Affinage

RNF168

E3 ubiquitin-protein ligase RNF168 · UniProt Q8IYW5

Length
571 aa
Mass
65.0 kDa
Annotated
2026-06-10
100 papers in source corpus 59 papers cited in narrative 58 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

RNF168 is a RING-type E3 ubiquitin ligase that orchestrates the chromatin ubiquitylation cascade governing DNA double-strand break (DSB) repair pathway choice (PMID:19203579, PMID:22980979). It is recruited to damage sites downstream of RNF8 through recognition of K63-linked ubiquitin conjugates by its tandem ubiquitin-binding modules (MIU and the UIM/MIU-related UMI), which fold as single α-helices that simultaneously engage distal and proximal ubiquitin to confer K63-chain specificity (PMID:19203579, PMID:21041483, PMID:29330428); RNF8-ubiquitylated adaptors including L3MBTL2 and polyubiquitylated linker histone H1 provide the docking signal that triggers its accrual (PMID:29581593, PMID:39363740). Once engaged, RNF168 monoubiquitylates nucleosomal H2A/H2AX specifically at the bidentate N-terminal K13/K15 site—activity that RNF8 cannot perform—and builds K63- and K27-linked chains on top of this mark (PMID:22980979, PMID:22713238, PMID:25578731). Site selection depends on engagement of the nucleosome acidic patch, which stimulates discharge of ubiquitin from the E2 (UBC13/UbcH5c) and orients catalysis toward K13/15, as defined by reconstitution, NMR, and cryo-EM studies that established a monomeric "helix-anchoring" mode and a ubiquitin-recognition-driven amplification loop (PMID:24518117, PMID:30988309, PMID:38242129, PMID:39394267). These marks recruit downstream repair effectors: RNF168 K63-ubiquitylates 53BP1 and generates the mono-ubiquitylated H2A-K15 mark read by 53BP1 in the context of H4K20 methylation, while also engaging BARD1-BRCA1-PALB2-RAD51 through a dedicated PALB2-interacting domain and the BARD1 BUDR motif to promote homologous recombination (PMID:24324146, PMID:28240985, PMID:28506460, PMID:34408138). RNF168 thereby acts in a pathway parallel to BRCA1 for PALB2/RAD51 loading and balances end resection and NHEJ versus HR (PMID:30704900, PMID:34481157). Its activity is amplified by K63-polyubiquitin-triggered liquid-liquid phase separation via an intrinsically disordered region (PMID:38968116) and is restrained by mTOR-S6K1 phosphorylation at Ser60, CDK1/2-PIN1-driven SUMOylation coupled to p97-mediated chromatin extraction, and multiple deubiquitylases (USP3, USP7, USP14, USP44) (PMID:29403037, PMID:40229270, PMID:23615962, PMID:24196443, PMID:25894431, PMID:29995557). Beyond histones, RNF168 ubiquitylates non-histone substrates including JMJD2A, TOP2α, PARP1, and DHX9 to coordinate genome stability and R-loop resolution (PMID:22373579, PMID:27558965, PMID:30037213, PMID:33529165).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 2009 High

    Established RNF168 as the chromatin-associated amplifier of the DSB ubiquitin signal, answering how RNF8-initiated ubiquitylation is propagated to retain repair factors.

    Evidence Co-IP, ubiquitin-binding assays, RNAi, DSB foci imaging, and in vitro/in vivo ubiquitylation showing MIU-mediated ubiquitin binding and RNF8-dependent assembly amplifying K63 conjugates on H2A/H2AX

    PMID:19203579 PMID:19500350

    Open questions at the time
    • Did not define the precise nucleosomal acceptor lysines
    • Did not resolve the direct vs adaptor-mediated recruitment cue
  2. 2012 High

    Resolved the catalytic division of labor between RNF8 and RNF168 by showing RNF168 monoubiquitylates nucleosomal H2A/H2AX at a novel bidentate K13/K15 site, defining the actual signaling mark.

    Evidence In vitro nucleosomal ubiquitylation, structure-based RING mutagenesis, MS site mapping, and histone lysine mutagenesis

    PMID:22713238 PMID:22980979

    Open questions at the time
    • Did not explain the structural basis of acidic-patch engagement
    • Did not address how K13/15 marks are read by effectors
  3. 2012 Medium

    Extended RNF168 function beyond histones, showing it degrades JMJD2A/KDM4A to clear a 53BP1 competitor and links to PARP1/SMARCA5-dependent recruitment.

    Evidence In vivo ubiquitylation, reciprocal Co-IP, RNAi epistasis, laser micro-irradiation

    PMID:22373579 PMID:23264744

    Open questions at the time
    • Single-lab Co-IP without reconstitution for JMJD2A
    • PARP-dependence of recruitment not structurally defined
  4. 2013 Medium

    Defined the E2 partnership and substrate scope, identifying RAD6 as a cognate E2 for H1.2 and 53BP1 itself as a direct K63-ubiquitylation target required for its recruitment.

    Evidence E2 RNAi screen, Co-IP, in vitro ubiquitylation, K63-specific ubiquitin mutants, checkpoint assays

    PMID:23525009 PMID:24324146

    Open questions at the time
    • Multiple candidate E2s leave the in vivo functional E2 ambiguous
    • 53BP1 ubiquitylation site not mapped
  5. 2013 Medium

    Identified the deubiquitylase layer (USP3, USP44) that counteracts RNF168 at K13/15 and K118/119, establishing reversibility of the mark.

    Evidence DUB overexpression screens, in vitro/in vivo deubiquitylation assays with site-specific readout, immunofluorescence

    PMID:23615962 PMID:24196443

    Open questions at the time
    • Relative contribution of each DUB in vivo unresolved
    • Single-lab assays
  6. 2014 High

    Provided the mechanistic basis for site specificity by showing the nucleosome acidic patch stimulates E2~Ub discharge and directs ubiquitin to K13/15, with in vivo confirmation via viral acidic-patch perturbation.

    Evidence In vitro ubiquitylation with acidic-patch mutant nucleosomes, fluorescence E2~Ub discharge assay, LANA peptide perturbation in cells

    PMID:24518117 PMID:24603765

    Open questions at the time
    • Atomic RNF168-nucleosome interface not yet resolved
    • Did not define E2 orientation on the nucleosome
  7. 2014 High

    Refined RNF168 architecture and its non-canonical E2 relationship, identifying the UMI ubiquitin-binding module and showing RNF168 (unlike RNF8) does not stably bind UBC13.

    Evidence Mutagenesis, ubiquitin-binding assays, RNF168 RING crystal structure, in vitro/in vivo Co-IP, domain swaps

    PMID:21041483 PMID:23255131

    Open questions at the time
    • Functional consequence of weak UBC13 association left open
    • Did not explain how transient E2 engagement supports processive marking
  8. 2014 Medium

    Broadened RNF168's regulatory and substrate repertoire, implicating NEDD8 conjugation, TOP2α decatenation control, and downstream methyltransferase recruitment (SET8).

    Evidence In vivo neddylation/ubiquitylation assays, Co-IP, decatenation assay, RNAi epistasis

    PMID:24634510 PMID:27558965 PMID:31760894

    Open questions at the time
    • Neddylation requirement for ligase activity not structurally validated
    • SET8 placement based on Co-IP/epistasis only
  9. 2015 Medium

    Expanded chain-type and substrate diversity, showing RNF168 builds K27-linked chains as a major damage mark and degrades FOXM1, while DUB USP7 stabilizes RNF168 itself.

    Evidence In vitro ubiquitylation with chain mutants, MS linkage analysis, Co-IP, cycloheximide chase, SUMO-defective mutant analysis

    PMID:25578731 PMID:25894431 PMID:25999347 PMID:26675234 PMID:27526106

    Open questions at the time
    • Relative in vivo abundance of K27 vs K63 marks not quantified across systems
    • Most regulator interactions rest on single-lab Co-IP
  10. 2017 High

    Connected the H2A-K13/15 mark to specific downstream readers, mapping direct RNF168-PALB2 binding for HR and resolving the structural competition between 53BP1, RNF169, and RAD18 for ubiquitylated nucleosomes.

    Evidence Co-IP and domain mapping, HR assays, methyl-TROSY NMR with cryo-EM validation, molecular dynamics

    PMID:28240985 PMID:28406400 PMID:28506460

    Open questions at the time
    • In vivo balance between competing readers in different cell-cycle phases not fully resolved
  11. 2017 Medium

    Placed RNF168 within an upstream histone H1 ubiquitylation cascade by identifying HUWE1-dependent H1 ubiquitylation as required for RNF168 recruitment.

    Evidence Quantitative di-Gly proteomics, RNAi epistasis, DSB foci imaging

    PMID:29127375

    Open questions at the time
    • Direct biochemical reconstitution of H1-Ub-driven RNF168 recruitment not yet shown at this stage
  12. 2018 High

    Defined the recruitment adaptor (ubiquitylated L3MBTL2), the K63-chain-reading UDM1/UDM2 modules structurally, and negative regulation by RNF126, integrating recruitment with structure.

    Evidence Co-IP, in vivo ubiquitylation, RNAi epistasis, X-ray crystallography of UDM1/UDM2 with K63-diubiquitin, catalytic mutant analysis

    PMID:29330428 PMID:29581593 PMID:30529286

    Open questions at the time
    • Whether L3MBTL2 is the sole RNF8-dependent docking signal not excluded
  13. 2018 High

    Established kinase and metabolic restraint of RNF168, with mTORC1-S6K1 Ser60 phosphorylation inhibiting activity and driving degradation, plus DUB control by USP14 and PRMT5-dependent expression.

    Evidence In vitro kinase assay, phospho-specific antibodies, mouse tumor model, Co-IP with domain mapping, immunoblot

    PMID:29403037 PMID:29995557 PMID:31533041

    Open questions at the time
    • Integration of metabolic signaling with acute DDR kinetics not resolved
    • PRMT5-RNF168 axis correlative in part
  14. 2018 Medium

    Added PARP-coupled substrate control by showing RNF168 K48-ubiquitylates PARP1 for degradation in a PAR-dependent manner, tuning HR/NHEJ balance.

    Evidence MS site mapping, in vivo ubiquitylation, comet and HR/NHEJ reporter assays

    PMID:30037213

    Open questions at the time
    • No in vitro reconstitution of PAR-dependent ubiquitylation
    • Single-lab study
  15. 2019 High

    Placed RNF168 in a BRCA1-parallel pathway for PALB2/RAD51 loading and defined the BARD1 BUDR-mediated reader mechanism downstream of mUb-H2A.

    Evidence Mouse genetic epistasis, RAD51/PALB2 foci imaging, PARP inhibitor sensitivity, Brca1 coiled-coil mutant epistasis

    PMID:30704900 PMID:34408138

    Open questions at the time
    • Quantitative contribution of RNF168 vs BRCA1 routes across cell types not delineated
  16. 2019 High

    Extended RNF168 to replication-stress and R-loop biology by showing it ubiquitylates DHX9 to enable R-loop resolution and is structurally shown to direct UBC13 toward K13/15 on the nucleosome.

    Evidence Co-IP, in vivo ubiquitylation, S9.6 R-loop detection, NMR with crosslinking MS and structural modeling

    PMID:30988309 PMID:33529165

    Open questions at the time
    • DHX9 ubiquitylation site/chain type not fully defined
    • Structural model not yet a near-atomic experimental structure
  17. 2020 Medium

    Generalized the substrate to H2A variants (H2AZ, macroH2A) and defined a bipartite electrostatic orientation mechanism on the nucleosome.

    Evidence In vitro ubiquitylation with acidic-patch and alpha1-extension mutants, immunofluorescence

    PMID:32424115

    Open questions at the time
    • Functional role of variant ubiquitylation in DDR not established
  18. 2021 Medium

    Connected RNF168 to interstrand crosslink repair and resection control, showing SLX4 recruitment via K63-chain recognition and dual roles in promoting and restraining end resection.

    Evidence siRNA screen, genetic epistasis survival assays, NHEJ/resection assays, laser-induced ICL tracks

    PMID:34481157 PMID:34706224

    Open questions at the time
    • Context-dependent switch between resection-promoting and -restricting roles mechanistically unresolved
  19. 2021 Medium

    Identified additional upstream activators, including RNF8-ubiquitylated KMT5A that stimulates RNF168 H2A activity via acidic-patch residues, linking H4K20me to H2A ubiquitylation.

    Evidence In vitro ubiquitylation, Co-IP, R188/R189 mutagenesis, ChIP

    PMID:33710666

    Open questions at the time
    • Single-lab; quantitative contribution of KMT5A activation in vivo unclear
  20. 2023 Medium

    Revealed phase separation and chromatin-extraction layers of regulation, with SUMOylation-driven LLPS restricting recruitment and HDAC6 gating RNF168 access to H2A.

    Evidence In vitro LLPS and SUMOylation assays, NHEJ reporters, Co-IP, in vivo ubiquitylation, K116 mutagenesis

    PMID:37350666 PMID:37503842

    Open questions at the time
    • Apparent opposing effects of SUMO/LLPS on activity require reconciliation across studies
    • Single-lab reconstitutions
  21. 2024 High

    Delivered near-atomic structural mechanism of the full reaction cycle, defining a monomeric helix-anchoring mode and how ubiquitin recognition drives site-specific K13/K15 dual monoubiquitination.

    Evidence Cryo-EM (including chemical ubiquitin-mimetic crosslinkers) and NMR with in vitro ubiquitylation and mutagenesis

    PMID:38242129 PMID:39394267

    Open questions at the time
    • Dynamics of the amplification loop in chromatin context not fully captured
  22. 2024 High

    Established linker-histone-driven activation and a K63-chain-triggered LLPS feedback loop, plus a replication-specific PCNA-binding function separable from DSB signaling.

    Evidence Chemically synthesized ubiquitylated H1.0/H1, cryo-EM of chromatosome complexes, in vitro LLPS with IDR deletion, DPIP/MIU1 mutagenesis, DNA fiber assays

    PMID:38968116 PMID:39363740 PMID:39377639 PMID:39445802

    Open questions at the time
    • In vivo position-specific H1 ubiquitylation patterns not mapped
    • Interplay of LLPS feedback with negative regulators unresolved
  23. 2024 Medium

    Defined the productive E2 (UBE2D3) for chromatin ubiquitination while showing it also caps RNF168 hyperaccumulation through a PP2A-KAP1 axis.

    Evidence RNAi/CRISPR, Co-IP, telomere NHEJ and phosphorylation assays

    PMID:38866770

    Open questions at the time
    • Mechanism of UBE2D3-imposed accumulation limit not structurally defined
  24. 2025 Medium

    Resolved opposing SUMO-based regulatory inputs: CDK1/2-PIN1-driven SUMOylation triggers p97-mediated chromatin removal, while ZNF451-mediated SUMO2 stabilizes and enhances RNF168.

    Evidence Site-specific mutagenesis (T208/K210), in vivo SUMOylation assays, Co-IP, epistasis, radiosensitivity assays

    PMID:40055579 PMID:40229270

    Open questions at the time
    • How distinct SUMO modifications produce opposite outcomes mechanistically unresolved
    • Single-lab studies

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many positive and negative regulatory layers (phosphorylation, SUMOylation, LLPS, DUBs, p97 extraction, competing E2s) are temporally integrated to set DSB repair pathway choice in vivo remains unresolved.
  • No unified quantitative model of RNF168 regulation across the DDR timeline
  • Non-DDR substrate roles (STAT1, RhoC, ANXA7) remain low-confidence and mechanistically thin

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 6 GO:0140096 catalytic activity, acting on a protein 6 GO:0042393 histone binding 4 GO:0016874 ligase activity 3 GO:0098772 molecular function regulator activity 2 GO:0003723 RNA binding 1
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 3 GO:0005694 chromosome 3
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-4839726 Chromatin organization 5 R-HSA-73894 DNA Repair 5 R-HSA-69306 DNA Replication 1
Partners
53BP1BARD1L3MBTL2PALB2PARP1RNF8UBE2D3USP7

Evidence

Reading pass · 58 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 RNF168 is a chromatin-associated RING finger E3 ubiquitin ligase that binds ubiquitin via MIU domains, assembles at DSBs in an RNF8-dependent manner, and amplifies K63-linked ubiquitin conjugates on H2A and H2AX to levels required for retention of 53BP1 and BRCA1 at damage sites. Co-IP, ubiquitin-binding assays, RNAi knockdown, immunofluorescence at DSB foci, in vivo and in vitro ubiquitylation assays Cell High 19203579
2009 RNF168 contains two MIU (motif interacting with ubiquitin) domains whose inactivation impairs ubiquitin binding in vitro and reduces chromatin association in vivo; RNF168 ubiquitylates H2A and H2AX (but not H2B) forming K63-linked polyubiquitin chains in vitro and in vivo. In vitro ubiquitin-binding assay, in vitro/in vivo ubiquitylation assay, mutagenesis of MIU domains, immunofluorescence BMC molecular biology High 19500350
2012 RNF168 (not RNF8) catalyzes monoubiquitination of nucleosomal H2A/H2AX specifically at K13-15; RNF8 is inactive toward nucleosomal H2A. A charged residue in the RNF168 RING domain determines nucleosomal substrate recognition. K63-linked ubiquitin chains are conjugated on top of RNF168-dependent K13-15 monoubiquitination, not K118-119. In vitro nucleosomal ubiquitylation assay, structure-based mutagenesis of RING domains, mass spectrometry to map ubiquitylation sites Cell High 22980979
2012 RNF168 ubiquitylates JMJD2A/KDM4A, targeting it for proteasomal degradation; this removes a competitor of 53BP1 for dimethylated H4K20, thereby allowing 53BP1 recruitment to DNA damage sites. In vivo ubiquitylation assay, co-IP, RNAi knockdown epistasis, immunofluorescence at DSB foci The EMBO journal Medium 22373579
2012 RNF168 ubiquitylates histone H2A at a novel N-terminal 'bidentate' site comprising K13 and K15; inactivating both N-terminal (K13/K15) and C-terminal (K118/K119) sites is required to fully abolish damage-induced ubiquitination, indicating these are unique, non-redundant acceptors. Mutagenesis of histone lysine residues, in vivo ubiquitylation assay, immunofluorescence Cell cycle High 22713238
2012 SMARCA5/SNF2H is recruited to DSBs in a PARP1-dependent manner, interacts with RNF168 in a DNA damage- and PARP-dependent manner, and promotes RNF168 accumulation at DSBs; RNF168 itself becomes poly(ADP-ribosyl)ated after DNA damage. Co-IP, immunofluorescence, RNAi knockdown, laser micro-irradiation Journal of cell science Medium 23264744
2013 RNF168 mediates K63-linked ubiquitylation of 53BP1, which is required for the initial recruitment of 53BP1 to DSBs and for its functions in DNA repair and checkpoint activation. In vivo ubiquitylation assay, Co-IP, K63-specific ubiquitin mutants, immunofluorescence, checkpoint assays Proceedings of the National Academy of Sciences of the United States of America Medium 24324146
2013 USP44 counteracts RNF8/RNF168-mediated ubiquitylation of H2A and is specifically recruited to RNF168-generated ubiquitylation products at DSBs, acting as a negative regulator at the level of RNF168 accrual. DUB overexpression screen, H2A deubiquitylation assay, immunofluorescence, RNAi The Journal of biological chemistry Medium 23615962
2013 USP3 removes ubiquitin at K13 and K15 of H2A/γH2AX (RNF168 target sites) as well as K118/K119 of H2AX in response to DNA damage, counteracting RNF168-mediated ubiquitination. In vitro deubiquitylation assay, co-IP, immunofluorescence, ectopic expression experiments Cell cycle Medium 24196443
2013 RNF168 forms a functional complex with RAD6A/RAD6B E2 enzymes; this RNF168-RAD6 complex ubiquitinates histone H1.2 in vitro and regulates DNA damage-induced H1.2 ubiquitination in vivo. E2 RNAi screen, Co-IP, in vitro ubiquitylation assay, immunofluorescence Journal of cell science Medium 23525009
2014 The nucleosome acidic patch is required for RNF168-dependent H2A/H2AX ubiquitination at K13/15 both in vitro and in vivo; H2A/H2B dimers and nucleosomes actively stimulate E3-mediated discharge of ubiquitin from E2, redirecting the reaction toward the target lysines. In vitro ubiquitylation assay with acidic-patch mutant nucleosomes, viral LANA peptide perturbation in vivo, fluorescence-based E2~Ub discharge assay Nature communications High 24518117
2014 The nucleosome acidic patch is required for both RNF168-dependent H2AX ubiquitination and DDR factor (53BP1, BRCA1) recruitment in vivo; perturbation of the acidic patch by the LANA viral peptide phenocopies RNF168 loss. In vitro ubiquitylation assay, viral LANA peptide expression, RNAi, immunofluorescence PLoS genetics Medium 24603765
2014 RNF168 contains a novel UBD designated UMI (UIM- and MIU-related UBD); the UMI binds ubiquitin via two leucine residues and is required together with MIU domains for proper RNF168 localization and H2A ubiquitination. Mutagenesis, ubiquitin-binding assays, immunofluorescence, in vivo ubiquitylation assay Molecular and cellular biology Medium 21041483
2014 RNF168 mediates NEDD8 conjugation (neddylation) to H2A and is itself neddylated; neddylation of RNF168 is required for its interaction with E2 enzyme Ubc13 and its ubiquitin ligase activity. H2A neddylation antagonizes H2A ubiquitylation. In vivo neddylation assay, Co-IP, mutagenesis, immunofluorescence Journal of cell science Medium 24634510
2014 RNF168 interacts with and ubiquitylates topoisomerase IIα (TOP2α), regulating its decatenation activity and chromatin association; USP10 counteracts this by deubiquitylating TOP2α. Co-IP, in vivo ubiquitylation assay, decatenation assay, RNAi Nature communications Medium 27558965
2015 RNF168 promotes K27-linked (noncanonical) ubiquitin chain formation both in vitro and in vivo; K27-ubiquitin on chromatin is the major ubiquitin mark upon DNA damage and is directly recognized by 53BP1, Rap80, RNF168, and RNF169. In vitro ubiquitylation assay with K27R ubiquitin mutants, mass spectrometry chain-linkage analysis, immunofluorescence with ubiquitin mutants in cells Cell reports Medium 25578731
2015 USP7 deubiquitinase physically binds RNF168, stabilizes it against DNA damage-induced degradation, and its deubiquitylase activity toward RNF168 is required to maintain H2A ubiquitination and downstream BRCA1/53BP1 foci formation. Co-IP (in vitro and in vivo), in vivo ubiquitylation assay, overexpression rescue experiments, RNAi Cell cycle Medium 25894431
2015 LSD1 is recruited to DSBs in an RNF168-dependent manner and interacts directly with RNF168 and 53BP1; RNF168-dependent 53BP1 ubiquitination requires CK2-mediated phosphorylation of LSD1 at S131/S137, which promotes LSD1-RNF168 interaction. Co-IP, immunofluorescence, phosphorylation assay (CK2/WIP1), mutagenesis Nucleic acids research Medium 25999347
2015 RNF168 partially localizes to PML nuclear bodies via its UMI/MIU1 ubiquitin-interacting region; RNF168 binds hybrid SUMO2-K63 ubiquitin chains preferentially over K63-ubiquitin chains alone (confirmed in vitro); RNF168 overexpression increases ubiquitylation and SUMO2 modification of PML. shRNA screen, in vitro ubiquitin/SUMO chain binding assay, Co-IP, immunofluorescence Journal of cell science Medium 26675234
2016 RNF168 interacts with FOXM1 and mediates its K48-linked polyubiquitination and proteasomal degradation in response to epirubicin; SUMOylation of FOXM1 is required for RNF168 recruitment to FOXM1; RNF8 recruits RNF168 to this substrate. Co-IP, in vivo ubiquitylation assay, cycloheximide chase, SUMO-defective mutant analysis, gene promoter-reporter assay Oncogenesis Medium 27526106
2017 RNF168 directly interacts with PALB2 via a newly identified PALB2-interacting domain (PID) in RNF168 and the WD40 domain in PALB2; this interaction links H2A ubiquitylation to PALB2-dependent homologous recombination at DSBs in S/G2 cells. Co-IP, pull-down, mutagenesis of PID domain, HR assay, immunofluorescence eLife High 28240985
2017 RNF169 (RNF168 paralog) binds ubiquitylated H2A-K13/15 on the nucleosome via a three-pronged mechanism involving a canonical ubiquitin-binding helix and two arginine-rich motifs contacting the nucleosome acidic patch; this high-affinity binding displaces 53BP1 from ubiquitylated chromatin. Methyl-TROSY NMR, molecular dynamics simulations, cryo-EM validation, biochemical binding assays eLife High 28406400
2017 53BP1 binds RNF168-mediated mono-ubiquitylated H2A-K15 in NCP dimethylated at H4K20; RNF169 stabilizes a pre-existing ubiquitin orientation on the nucleosome via a conformational selection mechanism to outcompete 53BP1; RAD18 binds tightly to ubiquitylated NCP through a domain contacting both ubiquitin and nucleosome surfaces accessed by 53BP1. NMR spectroscopy, biochemical binding assays, mutagenesis Molecular cell High 28506460
2017 HUWE1-mediated histone H1 ubiquitylation at multiple lysines is required upstream for RNF168 recruitment and 53BP1 assembly at DSBs; HUWE1 depletion reduces RNF168 foci without affecting MDC1 (upstream of H1 ubiquitylation). Quantitative di-Gly proteomics, RNAi, immunofluorescence at DSB foci Scientific reports Medium 29127375
2018 mTORC1-S6K1 phosphorylates RNF168 at Ser60, inhibiting its E3 ligase activity and accelerating its proteasomal degradation; a phospho-deficient S60A mutant rescues DNA damage repair defects caused by LKB1 loss. In vitro kinase assay, phospho-specific antibody, co-IP, proteasome assay, mutagenesis, mouse tumor model Nature cell biology High 29403037
2018 L3MBTL2 is ubiquitylated by RNF8 and the resulting ubiquitylated L3MBTL2 directly recruits RNF168 to DNA damage sites, providing the mechanistic link between RNF8 and RNF168 in sequential DSB signaling. Co-IP, in vivo ubiquitylation assay, immunofluorescence, RNAi epistasis Nature cell biology High 29581593
2018 Crystal structures of RNF168 UDM1 and UDM2 bound to K63-linked diubiquitin reveal that both modules fold as single α-helices that simultaneously contact distal and proximal ubiquitin moieties, conferring K63-chain specificity; UDM2 interaction with ubiquitylated targets primarily drives RNF168 recruitment to DSBs. X-ray crystallography, biochemical binding assays, mutagenesis, immunofluorescence in U2OS cells Nature communications High 29330428
2018 RNF168 ubiquitinates PARP1 via K48-linked chains on multiple lysines, accelerating PARP1 degradation in the presence of PAR chains; PAR-binding by RNF168 is required for this activity and for regulating HR/NHEJ balance. Mass spectrometry (ubiquitination site mapping), in vivo ubiquitylation assay, Co-IP, comet assay, HR/NHEJ reporter assays Molecules and cells Medium 30037213
2018 RNF126 directly interacts with RNF168 and ubiquitinates it; RNF126 overexpression diminishes H2AX ubiquitination and downstream 53BP1/RAP80 foci in a catalytic activity-dependent manner, negatively regulating RNF168 function. Co-IP, in vivo ubiquitylation assay, immunofluorescence, HR reporter assay, catalytic mutant analysis Genomics, proteomics & bioinformatics Medium 30529286
2019 RNF168 directly ubiquitylates DHX9 helicase to facilitate its recruitment to R-loop-prone genomic loci; loss of RNF168 impairs DHX9 recruitment and R-loop resolution, leading to DSBs in BRCA1/2-mutant cells. Co-IP (interactome assay), in vivo ubiquitylation assay, immunofluorescence, R-loop detection (S9.6 antibody), genetic epistasis The Journal of clinical investigation Medium 33529165
2019 RNF168 acts redundantly with BRCA1 to load PALB2 onto damaged DNA; loss of RNF168 negates the synthetic rescue of BRCA1 deficiency by 53BP1 deletion, placing RNF168 in a pathway parallel to BRCA1 for RAD51 loading. Mouse genetics (epistasis), immunofluorescence for RAD51/PALB2 foci, PARP inhibitor sensitivity assay, forced PALB2 targeting rescue Molecular cell High 30704900
2019 RNF168-generated mUb-H2A recruits BARD1 through a BRCT domain ubiquitin-dependent recruitment motif (BUDR); BARD1-BRCA1 then accumulate PALB2-RAD51 at DSBs via the BRCA1 coiled-coil domain–PALB2 interaction. Co-IP, mouse genetics (Brca1CC mutant epistasis), immunofluorescence for PALB2/RAD51 foci Nature communications High 34408138
2019 HPV E7 oncoprotein directly binds a regulatory domain of RNF168 without affecting its enzymatic activity, subverting RNF168 function at DSBs; RNF168 is required for viral genome amplification in differentiated keratinocytes. Co-IP (direct binding), immunofluorescence, RNAi knockdown, viral genome amplification assay Proceedings of the National Academy of Sciences of the United States of America Medium 31501315
2019 PRMT5 sustains RNF168 expression; RNF168 and SMURF2 serve as stabilizer and destabilizer of H2AX, respectively, through dynamic interactions with H2AX; loss of PRMT5 (in MTAP-deficient cells) attenuates RNF168, leading to H2AX destabilization by SMURF2. Co-IP, in vivo ubiquitylation assay, RNAi, immunoblot Cell reports Medium 31533041
2019 NMR and biochemical studies show RNF168 binds the nucleosome acidic patch and directs the E2 enzyme UBC13 toward K13/15; the structural model defines the basis for site specificity. NMR spectroscopy, crosslinking mass spectrometry, mutagenesis, data-driven structural modelling Nature communications High 30988309
2014 RNF168 and its cognate E2 UBC13 do not stably associate in vitro or in vivo, in contrast to the RNF8-UBC13 interaction; crystal structure of the RNF168 RING domain reveals differences at the UBC13-binding interface compared to other UBC13-binding E3s; RNF8 and RNF168 RING domains are not functionally interchangeable. X-ray crystallography, in vitro and in vivo Co-IP, domain-swap mutagenesis Cell cycle High 23255131
2018 USP14 deubiquitinase directly interacts with RNF168 via RNF168's MIU1 domain; USP14 activity negatively regulates RNF168 protein levels and RNF168-dependent H2A ubiquitination and 53BP1 recruitment; USP14 is itself a substrate of autophagy via SQSTM1. Co-IP, immunofluorescence, DUB activity assay, RNAi, domain mapping (MIU1) Autophagy Medium 29995557
2020 RNF168 ubiquitinates H2A variants H2AZ and macroH2A1/2 at their divergent N-terminal tail lysines; the positively charged alpha1-extension helix of H2A variants and the RNF168 UMI acidic residues are essential for this reaction; a bipartite electrostatic interaction directs RNF168 orientation on the nucleosome. In vitro ubiquitylation assay, mutagenesis of nucleosome acidic patch and alpha1-extension helix, immunofluorescence Nature communications Medium 32424115
2021 RNF8-ubiquitinated KMT5A is recruited to DSBs and binds RNF168; KMT5A promotes RNF168 catalytic activity toward H2A via its H2A acidic-patch interacting residues R188/R189, linking H4K20 monomethylation to H2A ubiquitination. In vitro ubiquitylation assay, Co-IP, mutagenesis (R188/R189), ChIP, immunofluorescence FASEB journal Medium 33710666
2021 RNF168 is required for SLX4/FANCP recruitment to interstrand crosslink damage sites; RNF168 is epistatic with SLX4 in promoting mitomycin C tolerance; RNF168-generated K63-linked ubiquitin chains are recognized by the tandem UBZ4 domains of SLX4. siRNA screen with GFP-SLX4, immunofluorescence, genetic epistasis (survival assays), laser-induced ICL tracks Cell reports Medium 34706224
2021 RNF168 facilitates ubiquitin signaling in RNF8/RNF168-dependent pathways that both prevent and promote DNA end resection in G0/G1 lymphocytes; combined deficiency of XLF and RNF168 leads to diminished NHEJ; in 53BP1-deficient cells, loss of RNF168 diminishes resection. Genetic knockouts in lymphocytes, NHEJ reporter assays, end-resection assays DNA repair Medium 34481157
2023 SUMOylated RNF168 undergoes liquid-liquid phase separation (LLPS), restricting its recruitment to DNA damage sites and reducing H2A ubiquitination; SENP1 deSUMOylates RNF168, preventing LLPS and promoting RNF168 activity and NHEJ repair. In vitro LLPS assay, SUMOylation assay, immunofluorescence, NHEJ reporter, SENP1 knockdown/overexpression Cancer research Medium 37350666
2023 HDAC6 interacts with H2A/H2A.X in unstressed cells to prevent RNF168 access; upon DSBs, RNF168 ubiquitinates HDAC6 at K116 leading to its proteasomal degradation and allowing RNF168-H2A/H2A.X interaction and subsequent H2A ubiquitination. Co-IP, in vivo ubiquitylation assay, immunofluorescence, mutagenesis (K116) Nucleic acids research Medium 37503842
2024 Cryo-EM and NMR structures reveal the full reaction cycle of RNF168 modifying the nucleosome: RNF168 engages the nucleosome via a canonical ubiquitin-binding domain that contacts both ubiquitin and the nucleosome surface, clarifying how ubiquitin recognition drives a signal amplification loop for site-specific H2A K13/15 ubiquitination. Cryo-EM, NMR spectroscopy, in vitro ubiquitylation assay, mutagenesis Molecular cell High 38242129
2024 Cryo-EM structures of RNF168-UbcH5c~Ub-nucleosome complexes captured during H2A K13 and K15 monoubiquitination reveal a 'helix-anchoring' mode for monomeric RNF168 on the nucleosome, distinct from the 'compass-binding' mode of dimeric E3 ligases; both K13 and K15 can be independently monoubiquitinated (adjacent dual monoubiquitination). Cryo-EM with chemically synthesized ubiquitin-mimetic crosslinkers, in vitro ubiquitylation assay, mutagenesis Nature chemical biology High 39394267
2024 K63-linked polyubiquitin chains trigger RNF168 condensation (LLPS) in vitro and in vivo; an intrinsically disordered region (aa 460-550) is essential for RNF168 LLPS; LLPS enhances RNF168-mediated H2A.X ubiquitination, forming a positive feedback loop; LLPS deficiency delays 53BP1/BRCA1 recruitment and impairs DSB repair. In vitro LLPS assay with purified proteins, domain deletion mutagenesis, immunofluorescence, in vivo irradiation assays Proceedings of the National Academy of Sciences of the United States of America Medium 38968116
2024 K63-linked polyubiquitylated linker histone H1.0 directly stimulates RNF168 ubiquitylation activity on nucleosomal H2A by enhancing RNF168 affinity for the chromatosome; cryo-EM of the RNF168/UbcH5c-Ub/H1.0-K63-Ub3 chromatosome complex reveals the UDM1 domain contacts K63-ubiquitin on H1.0. Chemical synthesis of ubiquitylated H1.0 (CAEPL strategy), in vitro ubiquitylation assay, cryo-EM Angewandte Chemie High 39363740
2024 RNF168 contains a degenerate PCNA-interacting peptide (DPIP) motif that together with MIU1 mediates binding to mono-ubiquitylated PCNA at replication factories; this PCNA interaction is required for RNF168 recruitment to replication sites and support of ongoing DNA replication, but is fully dispensable for DSB signaling (53BP1 foci). Mutagenesis (DPIP/MIU1 double mutant), Co-IP with PCNA, immunofluorescence at replication factories, DNA fiber assay, 53BP1 foci formation assay Nucleic acids research High 39445802
2024 K63-ubiquitylated H1 at different positions (K17, K46, K64, K96) stimulates RNF168 H2A ubiquitylation in a position-dependent manner; H1K17Ub2 shows the strongest RNF168 activation; di-ubiquitin binding (not monoubiquitin) drives RNF168 recruitment to DSB sites. Click chemistry synthesis of site-specific H1-diUb, in vitro ubiquitylation assay on nucleosome arrays, introduction of H1K17Ub2 into living cells Angewandte Chemie Medium 39377639
2024 UBE2D3 E2 enzyme promotes RNF168-dependent chromatin ubiquitination and 53BP1 recruitment for NHEJ; simultaneously, UBE2D3 limits RNF168 hyperaccumulation; defective UBE2D3 leads to RNF168 hyperaccumulation that aberrantly activates PP2A phosphatase to restrict KAP1-S824 phosphorylation and NHEJ. RNAi/CRISPR, Co-IP, immunofluorescence, telomere NHEJ assay, phosphorylation assays Nature communications Medium 38866770
2025 CDK1/2 phosphorylates RNF168 at T208, enabling PIN1 isomerase binding; PIN1 promotes SUMOylation of RNF168 at K210 (adjacent to the SPaCR motif); SUMOylation leads to p97/VCP-mediated removal of RNF168 from damaged chromatin, limiting ubiquitin signaling. Mutagenesis (T208, K210), Co-IP, in vivo SUMOylation assay, immunofluorescence, radiosensitivity assay Nature communications Medium 40229270
2025 ZNF451 SUMO E3 ligase catalyzes SUMO2 modification of RNF168, stabilizing it and enhancing its accumulation at DSBs to increase H2A/H2AX ubiquitination; ZNF451 and RNF8 jointly regulate RNF168 recruitment in a competitive-cooperative manner. SUMOylation assay, Co-IP, immunofluorescence, mutagenesis, epistasis (double ZNF451/RNF8 depletion) Cell death and differentiation Medium 40055579
2021 RNF168 interacts with STAT1 in the nucleus, stabilizing STAT1 protein by inhibiting its poly-ubiquitination and proteasomal degradation in esophageal cancer cells. Co-IP, immunoblot, RNAi knockdown Journal of cellular and molecular medicine Low 30506884
2021 RNF168 directly interacts with RhoC and promotes its K48-linked ubiquitylation and proteasomal degradation in NSCLC and gastric cancer cells, suppressing cancer stem cell-like traits. Co-IP, in vivo ubiquitylation assay, immunoblot, overexpression/knockdown Environmental toxicology / Biochemical and biophysical research communications Low 33865221 34873829
2018 RNF17 E3 ligase and its cognate E2 UBE2U function upstream of RNF168 to regulate 53BP1 foci formation at DSBs; RNF17-UBE2U constitutes a new E2-E3 module regulating the RNF168 pathway. RNAi-based E2 screen, immunofluorescence for 53BP1 foci, Co-IP for UBE2U-RNF17 interaction The Journal of biological chemistry Low 27903633
2014 BCL10 is recruited to DSBs in an ATM- and RNF8-dependent manner; ATM-dependent BCL10 phosphorylation promotes BCL10-UBC13 interaction; RNF8-mediated BCL10 ubiquitination enhances BCL10 and UBC13 binding to RNF168, facilitating RNF168-dependent H2AX monoubiquitination. Co-IP, in vivo ubiquitylation assay, immunofluorescence, ATM inhibitor experiments Cell cycle Low 24732096
2014 RNF168 and SET8 methyltransferase form stable complexes in vivo; SET8 recruitment to DSBs is abolished by RNF8 or RNF168 knockdown or by proteasome inhibition that depletes free ubiquitin, placing SET8 downstream of RNF168 in the DSB pathway. Co-IP, RNAi epistasis, proteasome inhibitor, immunofluorescence Cell cycle Low 31760894
2024 RNF168 promotes ubiquitination and degradation of ANXA7, suppressing autophagy and inducing NLRP3 inflammasome-mediated pyroptosis; ELK1 transcription factor regulates RNF168 expression in this colitis context. Co-IP, ubiquitination assay, siRNA knockdown, in vivo mouse model Apoptosis Low 41518435

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins. Cell 762 19203579
2012 RNF168 ubiquitinates K13-15 on H2A/H2AX to drive DNA damage signaling. Cell 544 22980979
2012 RNF8- and RNF168-dependent degradation of KDM4A/JMJD2A triggers 53BP1 recruitment to DNA damage sites. The EMBO journal 296 22373579
2015 RNF168 promotes noncanonical K27 ubiquitination to signal DNA damage. Cell reports 170 25578731
2010 A viral E3 ligase targets RNF8 and RNF168 to control histone ubiquitination and DNA damage responses. The EMBO journal 151 20075863
2012 A novel ubiquitin mark at the N-terminal tail of histone H2As targeted by RNF168 ubiquitin ligase. Cell cycle (Georgetown, Tex.) 142 22713238
2012 Poly(ADP-ribosyl)ation links the chromatin remodeler SMARCA5/SNF2H to RNF168-dependent DNA damage signaling. Journal of cell science 120 23264744
2013 The deubiquitylating enzyme USP44 counteracts the DNA double-strand break response mediated by the RNF8 and RNF168 ubiquitin ligases. The Journal of biological chemistry 117 23615962
2009 RNF168, a new RING finger, MIU-containing protein that modifies chromatin by ubiquitination of histones H2A and H2AX. BMC molecular biology 110 19500350
2018 The mTOR-S6K pathway links growth signalling to DNA damage response by targeting RNF168. Nature cell biology 108 29403037
2013 USP3 counteracts RNF168 via deubiquitinating H2A and γH2AX at lysine 13 and 15. Cell cycle (Georgetown, Tex.) 101 24196443
2019 BRCA1 Haploinsufficiency Is Masked by RNF168-Mediated Chromatin Ubiquitylation. Molecular cell 96 30704900
2018 L3MBTL2 orchestrates ubiquitin signalling by dictating the sequential recruitment of RNF8 and RNF168 after DNA damage. Nature cell biology 89 29581593
2013 RNF168 ubiquitylates 53BP1 and controls its response to DNA double-strand breaks. Proceedings of the National Academy of Sciences of the United States of America 85 24324146
2014 Nucleosome acidic patch promotes RNF168- and RING1B/BMI1-dependent H2AX and H2A ubiquitination and DNA damage signaling. PLoS genetics 82 24603765
2023 SENP1 Decreases RNF168 Phase Separation to Promote DNA Damage Repair and Drug Resistance in Colon Cancer. Cancer research 81 37350666
2014 The nucleosome acidic patch plays a critical role in RNF168-dependent ubiquitination of histone H2A. Nature communications 81 24518117
2017 Mechanisms of Ubiquitin-Nucleosome Recognition and Regulation of 53BP1 Chromatin Recruitment by RNF168/169 and RAD18. Molecular cell 77 28506460
2015 USP7 deubiquitinase promotes ubiquitin-dependent DNA damage signaling by stabilizing RNF168. Cell cycle (Georgetown, Tex.) 75 25894431
2018 USP14 regulates DNA damage repair by targeting RNF168-dependent ubiquitination. Autophagy 71 29995557
2017 A PALB2-interacting domain in RNF168 couples homologous recombination to DNA break-induced chromatin ubiquitylation. eLife 71 28240985
2017 DNA damage-induced histone H1 ubiquitylation is mediated by HUWE1 and stimulates the RNF8-RNF168 pathway. Scientific reports 67 29127375
2021 RNF168 regulates R-loop resolution and genomic stability in BRCA1/2-deficient tumors. The Journal of clinical investigation 65 33529165
2011 Homozygous deficiency of ubiquitin-ligase ring-finger protein RNF168 mimics the radiosensitivity syndrome of ataxia-telangiectasia. Cell death and differentiation 65 21394101
2015 Modulation of LSD1 phosphorylation by CK2/WIP1 regulates RNF168-dependent 53BP1 recruitment in response to DNA damage. Nucleic acids research 63 25999347
2009 The RNF8/RNF168 ubiquitin ligase cascade facilitates class switch recombination. Proceedings of the National Academy of Sciences of the United States of America 62 20080757
2010 UMI, a novel RNF168 ubiquitin binding domain involved in the DNA damage signaling pathway. Molecular and cellular biology 60 21041483
2019 Human papillomavirus E7 oncoprotein targets RNF168 to hijack the host DNA damage response. Proceedings of the National Academy of Sciences of the United States of America 59 31501315
2014 RNF168-mediated H2A neddylation antagonizes ubiquitylation of H2A and regulates DNA damage repair. Journal of cell science 59 24634510
2021 RNF168-mediated localization of BARD1 recruits the BRCA1-PALB2 complex to DNA damage. Nature communications 57 34408138
2015 USP11 Is a Negative Regulator to γH2AX Ubiquitylation by RNF8/RNF168. The Journal of biological chemistry 57 26507658
2019 Structural basis of specific H2A K13/K15 ubiquitination by RNF168. Nature communications 49 30988309
2017 The RNF168 paralog RNF169 defines a new class of ubiquitylated histone reader involved in the response to DNA damage. eLife 48 28406400
2016 RNF168 and USP10 regulate topoisomerase IIα function via opposing effects on its ubiquitylation. Nature communications 47 27558965
2012 RING finger nuclear factor RNF168 is important for defects in homologous recombination caused by loss of the breast cancer susceptibility factor BRCA1. The Journal of biological chemistry 44 23055523
2016 Tumors overexpressing RNF168 show altered DNA repair and responses to genotoxic treatments, genomic instability and resistance to proteotoxic stress. Oncogene 43 27841863
2019 PML nuclear bodies are recruited to persistent DNA damage lesions in an RNF168-53BP1 dependent manner and contribute to DNA repair. DNA repair 40 31009828
2013 Put a RING on it: regulation and inhibition of RNF8 and RNF168 RING finger E3 ligases at DNA damage sites. Frontiers in genetics 38 23847653
2019 A PRMT5-RNF168-SMURF2 Axis Controls H2AX Proteostasis. Cell reports 37 31533041
2011 Recruitment of the cohesin loading factor NIPBL to DNA double-strand breaks depends on MDC1, RNF168 and HP1γ in human cells. Biochemical and biophysical research communications 37 21784059
2016 RNF168 cooperates with RNF8 to mediate FOXM1 ubiquitination and degradation in breast cancer epirubicin treatment. Oncogenesis 32 27526106
2016 Opposing roles of RNF8/RNF168 and deubiquitinating enzymes in ubiquitination-dependent DNA double-strand break response signaling and DNA-repair pathway choice. Journal of radiation research 30 26983989
2014 An RNF168 fragment defective for focal accumulation at DNA damage is proficient for inhibition of homologous recombination in BRCA1 deficient cells. Nucleic acids research 30 24829461
2013 RNF168 forms a functional complex with RAD6 during the DNA damage response. Journal of cell science 29 23525009
2020 Histone H2A variants alpha1-extension helix directs RNF168-mediated ubiquitination. Nature communications 28 32424115
2014 Regulation of 53BP1 protein stability by RNF8 and RNF168 is important for efficient DNA double-strand break repair. PloS one 28 25337968
2019 Cadmium disrupts the DNA damage response by destabilizing RNF168. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 27 31376412
2023 The HDAC6-RNF168 axis regulates H2A/H2A.X ubiquitination to enable double-strand break repair. Nucleic acids research 26 37503842
2018 Structural insights into two distinct binding modules for Lys63-linked polyubiquitin chains in RNF168. Nature communications 26 29330428
2022 A 1,2,3-Triazole Derivative of Quinazoline Exhibits Antitumor Activity by Tethering RNF168 to SQSTM1/P62. Journal of medicinal chemistry 24 36331508
2021 New answers to the old RIDDLE: RNF168 and the DNA damage response pathway. The FEBS journal 24 33797206
2015 Ectopic expression of RNF168 and 53BP1 increases mutagenic but not physiological non-homologous end joining. Nucleic acids research 24 25916843
2012 RNF8 and RNF168 but not HERC2 are required for DNA damage-induced ubiquitylation in chicken DT40 cells. DNA repair 22 23010445
2024 Mechanisms of RNF168 nucleosome recognition and ubiquitylation. Molecular cell 21 38242129
2020 RNF168-Mediated Ubiquitin Signaling Inhibits the Viability of BRCA1-Null Cancers. Cancer research 21 32213544
2018 RNF168 facilitates proliferation and invasion of esophageal carcinoma, possibly via stabilizing STAT1. Journal of cellular and molecular medicine 21 30506884
2018 RNF126 Quenches RNF168 Function in the DNA Damage Response. Genomics, proteomics & bioinformatics 21 30529286
2017 Novel Combined Immune Deficiency and Radiation Sensitivity Blended Phenotype in an Adult with Biallelic Variations in ZAP70 and RNF168. Frontiers in immunology 20 28603521
2012 Structural basis for role of ring finger protein RNF168 RING domain. Cell cycle (Georgetown, Tex.) 20 23255131
2024 Mechanism of nucleosomal H2A K13/15 monoubiquitination and adjacent dual monoubiquitination by RNF168. Nature chemical biology 19 39394267
2020 Ectopic RNF168 expression promotes break-induced replication-like DNA synthesis at stalled replication forks. Nucleic acids research 19 32182354
2024 Ubiquitin-induced RNF168 condensation promotes DNA double-strand break repair. Proceedings of the National Academy of Sciences of the United States of America 17 38968116
2024 Promotion of RNF168-Mediated Nucleosomal H2A Ubiquitylation by Structurally Defined K63-Polyubiquitylated Linker Histone H1. Angewandte Chemie (International ed. in English) 17 39363740
2015 Identification of RNF168 as a PML nuclear body regulator. Journal of cell science 16 26675234
2015 Ubiquitin-H2AX fusions render 53BP1 recruitment to DNA damage sites independent of RNF8 or RNF168. Cell cycle (Georgetown, Tex.) 15 25695757
2021 RNF168 is highly expressed in esophageal squamous cell carcinoma and contributes to the malignant behaviors in association with the Wnt/β-catenin signaling pathway. Aging 13 33493132
2018 RNF168 facilitates oestrogen receptor ɑ transcription and drives breast cancer proliferation. Journal of cellular and molecular medicine 13 29974997
2014 BCL10 regulates RNF8/RNF168-mediated ubiquitination in the DNA damage response. Cell cycle (Georgetown, Tex.) 12 24732096
2012 Three-dimensional imaging reveals the spatial separation of γH2AX-MDC1-53BP1 and RNF8-RNF168-BRCA1-A complexes at ionizing radiation-induced foci. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 12 22633816
2025 ZNF451 collaborates with RNF8 to regulate RNF168 localization and amplify ubiquitination signaling to promote DNA damage repair and regulate radiosensitivity. Cell death and differentiation 11 40055579
2023 Emerging Roles of RNF168 in Tumor Progression. Molecules (Basel, Switzerland) 11 36771081
2021 RNF8-ubiquitinated KMT5A is required for RNF168-induced H2A ubiquitination in response to DNA damage. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 11 33710666
2021 The RNF8 and RNF168 Ubiquitin Ligases Regulate Pro- and Anti-Resection Activities at Broken DNA Ends During Non-Homologous End Joining. DNA repair 11 34481157
2021 RNF168 E3 ligase participates in ubiquitin signaling and recruitment of SLX4 during DNA crosslink repair. Cell reports 11 34706224
2017 Clinical and Biological Manifestation of RNF168 Deficiency in Two Polish Siblings. Frontiers in immunology 11 29255463
2018 A Novel Reciprocal Crosstalk between RNF168 and PARP1 to Regulate DNA Repair Processes. Molecules and cells 10 30037213
2016 An E2-guided E3 Screen Identifies the RNF17-UBE2U Pair as Regulator of the Radiosensitivity, Immunodeficiency, Dysmorphic Features, and Learning Difficulties (RIDDLE) Syndrome Protein RNF168. The Journal of biological chemistry 9 27903633
2024 A Site-Specific Click Chemistry Approach to Di-Ubiquitylate H1 Variants Reveals Position-Dependent Stimulation of the DNA Repair Protein RNF168. Angewandte Chemie (International ed. in English) 8 39377639
2024 A RAD18-UBC13-PALB2-RNF168 axis mediates replication fork recovery in BRCA1-deficient cancer cells. Nucleic acids research 7 38943334
2023 Degradation of Ubiquitin-Editing Enzyme A20 following Autophagy Activation Promotes RNF168 Nuclear Translocation and NF-κB Activation in Lupus Nephritis. Journal of innate immunity 7 36944318
2023 UBA80 and UBA52 fine-tune RNF168-dependent histone ubiquitination and DNA repair. The Journal of biological chemistry 7 37451480
2021 RNF168 promotes RHOC degradation by ubiquitination to restrain gastric cancer progression via decreasing HDAC1 expression. Biochemical and biophysical research communications 7 33865221
2021 RNF168 suppresses the cancer stem cell-like traits of nonsmall cell lung cancer cells by mediating RhoC ubiquitination. Environmental toxicology 7 34873829
2014 The ubiquitin ligases RNF8 and RNF168 display rapid but distinct dynamics at DNA repair foci in living cells. The international journal of biochemistry & cell biology 6 25304081
2024 UBE2D3 facilitates NHEJ by orchestrating ATM signalling through multi-level control of RNF168. Nature communications 5 38866770
2024 PCNA-binding activity separates RNF168 functions in DNA replication and DNA double-stranded break signaling. Nucleic acids research 5 39445802
2019 Context Matters: RNF168 Connects with PALB2 to Rewire Homologous Recombination in BRCA1 Haploinsufficiency. Molecular cell 5 30901561
2018 Calling RNF168 to action. Cell stress 5 31225475
2025 PIN1-SUMO2/3 motif suppresses excessive RNF168 chromatin accumulation and ubiquitin signaling to promote IR resistance. Nature communications 4 40229270
2021 MRE11 and UBR5 Co-Operate to Suppress RNF168-Mediated Fusion of Dysfunctional Telomeres. Frontiers in oncology 4 34881184
2019 SET8 localization to chromatin flanking DNA damage is dependent on RNF168 ubiquitin ligase. Cell cycle (Georgetown, Tex.) 4 31760894
2017 Retroviral insertional mutagenesis implicates E3 ubiquitin ligase RNF168 in the control of cell proliferation and survival. Bioscience reports 4 28754805
2025 TRIM39-mediated deubiquitination upregulates RNF168 to evade autophagy-ferroptosis in triple-negative breast cancer. NPJ breast cancer 2 41034232
2020 Not Black or White but Shades of Gray: Homologous Recombination Deficiency as a Continuous Variable Modulated by RNF168. Cancer research 1 32616507
2026 RNF168 promotes chronic colitis through ANXA7-mediated autophagy and NLRP3-driven pyroptosis. Apoptosis : an international journal on programmed cell death 0 41518435
2026 The mutual regulation of SOX12 and RNF168 modulates cisplatin resistance in esophageal squamous cell carcinoma cells by regulating DNA damage repair. Cell & bioscience 0 41555391
2026 Targeting the USP7-PRMT6 epigenetic axis overcomes chemoresistance in breast cancer by coordinating H3R2me2a deposition and RNF168 methylation for DNA repair and ferroptosis blockade. Cell death and differentiation 0 41617976
2026 Lupenone regulates LOXL2-mediated PANoptosis signaling through E3 ubiquitin ligases RNF168 to improve radiation-induced lung injury. Phytomedicine : international journal of phytotherapy and phytopharmacology 0 41722124
2025 RNF168 dephosphorylation ameliorates cognitive decline in Aβ-based mouse models of Alzheimer's disease. Acta neuropathologica communications 0 40993809
2023 Topology of Ubiquitin Chains in the Chromatosomal Environment of the E3 Ubiquitin Ligase RNF168. Biochemistry. Biokhimiia 0 38462450

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