides combinatorial targeting by binding Cbx proteins, the Polycomb cbox, and RYBP at a shared surface, directing PRC1 to distinct chromatin loci (PMID:20696397, PMID:19791798). RNF2 governs higher-order genome organization in X chromosome inactivation initiation and imprinted gene silencing, acting non-redundantly with PRC2 (PMID:15509584, PMID:18848501), and beyond chromatin it sustains DNA replication-fork progression by limiting R-loops and transcription–replication conflicts, with the FBXL10–RNF68–RNF2 complex seeding H2AK119ub at DNA-damage sites to promote homologous recombination (PMID:30413623, PMID:32142505, PMID:29985131). RNF2 additionally ubiquitinates a range of non-histone substrates — AMBRA1, p53 (with MDM2), STAT1 (K33-linked, suppressing interferon signaling), and others — coupling Polycomb to autophagy, apoptosis, and innate immunity (PMID:24980959, PMID:23318437, PMID:29242538). Its targeting and dual catalytic/non-catalytic outputs are modulated by p38/ERK and MEK1 phosphorylation and by O-GlcNAcylation (PMID:19405034, PMID:26450788, PMID:26100231). De novo missense variants p.R70H and p.S82R cause a neurodevelopmental disorder, acting as loss-of-function alleles that disrupt the Ring1B–BMI1 or Ring1B–H2A interface (PMID:33864376).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1998 Medium

    Established the physical basis of Polycomb assembly by showing RNF2/RING1B directly heterodimerizes with Bmi-1 through their RING fingers, defining the core protein–protein architecture later found to be catalytic.

    Evidence Yeast two-hybrid and RING-finger domain mapping, also identifying a stable Ph/MPh2 heterotrimer

    PMID:9627119

    Open questions at the time
    • No catalytic function assigned to the dimer
    • In vitro interaction only, no structure
  2. 2003 High

    Demonstrated that Rnf2 is genetically essential, with loss causing gastrulation arrest rescued by Cdkn2a inactivation, placing Polycomb repression of the Ink4a/ARF locus downstream of Rnf2 in development.

    Evidence Conventional knockout mouse with Rnf2 × Cdkn2a genetic epistasis; Co-IP confirming Bmi1 association

    PMID:12589020

    Open questions at the time
    • Did not define the molecular activity responsible
    • Other lethality contributors beyond Cdkn2a not resolved
  3. 2006 High

    Resolved the central question of which subunit is catalytic, establishing Ring1B as the H2A-ubiquitinating E3 whose activity is enhanced by BMI1, via crystal structures of the RING-RING heterodimer plus active-site mutagenesis.

    Evidence Crystal structures of Ring1B/Bmi1 RING-RING dimer, in vitro nucleosomal ubiquitination, E2/E3 interface mutagenesis (two companion studies)

    PMID:16710298 PMID:16714294

    Open questions at the time
    • How the dimer engages the nucleosome substrate not yet defined
    • E2 contacts not crystallized
  4. 2006 High

    Uncovered a self-modification requirement, showing Ring1B builds atypical mixed K6/K27/K48 polyubiquitin chains on itself that are necessary for its H2A ligase activity.

    Evidence In vitro ubiquitination with MS linkage mapping and mutant-ubiquitin controls

    PMID:17157253

    Open questions at the time
    • Mechanism by which self-chains stimulate catalysis unclear
    • In vivo relevance not yet shown
  5. 2010 High

    Defined a ubiquitin-based activation/degradation switch, showing E6-AP adds degradative K48 chains on the same lysines used for activating self-modification, while USP7 reverses ubiquitination to stabilize Ring1B.

    Evidence In vitro ubiquitination/deubiquitination, Co-IP, E6-AP knockout mouse with H2Aub and HoxB9 readouts

    PMID:20351251 PMID:20800574

    Open questions at the time
    • USP7 study did not distinguish activating vs degradative chains
    • Signals dictating switch direction in vivo unknown
  6. 2011 High

    Provided a substrate-recognition mechanism, showing the heterodimer presents UbcH5c on Ring1B and a heterodimer-unique basic surface that binds DNA, required for nucleosomal H2A ubiquitination.

    Evidence Crystal structure of Bmi1/Ring1B–UbcH5c, mutagenesis, in vitro ubiquitination, nucleosome docking

    PMID:21772249

    Open questions at the time
    • Full nucleosome-bound structure not experimentally determined
    • Acidic-patch contribution defined only later
  7. 2014 High

    Showed the nucleosome acidic patch is an essential docking determinant for RING1B/BMI1-mediated H2A ubiquitination, linking the mark to DNA damage response.

    Evidence In vitro ubiquitination with acidic-patch mutant nucleosomes, viral LANA peptide perturbation, ChIP, immunofluorescence

    PMID:24603765

    Open questions at the time
    • Structural detail of acidic-patch engagement inferred
    • Generality across PRC1 variants not tested here
  8. 2010 High

    Explained combinatorial chromatin targeting, showing the Ring1B C-terminal ubiquitin-like domain binds Cbx, the Pc cbox, and RYBP at a shared surface forming near-identical interfaces with structurally diverse partners.

    Evidence Crystal structure of C-RING1B–cbox, NMR, mutagenesis, Drosophila chromatin association (building on earlier NMR/structure work)

    PMID:18616292 PMID:19791798 PMID:20696397

    Open questions at the time
    • Which partner dominates at specific loci in vivo not fully resolved
    • Regulation of partner choice unknown
  9. 2008 High

    Established that PRC1 (via Rnf2) and PRC2 act non-redundantly in higher-order genome organization, each independently required for imprinted-cluster contraction and silencing, and for X-inactivation initiation.

    Evidence Conditional knockout embryos, 3D-FISH/RNA-FISH; earlier ES-cell conditional KO and Xi localization studies

    PMID:15509584 PMID:17620408 PMID:18848501

    Open questions at the time
    • Direct cause of genomic contraction not mechanistically defined
    • Relationship between H2Aub and folding unresolved
  10. 2015 High

    Revealed that much of PRC1-mediated repression and early development are independent of RING1B catalytic activity, separating enzymatic from scaffolding/targeting functions.

    Evidence Catalytic-dead RING1B knockin mouse, ChIP-seq, transcriptomics

    PMID:26385961

    Open questions at the time
    • Which functions strictly require catalysis not enumerated
    • Compensatory mechanisms not defined
  11. 2020 High

    Defined a non-canonical genome-protective role, showing RNF2/BMI1 suppress R-loops, transcription–replication conflicts, and fragile-site instability to sustain replication-fork progression.

    Evidence DNA fiber assays, proximity ligation, ChIP, CRISPR-KO, FANCD2/FANCI epistasis, RNaseH rescue (multiple studies)

    PMID:26272920 PMID:29985131 PMID:30413623 PMID:32142505

    Open questions at the time
    • How H2AK119ub mechanistically resolves R-loops unclear
    • Tissue/cell-type generality not fully mapped
  12. 2017 High

    Extended RNF2 beyond chromatin to immune signaling, showing nuclear RNF2 adds K33-linked ubiquitin to STAT1 at K379 to evict STAT1/STAT2 from DNA and suppress interferon-stimulated genes.

    Evidence E3 ligase screen, Co-IP, K379R mutagenesis, in vitro ubiquitination, ChIP, conditional KO

    PMID:29242538

    Open questions at the time
    • Upstream signals localizing RNF2 to STAT1 unknown
    • Whether PRC1 partners participate not addressed
  13. 2014 High

    Demonstrated non-histone proteasomal substrate ubiquitination by RNF2, exemplified by WASH-recruited AMBRA1 K48 ubiquitination that downregulates autophagy.

    Evidence Co-IP, in vitro ubiquitination, K45 mutagenesis, autophagy flux, RNF2/WASH depletion

    PMID:24980959

    Open questions at the time
    • Structural basis of substrate selection not defined
    • Relationship to PRC1 assembly unclear
  14. 2015 High

    Showed RNF2 drives cancer phenotypes through catalysis-dependent and catalysis-independent routes, with MEK1 phosphorylation recruiting UTX/p300 for transcriptional activation versus H2AK119ub-mediated silencing.

    Evidence Catalytic-dead mutant, ChIP-seq, MEK1 phosphorylation assay, melanoma models; supported by phospho-site and O-GlcNAc mapping

    PMID:19405034 PMID:26100231 PMID:26450788

    Open questions at the time
    • Switch between activator and repressor modes incompletely defined
    • Generality of activation function across loci unknown
  15. 2021 Medium

    Linked RNF2 to human disease, identifying de novo p.R70H and p.S82R variants in a neurodevelopmental disorder that act as loss-of-function alleles disrupting BMI1 or H2A interfaces.

    Evidence Structural analysis of variant positions and Drosophila in vivo functional assays

    PMID:33864376

    Open questions at the time
    • Interface disruption inferred from structure, not co-crystals of variants
    • Mammalian phenotypic modeling limited

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RNF2 selects between its many non-histone substrates (p53, SIK1, IRF4, RASSF10, GATA4) and how its diverse post-translational modifications and partner switches are coordinated in vivo to dictate chromatin versus non-chromatin output remains unresolved.
  • No unifying model of substrate choice
  • Spatiotemporal control of catalytic vs scaffold roles undefined
  • Many non-histone substrates rest on single-lab Co-IP/ubiquitination data

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 12 GO:0140096 catalytic activity, acting on a protein 7 GO:0042393 histone binding 3 GO:0140110 transcription regulator activity 3 GO:0003677 DNA binding 1
Localization
GO:0000228 nuclear chromosome 4 GO:0005634 nucleus 4
Pathway
R-HSA-392499 Metabolism of proteins 6 R-HSA-4839726 Chromatin organization 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1266738 Developmental Biology 3 R-HSA-69306 DNA Replication 3 R-HSA-9612973 Autophagy 2 R-HSA-168256 Immune System 1 R-HSA-73894 DNA Repair 1
Partners
BMI1CBXFBXL10MDM2RYBPSTAT1UBE3AUSP7
Complex memberships
FBXL10-RNF68-RNF2 (FRRUC)PRC1Ring1B-Fbxl10-BcoR complex

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 The RING domain of Ring1B is the catalytic E3 ubiquitin ligase subunit for histone H2A monoubiquitination; Bmi1 enhances this activity in vitro. Crystal structure of the Ring1B/Bmi1 RING-RING heterodimer reveals that Ring1B's N-terminal arm embraces the Bmi1 RING domain, and mutation of the critical E2/E3 interface residue in Ring1B abolishes activity while the equivalent Bmi1 mutation does not, demonstrating catalytic activity resides in Ring1B. In vitro ubiquitination assay, active-site mutagenesis, crystal structure of Ring1B/Bmi1 RING-RING heterodimer The EMBO journal High 16710298 16714294
2006 A 2.5-Å crystal structure of the Bmi1-Ring1B core domain complex shows Ring1B 'hugs' Bmi1 through extensive RING domain contacts and an N-terminal tail that wraps around Bmi1; both contact regions synergistically enhance E3 ligase activity toward nucleosomal H2A by stabilizing the E2 enzyme-substrate interaction. Crystal structure (2.5 Å), in vitro ubiquitin transfer assay, domain mapping The Journal of biological chemistry High 16714294
2011 Crystal structure of the Bmi1/Ring1B RING-RING heterodimer in complex with E2 enzyme UbcH5c shows UbcH5c contacts Ring1B only; additionally, the Bmi1/Ring1B dimer binds duplex DNA through a basic surface patch unique to the heterodimer, and mutation of this surface abolishes H2A ubiquitination activity, revealing a novel nucleosome substrate-recognition mechanism. Crystal structure of Bmi1/Ring1B-UbcH5c complex, mutagenesis, in vitro ubiquitination assay, computational nucleosome docking The EMBO journal High 21772249
2006 Ring1B generates atypical mixed K6-, K27-, and K48-based polyubiquitin chains through self-ubiquitination; this non-canonical self-modification is required for Ring1B's ability to monoubiquitinate histone H2A in vitro. Bmi1 has no self-ubiquitinating activity. Both Ring1B and Bmi1 are degraded by an exogenous E3 independent of their RING domains. In vitro ubiquitination assay, mass spectrometry linkage mapping, mutant ubiquitin analysis Molecular cell High 17157253
2010 E6-AP (UBE3A) ubiquitin ligase targets Ring1B for K48-linked polyubiquitination and proteasomal degradation; both Ring1B self-ubiquitination and E6-AP-mediated ubiquitination target the same lysine residues, creating mutually exclusive modifications that dictate activation versus degradation. E6-AP knockout mice display elevated Ring1B and ubiquitinated H2A levels with repressed HoxB9 expression in vivo. In vitro ubiquitination assay, co-immunoprecipitation, E6-AP knockout mouse analysis, immunoblot Proceedings of the National Academy of Sciences of the United States of America High 20351251
2010 USP7 deubiquitinase interacts with Ring1B (via its RING domain) and directly deubiquitinates Ring1B both in vitro and in vivo, stabilizing Ring1B without discriminating between its activating and proteolysis-targeting polyubiquitin chain forms. USP7 is also found in a complex with other Polycomb proteins. Co-immunoprecipitation, in vitro deubiquitination assay, in vivo ubiquitination analysis Biochemical and biophysical research communications Medium 20800574
2003 Genetic ablation of Rnf2 (Ring1B) in mice causes gastrulation arrest and early embryonic lethality; this phenotype is partially rescued by concurrent genetic inactivation of the Cdkn2a (Ink4a/ARF) locus, placing Polycomb-mediated Cdkn2a repression downstream of Rnf2 during early development. Conventional knockout mouse, genetic epistasis (Rnf2 null × Cdkn2a null double mutant) Proceedings of the National Academy of Sciences of the United States of America High 12589020
2004 Ring1B localizes to the inactive X chromosome (Xi) in female trophoblast stem (TS) and differentiating embryonic stem (ES) cells, and ubiquitinated H2A at K119 co-enriches at Xi; this enrichment is transient during differentiation, implicating Ring1B-mediated H2AK119ub in initiation but not maintenance of X chromosome inactivation. Immunofluorescence, chromatin immunoprecipitation, cell fractionation in TS and ES cells The Journal of biological chemistry Medium 15509584
2007 Ring1B deletion in mouse ES cells causes loss of several PRC1 proteins (unanticipated function in regulating PcG protein levels), derepression of lineage genes, and establishes chromosome-wide H2AK119ub upon Xist expression; however, Xist-mediated X chromosome silencing initiation is independent of Ring1B. Conditional knockout mouse ES cells, immunoblot, immunofluorescence, gene expression analysis The Journal of cell biology High 17620408
2008 In vivo, Polycomb proteins Ezh2 (PRC2) and Rnf2 (PRC1) are each independently required for genomic contraction of imprinted clusters and imprinted gene silencing, establishing that PRC1 (via Rnf2) and PRC2 perform non-redundant roles in establishing higher-order chromatin organization at imprinted loci. Conditional knockout mouse embryos (Rnf2 and Ezh2 separately), 3D-FISH for genomic contraction, RNA FISH for imprinted gene expression Developmental cell High 18848501
2007 Proteomics of in vivo biotinylated Ring1B identifies ~50 interacting proteins in erythroid cells, including LSD1/Aof2 and Fbxl10/Jhdm1B histone demethylases, BcoR corepressor, CK2α, Skp1, and Nspc1/Pcgf1, forming a novel Ring1B-Fbxl10-BcoR complex distinct from canonical PRC1 and E2F6 complexes. Streptavidin pulldown of biotinylated Ring1B, mass spectrometry identification, co-purification of Fbxl10 complex Molecular & cellular proteomics Medium 17296600
2010 The C-terminal domain of Ring1B (C-RING1B) binds both the Polycomb (Pc) cbox domain and RYBP at the same surface, with each partner forming a nearly identical intermolecular beta sheet with C-Ring1B despite having no sequence identity, suggesting PcG targeting to different chromatin locations relies on structurally diverse binding partners of C-Ring1B. Crystal structure of C-RING1B–Pc cbox complex, NMR, mutagenesis, transcription repression assays, Drosophila in vivo chromatin association Structure High 20696397
2009 The C-terminal domain of Ring1B adopts a ubiquitin-like fold with a conserved surface that mediates binding to Cbx proteins (PRC1 members) and homodimerization; mutational analysis confirms this conserved surface is responsible for Cbx interaction. Crystal structure of C-terminal Ring1B domain, mutational analysis, binding assays Biochemistry High 19791798
1998 Bmi-1 directly interacts with the RING finger protein dinG/RING1B via their RING finger domains (heterodimerization requires intact RING fingers of both proteins plus additional flanking residues); both proteins also independently interact with the Polyhomeotic protein MPh2 through non-RING domains, forming a stable heterotrimer. Yeast two-hybrid, domain mapping with RING finger mutants Oncogene Medium 9627119
2002 Ring1B forms protein complexes containing Rae28/Mph1, M33, and Mel18 (other PcG proteins) that associate with chromosomal DNA in vivo; a hypomorphic Ring1B mouse displays posterior homeotic transformations and mild Hox gene derepression, and Ring1B overexpression in chick embryos represses Hoxb9, confirming Ring1B's role in Hox gene regulation by PcG complexes. Co-immunoprecipitation from embryo extracts, hypomorphic knockin mouse, chick embryo overexpression, RNA in situ hybridization Development Medium 12183370
2014 RNF2 is recruited by WASH to ubiquitinate AMBRA1 via K48-linked chains at lysine 45, targeting AMBRA1 for proteasomal degradation and thereby downregulating autophagy; WASH deficiency impairs RNF2–AMBRA1 association and prevents AMBRA1 degradation. Co-immunoprecipitation, in vitro ubiquitination assay, site-directed mutagenesis (K45), autophagy flux assay, RNF2 and WASH knockdown/knockout Cell research High 24980959
2013 Aurora B kinase phosphorylates histone H3S28 at active promoters in resting B cells, which inhibits Ring1B-mediated H2A ubiquitination and enhances binding and activity of the USP16 deubiquitinase at transcribed genes; conditional knockout of either Aurora B or Ring1B reduces RNA Pol II binding to promoters and decreases cell viability in quiescent lymphocytes. Conditional knockout, ChIP-seq, in vitro ubiquitination assay, kinase assay Molecular cell High 24034696
2013 RNF2 functions as an E3 ligase that targets p53 for proteasomal degradation; this activity requires Bmi1. RNF2 directly binds both p53 and MDM2, promotes MDM2-mediated p53 ubiquitination, and increases MDM2 stability by inhibiting its ubiquitination. RNF2 knockdown increases p53 protein levels and half-life and induces apoptosis in p53-dependent manner. Co-immunoprecipitation, in vitro ubiquitination assay, protein half-life measurement, RNF2 knockdown/overexpression in isogenic p53+/+ and p53-/- cells Oncogene Medium 23318437
2013 RNF2 (with Bmi1) acts as an E3 ligase that targets p53 for degradation specifically in germ-cell tumor lines; knockdown of RNF2 induces p53-dependent apoptosis and reduces tumor xenograft growth, while simultaneous p53 knockdown rescues these effects. Co-immunoprecipitation, in vitro ubiquitination assay, xenograft tumor models, RNF2/p53 double knockdown Proceedings of the National Academy of Sciences of the United States of America Medium 23319651
2017 Nuclear RNF2 directly binds STAT1 after interferon stimulation and promotes K33-linked polyubiquitination of STAT1 at K379 (within its DNA-binding domain), causing STAT1/STAT2 dissociation from DNA and suppression of interferon-stimulated gene transcription; RNF2 deficiency enhances ISG expression and antiviral responses. High-content E3 ligase screen, co-immunoprecipitation, site-directed mutagenesis (K379R), in vitro ubiquitination assay, ChIP, RNF2 conditional knockout Nature immunology High 29242538
2014 The nucleosome acidic patch is required for RING1B/BMI1-dependent H2A ubiquitination both in vivo and in vitro; nucleosomes with mutated acidic patch are defective substrates for RING1B/BMI1 ubiquitination in vitro, and perturbation of the acidic patch in vivo by viral LANA peptide impairs H2AXub and DDR signaling. In vitro ubiquitination assay with acidic-patch mutant nucleosomes, in vivo viral LANA peptide expression, ChIP, immunofluorescence PLoS genetics High 24603765
2018 RNF2/Ring1B is required to support DNA replication fork progression; its depletion causes R-loop (RNA:DNA hybrid) accumulation that impairs replication. Mdm2 overexpression rescues RNF2 depletion for fork progression (and vice versa), and this rescue requires H2A ubiquitination sites K118/K119. RNaseH overexpression or CDK9 inhibition also rescues fork progression upon RNF2 depletion. DNA fiber assay, RNF2/Mdm2 knockdown, H2A K118/K119 mutant rescue, RNaseH overexpression, S9.6 antibody R-loop detection Proceedings of the National Academy of Sciences of the United States of America High 30413623
2015 RING1B/RING1A mono-ubiquitination of H2AK119 at pericentromeric heterochromatin is required for S-phase progression; conditional inactivation of both E3 ligases causes replication fork slowing and stalling specifically at pericentromeric regions during mid-S phase, with double-strand break accumulation at chromocenters, and this is rescued by targeted H2AK119ub at pericentromeric chromatin. Conditional double knockout of RING1A/RING1B, DNA fiber assay, γH2AX immunofluorescence, targeted monoubiquitination rescue via MBD1 fusion Journal of cell science High 26272920
2015 The E3 ubiquitin ligase activity of RING1B is dispensable for early mouse embryonic development and for much of PRC1-mediated gene repression in ES cells; PRC1 and PRC2 reinforce each other's chromatin binding but key PRC1 functions extend beyond RING1B's enzymatic activity. Catalytic-dead RING1B knockin mouse, ChIP-seq, gene expression analysis Genes & development High 26385961
2018 The FBXL10-RNF68-RNF2 ubiquitin ligase complex (FRRUC) is rapidly and transiently recruited to DNA damage sites in a PARP1- and TIMELESS-dependent manner; FRRUC promotes H2AK119ub at damage sites, local H2A decrease, H2A.Z incorporation, DSB signaling, and homologous recombination repair. FRRUC activity is also required for subsequent recruitment of BMI1-RNF2 and MEL18-RNF2 complexes at damage sites. Live imaging, ChIP, Co-immunoprecipitation, proximity ligation, RNF2 knockout/knockdown, HR reporter assay, PARP1 inhibition eLife High 29985131
2014 In pancreatic cancer, Ring1B physically interacts with Snail; Snail's carboxyl zinc fingers recruit Ring1B and Ring1A to target promoters, and Ring1B mediates H2AK119ub1 at these promoters to repress transcription and enable Snail-induced cell migration. EZH2 is required for Snail-Ring1A/B recruitment to target chromatin. Co-immunoprecipitation, ChIP assay, Ring1A/B double depletion, cell migration assay Cancer research Medium 24903147
2015 RING1B is O-GlcNAcylated at residues T250/S251 and S278; T250/S251 O-GlcNAcylation decreases during differentiation and regulates RING1B genomic targeting—non-O-GlcNAcylated RING1B is enriched near cell-cycle genes whereas O-GlcNAcylated RING1B is enriched near neuronal genes. Point mutagenesis of O-GlcNAc sites, ChIP-sequencing, mass spectrometry identification of modification sites Stem cell research Medium 26100231
2009 RNF2 is phosphorylated at Ser41 by p38 MAPK and at multiple additional serine residues by ERK1/2 (MEK1/2 pathway); mass spectrometry identified co-translational N-terminal Met excision coupled to N-acetylation of Ser2, and phospho-Ser41 as a p38 MAPK site. RNF2 phosphorylation differentially modulates transcription factor expression and histone H2B acetylation. 2D electrophoresis, kinase inhibitors (SB203580, PD98059), phosphatase treatment, mass spectrometry Proteomics Medium 19405034
2005 RNF2 physically interacts with the S6' ATPase subunit of the proteasomal 19S regulatory complex; S6' contacts RNF2 via its N-terminal RING domain and RNF2 contacts S6' via its C-terminal region. RNF2-S6' interaction increases S6' ATP hydrolysis activity, suggesting RNF2 may facilitate delivery of ubiquitinated substrates to the proteasome. Co-immunoprecipitation, domain mapping, in vitro ATPase activity assay The Biochemical journal Medium 15773819
2007 Prohibitin interacts with endogenous RNF2 in cells; co-depletion of either protein increases p16(Ink4a) expression, reducing E2F1 transcriptional activity via the p16-CDK4-Rb pathway. RNF2 and prohibitin are co-recruited to E2F1-responsive promoters (by ChIP), and their protein levels are interdependently regulated post-translationally. Co-immunoprecipitation, ChIP, siRNA knockdown, luciferase reporter assay Oncogene Medium 17873902
2003 Ring1B (Rnf2) and Ring1A proteins were identified as in vivo interactors of Bmi1 (by co-immunoprecipitation from cells), establishing their physical association within the PcG complex. Co-immunoprecipitation from mouse embryo/cell extracts Proceedings of the National Academy of Sciences of the United States of America Medium 12589020
2003 Ring1B and Rae28/Ph1 dissociate from chromatin upon chromatin condensation in mitotic prophase and during meiotic prophase in oocytes; this dissociation correlates temporally with transcriptional arrest in both mitosis and meiosis. Immunofluorescence with monoclonal antibodies in mitotic somatic cells and meiotic mouse oocytes Histochemistry and cell biology Medium 12883906
2017 RNF2 acts as an E3 ligase that targets SIK1 for ubiquitination and proteasomal degradation; direct physical interaction between RNF2 and SIK1 was demonstrated, and RNF2 knockdown restores SIK1 levels inhibiting HCC growth. Co-immunoprecipitation, in vitro ubiquitination assay, RNF2 knockdown rescue experiment, xenograft model Oncotarget Medium 27911266
2021 RNF2 acts as an E3 ligase that promotes ubiquitination and proteasomal degradation of IRF4; RNF2 physically interacts with IRF4 by co-immunoprecipitation, and RNF2 overexpression increases IRF4 ubiquitination and promotes colon cancer cell proliferation and invasion in an IRF4-dependent manner. Co-immunoprecipitation, ubiquitination assay, RNF2 overexpression/knockdown, xenograft model Biochimica et biophysica acta. Molecular cell research Medium 34670117
2015 RNF2-mediated invasive/metastatic behavior in melanoma depends on its ability to monoubiquitinate H2AK119 at the LTBP2 promoter, silencing this negative regulator of TGFβ signaling; in contrast, RNF2's oncogenic/proliferative activity does not require its catalytic activity but instead involves MEK1-mediated phosphorylation of RNF2, which recruits histone activators UTX and p300 to CCND2 promoter to drive its transcriptional upregulation. Gain- and loss-of-function studies, catalytic-dead RNF2 mutant, ChIP-seq, MEK1 phosphorylation assay, mouse and human melanoma models Cancer discovery High 26450788
2022 Bmi-1-RING1B complex directly ubiquitinates GATA4; GATA4 ubiquitination is recognized by p62 and targets GATA4 for selective autophagic (not proteasomal) degradation. Bmi-1 binds RING1B residues 1–179 and GATA4 C-terminus (residues 206–443 zinc fingers) via its residues 1–95; RING1B binds GATA4 C-terminus via its own C-terminus (residues 180–336). Co-immunoprecipitation, domain mapping, ubiquitination assay, autophagy flux assay, Bmi-1 knockout and transgenic mice, AAV9 in vivo gene delivery Clinical and translational medicine Medium 35390228
2021 De novo missense variants in RNF2 (p.R70H and p.S82R) are associated with a neurodevelopmental disorder; structural analyses indicate R70H likely disrupts the Ring1B–Bmi1 interaction interface, and S82R likely disrupts Ring1B–histone H2A interaction. Functional studies in Drosophila confirm both variants behave as loss-of-function alleles in vivo. Structural analysis of variant positions, Drosophila in vivo functional assay with equivalent alleles Human molecular genetics Medium 33864376
2017 Intrinsically disordered protein NUPR1 binds the C-terminal region of RING1B with affinity ~10 μM; the binding region on NUPR1 involves a hydrophobic patch at its 30s region (Ala33); mutation of Ala33 reduces binding in vitro, in silico, and in cellulo. Trifluoperazine inhibits the NUPR1–C-RING1B interaction. NMR mapping, ITC, computational docking, site-directed mutagenesis (A33Q, T68Q), bimolecular fluorescence complementation (in cellulo) Proceedings of the National Academy of Sciences of the United States of America Medium 28720707
2008 NMR analysis of the C-terminal region of RING1B (C-RING1B) shows it has flexible regions that transition to a conformationally tightened state upon binding the Pc cbox domain; both N- and C-terminal halves of C-RING1B can interact with each other intramolecularly, suggesting an intramolecular interaction that is stabilized by cbox binding. NMR spectroscopy, analytical ultracentrifugation, ITC, dissociation constant measurement Biochemistry Medium 18616292
2020 BMI1 and RNF2 suppress transcription-replication conflicts (TRCs) and common fragile site (CFS) instability; depletion of either causes slower replication forks, fork stalling, increased RNA Pol II occupancy at CFSs, increased RNAPII-replisome associations (proximity ligation), and increased FANCD2/RNH1 at CFSs (R-loop markers). RNF2-deficient cells depend on FANCD2/FANCI fork-protective factors for survival. DNA fiber assay, proximity ligation assay, ChIP, CRISPR-KO of RNF2, FANCD2/FANCI depletion epistasis PLoS genetics High 32142505
2020 RING1B colocalizes with EWSR1-FLI1 at active enhancers in Ewing sarcoma (in addition to its canonical repressive activity at Polycomb-regulated developmental genes), and is required for EWSR1-FLI1 recruitment to its enhancers and expression of key oncogenic targets; RING1B knockdown impairs xenograft tumor growth. ChIP-seq, RING1B knockdown, xenograft tumor model, pharmacological AURKB inhibition Science advances Medium 33097530
2021 RNF2 acts as an E3 ligase for RASSF10, promoting its ubiquitination and degradation; NPM-dependent downregulation of RNF2 is required to maintain stable RASSF10 levels for mitotic arrest (G2/M). Physical interaction between RNF2 and RASSF10 was demonstrated by co-immunoprecipitation. LC-MS/MS, co-immunoprecipitation, ubiquitination assay, RNF2 knockdown rescue, live cell imaging The Journal of biological chemistry Medium 34224728

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Structure and E3-ligase activity of the Ring-Ring complex of polycomb proteins Bmi1 and Ring1b. The EMBO journal 375 16710298
2003 Rnf2 (Ring1b) deficiency causes gastrulation arrest and cell cycle inhibition. Proceedings of the National Academy of Sciences of the United States of America 293 12589020
2008 Polycomb group proteins Ezh2 and Rnf2 direct genomic contraction and imprinted repression in early mouse embryos. Developmental cell 260 18848501
2006 Structure of a Bmi-1-Ring1B polycomb group ubiquitin ligase complex. The Journal of biological chemistry 207 16714294
2009 The helicases DinG, Rep and UvrD cooperate to promote replication across transcription units in vivo. The EMBO journal 206 19851282
2006 The polycomb protein Ring1B generates self atypical mixed ubiquitin chains required for its in vitro histone H2A ligase activity. Molecular cell 198 17157253
2004 Ring1b-mediated H2A ubiquitination associates with inactive X chromosomes and is involved in initiation of X inactivation. The Journal of biological chemistry 195 15509584
2007 Proteomics analysis of Ring1B/Rnf2 interactors identifies a novel complex with the Fbxl10/Jhdm1B histone demethylase and the Bcl6 interacting corepressor. Molecular & cellular proteomics : MCP 184 17296600
2007 Ring1B is crucial for the regulation of developmental control genes and PRC1 proteins but not X inactivation in embryonic cells. The Journal of cell biology 149 17620408
2011 Recognition of UbcH5c and the nucleosome by the Bmi1/Ring1b ubiquitin ligase complex. The EMBO journal 134 21772249
2015 The E3 ubiquitin ligase activity of RING1B is not essential for early mouse development. Genes & development 131 26385961
1999 Localization of membrane-associated guanylate kinase (MAGI)-1/BAI-associated protein (BAP) 1 at tight junctions of epithelial cells. Oncogene 106 10618722
2013 The aurora B kinase and the polycomb protein ring1B combine to regulate active promoters in quiescent lymphocytes. Molecular cell 98 24034696
2010 Ring1B and Suv39h1 delineate distinct chromatin states at bivalent genes during early mouse lineage commitment. Development (Cambridge, England) 96 20573702
2008 Ubiquitin E3 ligase Ring1b/Rnf2 of polycomb repressive complex 1 contributes to stable maintenance of mouse embryonic stem cells. PloS one 89 18493325
2014 RNF2 is recruited by WASH to ubiquitinate AMBRA1 leading to downregulation of autophagy. Cell research 85 24980959
2002 Involvement of the Polycomb-group gene Ring1B in the specification of the anterior-posterior axis in mice. Development (Cambridge, England) 84 12183370
2014 Nucleosome acidic patch promotes RNF168- and RING1B/BMI1-dependent H2AX and H2A ubiquitination and DNA damage signaling. PLoS genetics 82 24603765
2010 Regulation of the polycomb protein Ring1B by self-ubiquitination or by E6-AP may have implications to the pathogenesis of Angelman syndrome. Proceedings of the National Academy of Sciences of the United States of America 81 20351251
2007 Inactivation of the polycomb group protein Ring1B unveils an antiproliferative role in hematopoietic cell expansion and cooperation with tumorigenesis associated with Ink4a deletion. Molecular and cellular biology 81 18039844
2010 Polycomb group targeting through different binding partners of RING1B C-terminal domain. Structure (London, England : 1993) 79 20696397
2013 RNF2/Ring1b negatively regulates p53 expression in selective cancer cell types to promote tumor development. Proceedings of the National Academy of Sciences of the United States of America 77 23319651
2003 Characterization of the DNA damage-inducible helicase DinG from Escherichia coli. The Journal of biological chemistry 77 12748189
2007 The DinG protein from Escherichia coli is a structure-specific helicase. The Journal of biological chemistry 75 17416902
2017 Nuclear RNF2 inhibits interferon function by promoting K33-linked STAT1 disassociation from DNA. Nature immunology 65 29242538
2008 Redox control of the DNA damage-inducible protein DinG helicase activity via its iron-sulfur cluster. The Journal of biological chemistry 64 19074432
2014 Snail recruits Ring1B to mediate transcriptional repression and cell migration in pancreatic cancer cells. Cancer research 63 24903147
2010 Regulation of the Polycomb protein RING1B ubiquitination by USP7. Biochemical and biophysical research communications 63 20800574
2015 Immunological evaluation of OMV(PagL)+Bap(1-487aa) and AbOmpA(8-346aa)+Bap(1-487aa) as vaccine candidates against Acinetobacter baumannii sepsis infection. Molecular immunology 56 26277277
2015 Dual Roles of RNF2 in Melanoma Progression. Cancer discovery 56 26450788
2014 The polycomb component Ring1B regulates the timed termination of subcerebral projection neuron production during mouse neocortical development. Development (Cambridge, England) 56 25344075
2001 Production of monoclonal antibodies against mammalian Ring1B proteins. Hybridoma 55 11289226
1998 The Bmi-1 oncoprotein interacts with dinG and MPh2: the role of RING finger domains. Oncogene 55 9627119
2009 Maintenance of undifferentiated state and self-renewal of embryonic neural stem cells by Polycomb protein Ring1B. Stem cells (Dayton, Ohio) 53 19544461
2013 Knockdown of RNF2 induces apoptosis by regulating MDM2 and p53 stability. Oncogene 51 23318437
2018 Chromatin modifiers Mdm2 and RNF2 prevent RNA:DNA hybrids that impair DNA replication. Proceedings of the National Academy of Sciences of the United States of America 50 30413623
2007 The isolated C-terminal domain of Ring1B is a dimer made of stable, well-structured monomers. Biochemistry 50 17935356
2002 Ring up the curtain on DING proteins. FEBS letters 48 12135732
2020 Estrogen induces dynamic ERα and RING1B recruitment to control gene and enhancer activities in luminal breast cancer. Science advances 47 32548262
2018 PARP1-dependent recruitment of the FBXL10-RNF68-RNF2 ubiquitin ligase to sites of DNA damage controls H2A.Z loading. eLife 46 29985131
2007 Prohibitin interacts with RNF2 and regulates E2F1 function via dual pathways. Oncogene 46 17873902
2017 Intrinsically disordered chromatin protein NUPR1 binds to the C-terminal region of Polycomb RING1B. Proceedings of the National Academy of Sciences of the United States of America 44 28720707
2009 The epigenetic regulators Bmi1 and Ring1B are differentially regulated in pancreatitis and pancreatic ductal adenocarcinoma. The Journal of pathology 44 19585519
2019 Long non-coding RNA LINC00665 gastric cancer tumorigenesis by regulation miR-149-3p/RNF2 axis. OncoTargets and therapy 43 31695413
2009 Ring1B contains a ubiquitin-like docking module for interaction with Cbx proteins. Biochemistry 38 19791798
2013 The polycomb group protein ring1b/rnf2 is specifically required for craniofacial development. PloS one 37 24040141
2003 DING, a genistein target in human breast cancer: a protein without a gene. The Journal of nutrition 37 12840230
2002 The DING protein: an autocrine growth-stimulatory protein related to the human synovial stimulatory protein. Biochimica et biophysica acta 37 11997077
2018 Reversal of cisplatin resistance by microRNA-139-5p-independent RNF2 downregulation and MAPK inhibition in ovarian cancer. American journal of physiology. Cell physiology 35 29719173
2017 Knockdown of RNF2 induces cell cycle arrest and apoptosis in prostate cancer cells through the upregulation of TXNIP. Oncotarget 35 28029659
2019 Ring1b-dependent epigenetic remodelling is an essential prerequisite for pancreatic carcinogenesis. Gut 33 30954952
2017 Down-regulation of salt-inducible kinase 1 (SIK1) is mediated by RNF2 in hepatocarcinogenesis. Oncotarget 32 27911266
2015 RING1B O-GlcNAcylation regulates gene targeting of polycomb repressive complex 1 in human embryonic stem cells. Stem cell research 32 26100231
2003 Dissociation of mammalian Polycomb-group proteins, Ring1B and Rae28/Ph1, from the chromatin correlates with configuration changes of the chromatin in mitotic and meiotic prophase. Histochemistry and cell biology 31 12883906
2021 Emerging role of RNF2 in cancer: From bench to bedside. Journal of cellular physiology 30 33400276
2011 Switches, excitable responses and oscillations in the Ring1B/Bmi1 ubiquitination system. PLoS computational biology 30 22194680
2020 RING1B recruits EWSR1-FLI1 and cooperates in the remodeling of chromatin necessary for Ewing sarcoma tumorigenesis. Science advances 29 33097530
2019 LncRNA-MEG3 inhibits cell proliferation and invasion by modulating Bmi1/RNF2 in cholangiocarcinoma. Journal of cellular physiology 29 31119760
2012 Ring1b bookmarks genes in pancreatic embryonic progenitors for repression in adult β cells. Genes & development 29 23271347
2021 RNF2 ablation reprograms the tumor-immune microenvironment and stimulates durable NK and CD4+ T-cell-dependent antitumor immunity. Nature cancer 28 35121884
2015 Polycomb RING1A- and RING1B-dependent histone H2A monoubiquitylation at pericentromeric regions promotes S-phase progression. Journal of cell science 28 26272920
2009 Identification of X-DING-CD4, a new member of human DING protein family that is secreted by HIV-1 resistant CD4(+) T cells and has anti-viral activity. Biochemical and biophysical research communications 28 19720052
2018 Ring1A and Ring1B inhibit expression of Glis2 to maintain murine MOZ-TIF2 AML stem cells. Blood 27 29371181
2020 Transcription-replication conflicts as a source of common fragile site instability caused by BMI1-RNF2 deficiency. PLoS genetics 25 32142505
2014 The Polycomb group protein RING1B is overexpressed in ductal breast carcinoma and is required to sustain FAK steady state levels in breast cancer epithelial cells. Oncotarget 25 24742605
2012 Staphylococcus aureus DinG, a helicase that has evolved into a nuclease. The Biochemical journal 25 22166102
2022 Bmi-1-RING1B prevents GATA4-dependent senescence-associated pathological cardiac hypertrophy by promoting autophagic degradation of GATA4. Clinical and translational medicine 24 35390228
2021 Rare deleterious de novo missense variants in Rnf2/Ring2 are associated with a neurodevelopmental disorder with unique clinical features. Human molecular genetics 24 33864376
2012 Stimulation of Escherichia coli DNA damage inducible DNA helicase DinG by the single-stranded DNA binding protein SSB. FEBS letters 24 23036643
2023 RNF2 inhibits E-Cadherin transcription to promote hepatocellular carcinoma metastasis via inducing histone mono-ubiquitination. Cell death & disease 23 37037816
2019 Digital Image Analysis of BAP-1 Accurately Predicts Uveal Melanoma Metastasis. Translational vision science & technology 23 31110912
2009 RNF2 is the target for phosphorylation by the p38 MAPK and ERK signaling pathways. Proteomics 23 19405034
2021 Circ_0004104 Accelerates the Progression of Gastric Cancer by Regulating the miR-539-3p/RNF2 Axis. Digestive diseases and sciences 22 33449226
2021 HPIP protooncogene differentially regulates metabolic adaptation and cell fate in breast cancer cells under glucose stress via AMPK and RNF2 dependent pathways. Cancer letters 22 34302919
2017 Rnf2 knockdown reduces cell viability and promotes cell cycle arrest in gastric cancer cells. Oncology letters 22 28529595
2023 Targeted Degradation of PRC1 Components, BMI1 and RING1B, via a Novel Protein Complex Degrader Strategy. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 21 36737841
2012 The Polycomb group protein Ring1b is essential for pectoral fin development. Development (Cambridge, England) 21 22619390
2006 RNF2 interacts with the linker region of the human P-glycoprotein. International journal of oncology 21 17088979
2014 Trans-membrane transport of fluoranthene by Rhodococcus sp. BAP-1 and optimization of uptake process. Bioresource technology 19 24457306
2010 Polycomb group gene product Ring1B regulates Th2-driven airway inflammation through the inhibition of Bim-mediated apoptosis of effector Th2 cells in the lung. Journal of immunology (Baltimore, Md. : 1950) 19 20237291
2007 A DING phosphatase in Thermus thermophilus. Amino acids 19 17497305
2005 E3 ubiquitin ligase RNF2 interacts with the S6' proteasomal ATPase subunit and increases the ATP hydrolysis activity of S6'. The Biochemical journal 19 15773819
2018 The Polycomb proteins RING1B and EZH2 repress the tumoral pro-inflammatory function in metastasizing primary cutaneous squamous cell carcinoma. Carcinogenesis 18 29394319
2008 Structural transitions of the RING1B C-terminal region upon binding the polycomb cbox domain. Biochemistry 18 18616292
2008 PHB2 interacts with RNF2 and represses CP2c-stimulated transcription. Molecular and cellular biochemistry 18 18629613
2025 METTL3-Mediated m6A Modification Regulates the Polycomb Repressive Complex 1 Components BMI1 and RNF2 in Hepatocellular Carcinoma Cells. Molecular cancer research : MCR 17 39625677
2021 Knockdown of circ_0008344 contributes to radiosensitization in glioma via miR-433-3p/RNF2 axis. Journal of biosciences 17 34423784
2021 Intratumor Heterogeneity in Uveal Melanoma BAP-1 Expression. Cancers 16 33800007
2021 RNF2 promotes the progression of colon cancer by regulating ubiquitination and degradation of IRF4. Biochimica et biophysica acta. Molecular cell research 16 34670117
2020 Nuclear expression of BAP-1 in transvitreal incisional biopsies and subsequent enucleation of eyes with posterior choroidal melanoma. The British journal of ophthalmology 16 32522791
2019 Loss of the Polycomb group protein Rnf2 results in derepression of tbx-transcription factors and defects in embryonic and cardiac development. Scientific reports 16 30867528
2016 Overexpression of RNF2 Is an Independent Predictor of Outcome in Patients with Urothelial Carcinoma of the Bladder Undergoing Radical Cystectomy. Scientific reports 16 26869491
2011 Suppression of HIV-1 transcriptional elongation by a DING phosphatase. Journal of cellular biochemistry 16 21117063
2021 Molecular basis for RASSF10/NPM/RNF2 feedback cascade-mediated regulation of gastric cancer cell proliferation. The Journal of biological chemistry 15 34224728
2020 Hsa_circRNA_100146 Acts as a Sponge of miR-149-5p in Promoting Bladder Cancer Progression via Regulating RNF2. OncoTargets and therapy 15 33149615
2016 Radiosensitization of esophageal carcinoma cells by knockdown of RNF2 expression. International journal of oncology 15 26936624
2016 RING1B contributes to Ewing sarcoma development by repressing the NaV1.6 sodium channel and the NF-κB pathway, independently of the fusion oncoprotein. Oncotarget 15 27317769
2014 Ring1B promotes hepatic stem/progenitor cell expansion through simultaneous suppression of Cdkn1a and Cdkn2a in mice. Hepatology (Baltimore, Md.) 15 24497168
2010 Id1 enhances RING1b E3 ubiquitin ligase activity through the Mel-18/Bmi-1 polycomb group complex. Oncogene 15 20697353
2019 Knockdown of RNF2 enhances the radiosensitivity of squamous cell carcinoma in lung. Biochemistry and cell biology = Biochimie et biologie cellulaire 13 30673298

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