Affinage

UHRF1

E3 ubiquitin-protein ligase UHRF1 · UniProt Q96T88

Length
793 aa
Mass
89.8 kDa
Annotated
2026-06-10
100 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

UHRF1 (Np95/ICBP90) is a multi-domain epigenetic regulator that couples the recognition of replicated chromatin to the inheritance of DNA methylation, serving as the essential reader-writer that recruits and licenses DNMT1 at replicating heterochromatin (PMID:17994007, PMID:24013172). Its modular architecture integrates several chromatin signals: the SRA domain binds hemi-methylated CpG DNA and flips the methylated cytosine, a kinetically slow step that prolongs CpG-bound UHRF1 and increases the probability of DNMT1 recruitment (PMID:17994007, PMID:28112929), while the tandem Tudor domain reads H3K9me3 through an aromatic cage and the PHD finger contributes H3-tail recognition (PMID:20026581). Engagement of hemi-methylated DNA allosterically activates the RING-domain E3 ubiquitin ligase, which ubiquitylates the H3 tail at K18 and K23; this histone ubiquitin mark, read by the DNMT1 RFTS/UIM modules together with a direct UHRF1 UBL–DNMT1 contact, recruits DNMT1 to replication sites and is a prerequisite for maintenance methylation (PMID:24013172, PMID:27595565, PMID:29471350, PMID:39607687). Beyond DNMT1, UHRF1 stimulates the de novo methyltransferases DNMT3A/DNMT3B and antagonizes TET2-mediated demethylation, accounting for methylation loss exceeding that of DNMT1 depletion alone (PMID:38580649), and its RING-catalyzed H3K18ub enhances SUV39H1/H2 to nucleate H3K9me3 domains that silence tumor suppressor promoters (PMID:39631394). UHRF1 reader activities sustain cancer-specific DNA hypermethylation and tumor suppressor silencing (PMID:30956060), and it represses target genes through partners including HDAC1 and the Sin3A component SAP30 (PMID:15361834, PMID:36302855). Activity is tuned post-translationally by PKA phosphorylation at S298 (PMID:15178447), SET8 methylation at K385 driving its degradation (PMID:31400111), AKT1 phosphorylation at T210 stabilizing it via USP7 (PMID:36593255), and PCAF/HDAC1 acetylation at K490 controlling hemi-methylated DNA binding (PMID:32726623). UHRF1 additionally functions in genome maintenance—recruited to double-strand breaks by BRCA1 to K63-ubiquitylate RIF1 and promote homologous recombination (PMID:26727879), and binding interstrand-crosslink DNA to recruit ERCC1 and MUS81 nucleases (PMID:25818288)—and has nuclear-independent roles, including cytoplasmic suppression of AMPK via PP2A bridging (PMID:34561619) and TGF-β-induced cytoplasmic degradation of MHC-I (PMID:39362877).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2004 High

    Established that UHRF1 is both a methyl-DNA reader and an intrinsic histone E3 ligase, defining its dual reader-writer biochemistry before its inheritance role was known.

    Evidence In vitro methyl-CpG binding, Co-IP and ChIP, plus in vitro ubiquitin ligase assays with domain mutagenesis

    PMID:14993284 PMID:15361834

    Open questions at the time
    • Histone substrate residues not yet mapped
    • Functional link between reading and ligase activity unresolved
    • PKA-regulated promoter role (idx15) characterized only for topoisomerase IIalpha
  2. 2007 High

    Showed that SRA-mediated hemi-methylated DNA binding targets UHRF1 to replicating heterochromatin and loads DNMT1, establishing UHRF1 as essential for epigenetic inheritance of DNA methylation.

    Evidence Co-IP, live-cell imaging and genetic knockout in ESCs and embryos; in vitro H3K9me binding via PHD/SRA

    PMID:17967883 PMID:17994007

    Open questions at the time
    • Mechanism linking histone-mark reading to DNMT1 recruitment not yet defined
    • Relative contribution of DNA versus histone reading unclear
  3. 2009 Medium

    Extended UHRF1 function beyond DNMT1 to de novo methyltransferases, showing it interacts with DNMT3A/3B and drives silencing preceding DNA methylation.

    Evidence Co-IP and fluorescent reporter silencing assay in ESCs with genetic perturbation

    PMID:19798101

    Open questions at the time
    • Direct stimulation of DNMT3 catalysis not demonstrated here
    • Domain mediating DNMT3 contact unknown
  4. 2013 High

    Identified H3K23 ubiquitylation as the mechanistic link by which UHRF1 RING activity recruits DNMT1, resolving how reading is coupled to methylation maintenance.

    Evidence Xenopus egg extract reconstitution, in vitro DNMT1-ubiquitylated H3 binding, RING mutant cellular validation, mass spectrometry

    PMID:24013172

    Open questions at the time
    • Allosteric trigger for ligase activation not yet defined
    • Structural basis of DNMT1-ubiquitin recognition unresolved
  5. 2016 High

    Defined the allosteric logic of UHRF1: hemi-methylated DNA binding activates H3-tail ubiquitylation via reciprocal cooperativity between reader domains.

    Evidence In vitro ubiquitylation and binding assays with mutagenesis and structural analysis

    PMID:27595565

    Open questions at the time
    • Conformational intermediates not visualized
    • In vivo relevance of cooperativity vs. fixed-domain models partly open
  6. 2016 Medium

    Expanded UHRF1 into genome maintenance, showing BRCA1-dependent recruitment to DSBs where it ubiquitylates RIF1 to promote homologous recombination, and antagonism with SETDB1 at retrotransposons.

    Evidence Co-IP, phosphomutant and ubiquitination assays, laser DSB recruitment; conditional deletion with ChIP and retrotransposon analysis

    PMID:26727879 PMID:27151458

    Open questions at the time
    • RIF1 ubiquitylation site not mapped
    • Single-lab DSB recruitment without reciprocal validation
    • Generality of SETDB1 antagonism beyond IAPs unclear
  7. 2017 Medium

    Provided a kinetic mechanism for DNMT1 recruitment fidelity: SRA base-flipping of methylated cytosine is slow and prolongs CpG residence time.

    Evidence Fluorescent nucleobase surrogate stopped-flow kinetics and fluorescence spectroscopy

    PMID:28112929

    Open questions at the time
    • Link between residence time and in vivo DNMT1 loading inferred, not measured directly
    • Single-lab kinetic system
  8. 2018 High

    Resolved a second DNMT1-targeting input: a direct UHRF1 UBL–DNMT1 contact distinct from ubiquitin, acting together with H3K18/K23ub to localize DNMT1.

    Evidence Crystal structure of DNMT1 RFTS-ubiquitin complex, binding assays, mutagenesis, methylation analysis

    PMID:29471350

    Open questions at the time
    • Stoichiometry of dual interaction unknown
    • Temporal order of UBL binding vs. ubiquitin reading unresolved
  9. 2019 Medium

    Demonstrated that chromatin-reader (TTD/PHD/SRA) activities, not E3 ligase activity, sustain cancer-specific hypermethylation, and that post-translational methylation (SET8/K385) controls UHRF1 abundance.

    Evidence Domain-mutation transfection with genome-wide methylation; in vitro methylation and ubiquitination assays with methylation analysis

    PMID:30956060 PMID:31400111

    Open questions at the time
    • Reconciliation with ligase-dependent maintenance models (idx6) not addressed
    • Single-lab domain dissection
  10. 2020 Medium

    Showed acetylation (PCAF/HDAC1 at K490) and TTD-PHD linker splicing tune hemi-methylated DNA binding and H3K9me3 reading, adding layers of activity control.

    Evidence In vitro acetylation/binding assays with acetyl-mimetic mutants and genome-wide methylation; structural and biochemical analysis of splice variants

    PMID:32609811 PMID:32726623

    Open questions at the time
    • In vivo dynamics of K490 acetylation not quantified
    • Human relevance of murine V1 splice module unclear
  11. 2021 Medium

    Uncovered a non-epigenetic role: cytoplasmic/nuclear UHRF1 bridges PP2A to AMPK to suppress its activity, linking UHRF1 to metabolic signaling.

    Evidence Co-IP, in vitro phosphatase assay, genetic KO with metabolic phenotyping and hepatic overexpression

    PMID:34561619

    Open questions at the time
    • Structural basis of PP2A-AMPK bridging unknown
    • Single-lab finding
  12. 2023 High

    Established acute-depletion evidence that UHRF1 stimulates DNMT3A/3B and antagonizes TET2, and identified AKT1/USP7-dependent stabilization, broadening its methylation control and regulation.

    Evidence Auxin-inducible degron depletion with proteomics and methylation analysis; in vitro kinase assay with phosphomutant and interaction analysis

    PMID:36593255 PMID:38580649

    Open questions at the time
    • Mechanism of DNMT3/TET2 modulation not biochemically resolved
    • Interplay of T210 phosphorylation with K385 methylation degradation pathway unaddressed
  13. 2024 High

    Defined how UHRF1 RING activity writes a heritable silencing program: H3K18ub bookmarks low-density CpGs for re-methylation and nucleates SUV39H1/H2-driven H3K9me3 at tumor suppressor promoters.

    Evidence Genome-wide ChIP-seq, in vitro ubiquitylation assays, RING and DNMT1 UIM mutant epistasis after DNMT1 depletion/recovery

    PMID:39607687 PMID:39631394

    Open questions at the time
    • Quantitative partitioning of ligase- vs reader-dependent maintenance across the genome incomplete
    • Trigger selecting K18 vs K23 ubiquitylation unclear
  14. 2024 Medium

    Revealed a cytoplasmic immune-evasion function: TGF-beta-induced phosphorylation relocalizes UHRF1 to ubiquitylate and degrade MHC-I, suppressing antigen presentation.

    Evidence Immunofluorescence, Co-IP, phosphomutant analysis, MHC-I ubiquitination assay, genetic KO with immune readouts

    PMID:39362877

    Open questions at the time
    • Phosphorylation site and responsible kinase not fully defined
    • Single-lab finding without reciprocal validation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How UHRF1's many regulatory inputs (PKA, AKT1, SET8, PCAF, splicing, TGF-beta) are integrated to switch it between nuclear maintenance-methylation, DNA repair, and cytoplasmic metabolic/immune functions remains unresolved.
  • No unified model coordinating post-translational marks with subcellular localization
  • Structural mechanism of nuclear-cytoplasmic switching unknown
  • Relative in vivo weighting of ligase- vs reader-dependent maintenance pathways unsettled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 7 GO:0003677 DNA binding 6 GO:0140096 catalytic activity, acting on a protein 6 GO:0060090 molecular adaptor activity 4 GO:0140110 transcription regulator activity 4 GO:0042393 histone binding 3
Localization
GO:0000228 nuclear chromosome 4 GO:0005634 nucleus 4 GO:0005829 cytosol 3
Pathway
R-HSA-4839726 Chromatin organization 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-1640170 Cell Cycle 2 R-HSA-73894 DNA Repair 2 R-HSA-168256 Immune System 1
Partners
BRCA1DNMT1DNMT3ADNMT3BHDAC1RIF1SAP30USP7
Complex memberships
pericentric heterochromatin duplication body (pHDB)

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Np95/UHRF1 SRA domain binds hemi-methylated DNA and is required for localization to replicating heterochromatin; Np95 forms a complex with Dnmt1 and mediates loading of Dnmt1 to replicating heterochromatic regions. Np95-deficient ESCs and embryos lose global and local DNA methylation, establishing Np95 as essential for epigenetic inheritance of DNA methylation. Co-immunoprecipitation, live-cell imaging, genetic knockout (ESCs and embryos), biochemical fractionation Nature High 17994007
2004 ICBP90/UHRF1 SRA domain binds methyl-CpG dinucleotides and recruits HDAC1 via the same SRA domain, forming a complex that localizes to methylated promoters of tumor suppressor genes including p16INK4A and p14ARF. In vitro methyl-CpG binding assay, Co-immunoprecipitation, chromatin immunoprecipitation Oncogene Medium 15361834
2004 Np95/UHRF1 RING finger domain confers E3 ubiquitin ligase activity specific for core histones in vitro, with preference for histone H3 when endogenous core octamers co-immunoprecipitating with Np95 are used as substrate. The SRA-YDG domain is required for histone binding and chromatin association in vivo. In vitro ubiquitin ligase assay, Co-immunoprecipitation, domain mutagenesis Molecular and cellular biology High 14993284
2007 ICBP90/UHRF1 binds methyl-K9 histone H3 (H3K9me) via two functional domains: the PHD finger defines binding specificity and the SRA domain promotes binding activity. ICBP90 and Np95 are enriched in pericentric heterochromatin in an H3K9 methylation-dependent manner and are required for proper heterochromatin formation. In vitro biochemical binding assay, immunofluorescence, RNAi knockdown with heterochromatin phenotype Molecular and cellular biology Medium 17967883
2009 Np95/UHRF1 interacts with de novo DNA methyltransferases Dnmt3a and Dnmt3b (more strongly than with Dnmt1) and mediates epigenetic silencing of the CMV promoter in ESCs in a manner dependent on Np95, G9a, or Dnmt3a/3b, preceding DNA methylation. Co-immunoprecipitation, fluorescent reporter silencing assay in ESCs, genetic perturbation EMBO reports Medium 19798101
2009 Np95/UHRF1 tandem Tudor domain (TTD) binds histone H3 tails with trimethylated K9 (H3K9me3) but not acetylated K9, via three conserved aromatic residues forming an aromatic cage; mutations Y188A and Y191A abolish specific H3 tail binding. The SRA domain shows weak preference for hemimethylated CpG in vitro, but loss of genomic methylation does not affect Np95 binding kinetics in living cells. In vitro binding assay, mutagenesis, live-cell FRAP Nucleic acids research High 20026581
2013 UHRF1 RING finger domain ubiquitylates histone H3 at lysine 23 (H3K23ub), and this modification is a prerequisite for maintenance DNA methylation. DNMT1 preferentially associates with ubiquitylated H3 in vitro through its replication foci targeting sequence (RFTS). RING finger mutant UHRF1 fails to recruit DNMT1 to replication sites and fails to maintain DNA methylation. Xenopus egg extract reconstitution, in vitro binding assay, RING mutant transfection in mammalian cells, mass spectrometry Nature High 24013172
2016 Hemi-methylated DNA binding by UHRF1 SRA domain is required for DNA methylation but dispensable for chromatin interaction; HeDNA recognition allosterically activates UHRF1 E3 ubiquitin ligase activity toward multiple lysines on the H3 tail. Reciprocal positive cooperativity between UHRF1 histone- and DNA-binding domains governs chromatin interaction. In vitro ubiquitylation assay, mutagenesis, biochemical binding assays, structural analysis eLife High 27595565
2016 UHRF1 is recruited to DNA double-strand breaks (DSBs) by BRCA1 in S phase via the BRCT domain of BRCA1 and phosphorylated Ser674 of UHRF1. UHRF1 then mediates K63-linked polyubiquitination of RIF1, causing dissociation of RIF1 from 53BP1 and DSBs, thereby facilitating homologous recombination initiation. Co-immunoprecipitation, phosphomutant analysis, ubiquitination assay, laser-induced DSB recruitment assay, epistasis Nature communications Medium 26727879
2016 In the absence of DNMT1, prolonged binding of NP95/UHRF1 to hemimethylated DNA transiently disrupts SETDB1-dependent H3K9me3 deposition, derepressing IAP retrotransposons. When Np95 is deleted alone or with Dnmt1, IAPs remain silenced, revealing an antagonistic interplay between NP95-hemimethylated DNA binding and SETDB1-mediated repression. Conditional genetic deletion, ChIP, retrotransposon expression analysis, co-immunoprecipitation Cell stem cell Medium 27151458
2018 Crystal structure of DNMT1 RFTS domain in complex with ubiquitin reveals a unique ubiquitin binding mode. UHRF1 N-terminal ubiquitin-like domain (UBL) also binds directly to DNMT1 in a fashion distinct from ubiquitin, promoting DNMT1 subnuclear localization. Both the UBL-DNMT1 interaction and UHRF1 RING-catalyzed H3 ubiquitination (at K18 and/or K23) are required for proper DNMT1 localization and DNA methylation maintenance. Crystal structure determination, in vitro binding assay, mutagenesis, immunofluorescence, DNA methylation analysis Nucleic acids research High 29471350
2019 SET8 methyltransferase methylates UHRF1 at lysine 385, triggering ubiquitin-dependent proteasomal degradation of UHRF1 and consequently DNMT1, thereby preventing excessive DNA methylation. LSD1 demethylase antagonizes this by stabilizing both proteins. SET8-mediated UHRF1 downregulation in G2/M suppresses DNMT1-mediated methylation on post-replicated DNA. In vitro methylation assay, co-immunoprecipitation, ubiquitination assay, genetic perturbation, genome-wide methylation analysis Nucleic acids research Medium 31400111
2015 UHRF1 binds directly to interstrand crosslink (ICL)-containing DNA and is recruited to DNA lesions in vivo. UHRF1 physically interacts with ICL repair nucleases ERCC1 and MUS81 and promotes their recruitment to damage sites. UHRF1-deficient cells show retarded lesion processing and increased sensitivity to DNA-damaging agents. UHRF1 functions in parallel to the Fanconi anemia pathway. Affinity purification of ICL-binding activities, Co-immunoprecipitation, cell sensitivity assay, genetic epistasis Cell reports Medium 25818288
2006 Np95 is part of the pericentric heterochromatin duplication body (pHDB); functional ablation causes strong reduction in pericentromeric heterochromatin (PH) replication, hyperacetylation of H4 K8/K12/K16, and increased pericentromeric major satellite transcription. Immunofluorescence, RNAi knockdown, ChIP for histone acetylation, RT-PCR for satellite RNA Molecular biology of the cell Medium 17182844
2008 The PHD domain of Np95/UHRF1 is essential for large-scale reorganization of pericentromeric heterochromatin chromocenters independently of H3K9/H4K20 trimethylation, HP1 levels, DNA methylation, or cell cycle stage. The PHD domain increases restriction enzyme accessibility to nucleosomal DNA arrays in vitro. Domain deletion/mutation transfection with live-cell imaging, in vitro restriction enzyme accessibility assay Molecular biology of the cell Medium 18508923
2004 ICBP90/UHRF1 is phosphorylated by protein kinase A (PKA) at serine 298; this phosphorylation increases ICBP90 binding to the ICB2 element of the topoisomerase IIα gene promoter, enhances topoisomerase IIα expression, and accelerates exit from G1 phase. In vitro kinase assay, site-directed mutagenesis, reporter gene assay, FACS cell cycle analysis Biochemical and biophysical research communications Medium 15178447
2008 Np95/UHRF1 interacts with Eme1 (part of the Mus81-Eme1 endonuclease); they co-localize on chromatin following camptothecin-induced replication fork collapse, and this co-localization requires an intact RING finger domain of Np95. Co-immunoprecipitation, immunofluorescence co-localization, RING finger mutant analysis Biochemical and biophysical research communications Low 18692478
2017 The UHRF1 SRA domain flips the methylated cytosine (mC) from hemimethylated DNA; this base-flipping step is kinetically much slower than initial binding/sliding on non-methylated DNA, substantially increasing the lifetime of CpG-bound UHRF1 and thus the probability of DNMT1 recruitment. Fluorescent nucleobase surrogate incorporation, stopped-flow kinetics, fluorescence spectroscopy Journal of the American Chemical Society Medium 28112929
2019 UHRF1 histone-binding (TTD/PHD) and hemimethylated DNA-binding (SRA) activities, but not E3 ligase activity, are required for maintenance of cancer-specific DNA hypermethylation in colorectal cancer cells; disrupting either chromatin reader activity reverses hypermethylation and reactivates silenced tumor suppressor genes. Domain mutation transfection, genome-wide methylation analysis, gene expression assays, functional oncogenic assays Cancer cell Medium 30956060
2019 UHRF1 interacts with PRMT5, an arginine methyltransferase, and regulates repressive histone arginine modifications H4R3me2s and H3R2me2s in male germ cells; it also cooperates with the PIWI pathway. Conditional loss of UHRF1 causes DNA hypomethylation, retrotransposon upregulation, DNA damage response activation, and complete male sterility. Conditional KO, Co-immunoprecipitation, ChIP for histone modifications, bisulfite sequencing Nature communications Medium 31624244
2020 UHRF1 acetylation at K490, catalyzed by PCAF, attenuates its binding affinity to hemi-methylated DNA; HDAC1 deacetylates K490 to restore binding. Cells expressing acetyl-mimetic UHRF1 K490Q show deficiencies in inherited DNA methylation. In vitro acetylation assay, DNA binding assay, acetyl-mimetic/acetyl-deficient mutant analysis, genome-wide methylation analysis Cell reports Medium 32726623
2020 Alternative splicing in the TTD-PHD linker region of murine UHRF1 V1 (9 extra amino acids) anchors the linker in a surface groove of the TTD domain, creating a coupled TTD-PHD module with synergistic H3-tail binding, distinct cellular localization, and enhanced H3K9me3-nucleosome ubiquitylation activity. Human UHRF1 and mUHRF1 V2 (not V1) binding to H3K9me3 is allosterically regulated by phosphatidylinositol 5-phosphate. Structural analysis (NMR/crystallography implied), in vitro binding assay, ubiquitylation assay, cellular localization Nucleic acids research Medium 32609811
2021 UHRF1 interacts with AMPK and suppresses its activity under basal and stressed conditions by acting as a bridging factor targeting phosphatase PP2A to dephosphorylate AMPK, with no effect on upstream kinases LKB1/CAMKK2. UHRF1 promotes AMPK nuclear retention and suppresses nuclear AMPK activity toward substrates H2B and EZH2. Co-immunoprecipitation, in vitro kinase/phosphatase assay, genetic KO with metabolic phenotyping, hepatic overexpression Cell research Medium 34561619
2022 UHRF1 directly interacts with Sin3A-associated protein SAP30 through residues G572 and F573 in its SRA domain to repress gene expression including MXD4, a MYC antagonist, thereby maintaining self-renewal of leukemia-initiating cells. Co-immunoprecipitation, domain mutagenesis, genetic KO with gene expression analysis, rescue experiments Cell research Medium 36302855
2023 UHRF1 depletion causes greater DNA methylation loss than DNMT1 depletion alone; UHRF1 interacts with and promotes activity of DNMT3A and DNMT3B (de novo methyltransferases), and antagonizes active DNA demethylation by TET2, revealing non-canonical roles beyond DNMT1 stimulation. Auxin-inducible degron depletion, proteomics, genome-wide methylation analysis, genetic epistasis Nature communications High 38580649
2024 UHRF1-dependent H3K18ub accumulates at CpG islands following DNMT1 inhibition; H3K18ub enhances SUV39H1/H2 methyltransferase activity, nucleating new H3K9me3 domains at tumor suppressor gene promoters. Disrupting UHRF1 E3 ligase activity prevents H3K9me3 accumulation and promotes PRC2-dependent H3K27me3 as a tertiary repression layer. Genome-wide ChIP-seq, biochemical ubiquitylation assay, genetic disruption of UHRF1 RING domain, epistasis analysis Molecular cell High 39631394
2024 UHRF1 ubiquitin ligase activity is specifically required for maintenance of DNA methylation at low-density CpGs; DNMT1 UIM1 reads this signal while UIM2 disruption abolishes all DNMT1 maintenance methylation in a CpG-density-independent manner. UHRF1 ubiquitin ligase activity provides a 'bookmarking' function for DNA re-methylation following acute DNMT1 depletion. Integrative epigenomics (bisulfite sequencing), biochemical assays, UIM mutant analysis, DNMT1 depletion/recovery experiments Nucleic acids research Medium 39607687
2016 ICBP90/UHRF1 is identified as the major nuclear protein interacting with the MIF promoter -794 CATT5-8 microsatellite and is essential for MIF transcription in monocytes/macrophages, B and T lymphocytes, and synovial fibroblasts; TLR-induced MIF transcription is regulated in an ICBP90- and -794 CATT length-dependent manner. Oligonucleotide affinity chromatography, LC-MS, Co-immunoprecipitation, shRNA knockdown, reporter assay The Journal of clinical investigation Medium 26752645
2023 UHRF1 is required for maintenance of DNA methylation and transcriptional silencing in germinal center B cells; its deficiency causes G1-S cell cycle arrest by demethylating and derepressing cdkn1a, slfn1, and slfn2, impairing GC B cell proliferation, somatic hypermutation, and affinity maturation. Conditional KO, bisulfite sequencing, gene expression analysis, cell cycle analysis The Journal of experimental medicine Medium 29618490
2023 UHRF1 is predominantly cytoplasmic in mouse oocytes and preimplantation embryos; oocyte-specific KO causes impaired chromosome segregation, abnormal cleavage division, and preimplantation lethality attributable to cytoplasmic (not nuclear) defects. Proteomics of KO oocytes reveals downregulation of microtubule-associated proteins including tubulins, and disorganization of cytoplasmic lattices and mislocalization of mitochondria, ER, and subcortical maternal complex components. Oocyte-specific KO, nuclear transfer epistasis, proteomic analysis, immunofluorescence Life science alliance Medium 37225425
2023 AKT1 directly phosphorylates UHRF1 at Thr-210, stabilizing it by promoting interaction with deubiquitinase USP7 and reducing interaction with E3 ligase BTRC; inhibition of AKT1 phosphorylation leads to UHRF1 proteasomal degradation. Co-immunoprecipitation, in vitro kinase assay, phosphomutant analysis, proteasome inhibitor assay Oncogenesis Medium 36593255
2023 Diosgenin directly binds UHRF1 protein and induces its proteasomal degradation by reducing the interaction between UHRF1 and deubiquitinase USP7. Molecular docking, Co-immunoprecipitation, proteasome inhibitor assay, ubiquitination assay European journal of pharmacology Low 36681316
2024 Cytoplasmic UHRF1 in cancer cells promotes MHC-I ubiquitination and degradation. Cytoplasmic translocation of UHRF1 is induced by TGF-β-driven phosphorylation at a specific serine residue, enabling UHRF1 to bind MHC-I and suppress antigen presentation. Immunofluorescence, co-immunoprecipitation, phosphomutant analysis, MHC-I ubiquitination assay, genetic KO with immune assays Nature communications Medium 39362877

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature 990 17994007
2013 Uhrf1-dependent H3K23 ubiquitylation couples maintenance DNA methylation and replication. Nature 307 24013172
2014 UHRF1 overexpression drives DNA hypomethylation and hepatocellular carcinoma. Cancer cell 266 24486181
2004 ICBP90, an E2F-1 target, recruits HDAC1 and binds to methyl-CpG through its SRA domain. Oncogene 265 15361834
2007 ICBP90, a novel methyl K9 H3 binding protein linking protein ubiquitination with heterochromatin formation. Molecular and cellular biology 200 17967883
2004 Np95 is a histone-binding protein endowed with ubiquitin ligase activity. Molecular and cellular biology 161 14993289
2000 ICBP90, a novel human CCAAT binding protein, involved in the regulation of topoisomerase IIalpha expression. Cancer research 156 10646863
2009 Np95 interacts with de novo DNA methyltransferases, Dnmt3a and Dnmt3b, and mediates epigenetic silencing of the viral CMV promoter in embryonic stem cells. EMBO reports 146 19798101
2009 The multi-domain protein Np95 connects DNA methylation and histone modification. Nucleic acids research 142 20026581
2019 UHRF1 promotes aerobic glycolysis and proliferation via suppression of SIRT4 in pancreatic cancer. Cancer letters 135 30905812
2019 Defining UHRF1 Domains that Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties. Cancer cell 130 30956060
2003 ICBP90 belongs to a new family of proteins with an expression that is deregulated in cancer cells. British journal of cancer 128 12838312
2004 Down-regulation of nuclear protein ICBP90 by p53/p21Cip1/WAF1-dependent DNA-damage checkpoint signals contributes to cell cycle arrest at G1/S transition. Genes to cells : devoted to molecular & cellular mechanisms 124 15009091
2016 A cell cycle-dependent BRCA1-UHRF1 cascade regulates DNA double-strand break repair pathway choice. Nature communications 119 26727879
2016 Hemi-methylated DNA regulates DNA methylation inheritance through allosteric activation of H3 ubiquitylation by UHRF1. eLife 115 27595565
2005 The retinoblastoma gene and its product are targeted by ICBP90: a key mechanism in the G1/S transition during the cell cycle. Oncogene 112 16007129
2002 Targeted disruption of Np95 gene renders murine embryonic stem cells hypersensitive to DNA damaging agents and DNA replication blocks. The Journal of biological chemistry 105 12084726
2017 The epigenetic integrator UHRF1: on the road to become a universal biomarker for cancer. Oncotarget 98 28881702
2018 Structural and mechanistic insights into UHRF1-mediated DNMT1 activation in the maintenance DNA methylation. Nucleic acids research 96 29471350
2010 UHRF1-mediated tumor suppressor gene inactivation in nonsmall cell lung cancer. Cancer 96 21351083
2016 Signalling pathways in UHRF1-dependent regulation of tumor suppressor genes in cancer. Journal of experimental & clinical cancer research : CR 92 27839516
2012 UHRF1 promotes cell growth and metastasis through repression of p16(ink⁴a) in colorectal cancer. Annals of surgical oncology 91 22219067
2019 Coordinated Dialogue between UHRF1 and DNMT1 to Ensure Faithful Inheritance of Methylated DNA Patterns. Genes 90 30669400
2017 UHRF1: The key regulator of epigenetics and molecular target for cancer therapeutics. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 87 28218043
2002 Np95 is regulated by E1A during mitotic reactivation of terminally differentiated cells and is essential for S phase entry. The Journal of cell biology 85 12058012
1998 Cloning and mapping of Np95 gene which encodes a novel nuclear protein associated with cell proliferation. Mammalian genome : official journal of the International Mammalian Genome Society 82 9880673
2015 UHRF1 contributes to DNA damage repair as a lesion recognition factor and nuclease scaffold. Cell reports 79 25818288
2016 Activation of Endogenous Retroviruses in Dnmt1(-/-) ESCs Involves Disruption of SETDB1-Mediated Repression by NP95 Binding to Hemimethylated DNA. Cell stem cell 78 27151458
2006 Np95 is implicated in pericentromeric heterochromatin replication and in major satellite silencing. Molecular biology of the cell 75 17182844
2021 The multi-functionality of UHRF1: epigenome maintenance and preservation of genome integrity. Nucleic acids research 72 33939809
2010 Uhrf1 and Dnmt1 are required for development and maintenance of the zebrafish lens. Developmental biology 72 21126517
2019 SET8 prevents excessive DNA methylation by methylation-mediated degradation of UHRF1 and DNMT1. Nucleic acids research 71 31400111
2019 UHRF1 suppresses retrotransposons and cooperates with PRMT5 and PIWI proteins in male germ cells. Nature communications 71 31624244
2018 UHRF1 epigenetically orchestrates smooth muscle cell plasticity in arterial disease. The Journal of clinical investigation 67 29558369
2008 The PHD domain of Np95 (mUHRF1) is involved in large-scale reorganization of pericentromeric heterochromatin. Molecular biology of the cell 59 18508923
2016 Transcription factor ICBP90 regulates the MIF promoter and immune susceptibility locus. The Journal of clinical investigation 54 26752645
2000 Temporal and spatial localization of novel nuclear protein NP95 in mitotic and meiotic cells. Cell structure and function 51 10984098
2019 UHRF1 promotes renal cell carcinoma progression through epigenetic regulation of TXNIP. Oncogene 50 31043707
2021 UHRF1 promotes androgen receptor-regulated CDC6 transcription and anti-androgen receptor drug resistance in prostate cancer through KDM4C-Mediated chromatin modifications. Cancer letters 49 34265399
2017 Hinokitiol induces DNA demethylation via DNMT1 and UHRF1 inhibition in colon cancer cells. BMC cell biology 46 28241740
2002 Overexpression of ICBP90, a novel CCAAT-binding protein, overcomes cell contact inhibition by forcing topoisomerase II alpha expression. Anticancer research 44 12530060
2024 Prevotella copri exhausts intrinsic indole-3-pyruvic acid in the host to promote breast cancer progression: inactivation of AMPK via UHRF1-mediated negative regulation. Gut microbes 43 38773738
2017 Dynamics of Methylated Cytosine Flipping by UHRF1. Journal of the American Chemical Society 43 28112929
2012 UHRF1 expression is upregulated and associated with cellular proliferation in colorectal cancer. Oncology reports 41 23023523
2021 Nuclear UHRF1 is a gate-keeper of cellular AMPK activity and function. Cell research 40 34561619
2018 The Growing Complexity of UHRF1-Mediated Maintenance DNA Methylation. Genes 40 30513966
2024 Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells. Nature communications 39 38580649
2022 Crosstalk between macrophage-derived PGE2 and tumor UHRF1 drives hepatocellular carcinoma progression. Theranostics 39 35664070
2001 Dynamic changes in subnuclear NP95 location during the cell cycle and its spatial relationship with DNA replication foci. Experimental cell research 39 11161719
2022 Targeting UHRF1-SAP30-MXD4 axis for leukemia initiating cell eradication in myeloid leukemia. Cell research 36 36302855
2012 Exogenous expression of UHRF1 promotes proliferation and metastasis of breast cancer cells. Oncology reports 36 22552622
2021 UHRF1 downregulation promotes T follicular helper cell differentiation by increasing BCL6 expression in SLE. Clinical epigenetics 35 33568199
2022 Regulatory mechanism and biological function of UHRF1-DNMT1-mediated DNA methylation. Functional & integrative genomics 33 36372834
2013 Inhibiting UHRF1 expression enhances radiosensitivity in human esophageal squamous cell carcinoma. Molecular biology reports 32 23943380
2024 LXRα Promotes Abdominal Aortic Aneurysm Formation Through UHRF1 Epigenetic Modification of miR-26b-3p. Circulation 31 38557060
2020 UHRF1 Is a Novel Druggable Epigenetic Target in Malignant Pleural Mesothelioma. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 31 32927122
2018 Uhrf1 regulates germinal center B cell expansion and affinity maturation to control viral infection. The Journal of experimental medicine 31 29618490
2015 Shikonin causes apoptosis by up-regulating p73 and down-regulating ICBP90 in human cancer cells. Biochemical and biophysical research communications 31 26235879
2023 UHRF1 inhibition epigenetically reprograms cancer stem cells to suppress the tumorigenic phenotype of hepatocellular carcinoma. Cell death & disease 29 37380646
2023 Upregulation of UHRF1 Promotes PINK1-mediated Mitophagy to Alleviates Ferroptosis in Diabetic Nephropathy. Inflammation 29 38055118
2019 UHRF1 depletion and HDAC inhibition reactivate epigenetically silenced genes in colorectal cancer cells. Clinical epigenetics 29 31064417
2015 Conserved linker regions and their regulation determine multiple chromatin-binding modes of UHRF1. Nucleus (Austin, Tex.) 29 25891992
2011 Recruitment of Dnmt1 roles of the SRA protein Np95 (Uhrf1) and other factors. Progress in molecular biology and translational science 28 21507355
2004 Phosphorylation of ICBP90 by protein kinase A enhances topoisomerase IIalpha expression. Biochemical and biophysical research communications 28 15178447
2016 Uhrf1 Controls iNKT Cell Survival and Differentiation through the Akt-mTOR Axis. Cell reports 27 27050515
2024 DNA hypomethylation promotes UHRF1-and SUV39H1/H2-dependent crosstalk between H3K18ub and H3K9me3 to reinforce heterochromatin states. Molecular cell 26 39631394
2023 UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma. Nature communications 26 37407562
2020 Targeting UHRF1-dependent DNA repair selectively sensitizes KRAS mutant lung cancer to chemotherapy. Cancer letters 25 32814087
2019 Epigenetic mechanism and target therapy of UHRF1 protein complex in malignancies. OncoTargets and therapy 25 30666134
2020 Acetylation of UHRF1 Regulates Hemi-methylated DNA Binding and Maintenance of Genome-wide DNA Methylation. Cell reports 22 32726623
2019 UHRF1 is regulated by miR-124-3p and promotes cell proliferation in intrahepatic cholangiocarcinoma. Journal of cellular physiology 22 30989656
2006 Isolation and Characterization of a Novel Human Radiosusceptibility Gene, NP95. Radiation research 22 17067204
2023 PIP4K2B is mechanoresponsive and controls heterochromatin-driven nuclear softening through UHRF1. Nature communications 21 36918565
2017 Regulation of UHRF1 by microRNA-378 modulates medulloblastoma cell proliferation and apoptosis. Oncology reports 21 28901497
2024 Oncogenic Roles of UHRF1 in Cancer. Epigenomes 20 39051184
2023 Diosgenin inhibits prostate cancer progression by inducing UHRF1 protein degradation. European journal of pharmacology 19 36681316
2023 UHRF1 is essential for proper cytoplasmic architecture and function of mouse oocytes and derived embryos. Life science alliance 19 37225425
2022 UHRF1 overexpression promotes osteosarcoma metastasis through altered exosome production and AMPK/SEMA3E suppression. Oncogenesis 19 36068209
2020 CircFAT1 Suppresses Colorectal Cancer Development Through Regulating miR-520b/UHRF1 Axis or miR-302c-3p/UHRF1 Axis. Cancer biotherapy & radiopharmaceuticals 19 32379550
2003 ICBP90 expression is downregulated in apoptosis-induced Jurkat cells. Annals of the New York Academy of Sciences 19 15033738
2023 AKT1 regulates UHRF1 protein stability and promotes the resistance to abiraterone in prostate cancer. Oncogenesis 18 36593255
2021 Thymoquinone Is a Multitarget Single Epidrug That Inhibits the UHRF1 Protein Complex. Genes 18 33922029
2019 Epigenetic factors Dnmt1 and Uhrf1 coordinate intestinal development. Developmental biology 18 31394080
2023 UHRF1/UBE2L6/UBR4-mediated ubiquitination regulates EZH2 abundance and thereby melanocytic differentiation phenotypes in melanoma. Oncogene 17 36906655
2008 Interplay between Np95 and Eme1 in the DNA damage response. Biochemical and biophysical research communications 17 18692478
2023 Lenvatinib inhibited HCC cell migration and invasion through regulating the transcription and ubiquitination of UHRF1 and DNMT1. Biochemical pharmacology 16 36893815
2022 UHRF1 establishes crosstalk between somatic and germ cells in male reproduction. Cell death & disease 16 35440090
2009 ICBP90 mediates the ERK1/2 signaling to regulate the proliferation of Jurkat T cells. Cellular immunology 16 19328461
2025 Targeting of the G9a, DNMT1 and UHRF1 epigenetic complex as an effective strategy against pancreatic ductal adenocarcinoma. Journal of experimental & clinical cancer research : CR 15 39810240
2024 Roles of post-translational modifications of UHRF1 in cancer. Epigenetics & chromatin 15 38725075
2024 Aberrant cytoplasmic expression of UHRF1 restrains the MHC-I-mediated anti-tumor immune response. Nature communications 15 39362877
2018 UHRF1 mediates cell migration and invasion of gastric cancer. Bioscience reports 15 30352833
2018 Identifying deer antler uhrf1 proliferation and s100a10 mineralization genes using comparative RNA-seq. Stem cell research & therapy 15 30376879
2022 UHRF1 shapes both the trophoblast invasion and decidual macrophage differentiation in early pregnancy. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 14 35262949
2021 ICBP90 Regulates MIF Expression, Glucocorticoid Sensitivity, and Apoptosis at the MIF Immune Susceptibility Locus. Arthritis & rheumatology (Hoboken, N.J.) 14 33844457
2020 UHRF1 silences gelsolin to inhibit cell death in early stage cervical cancer. Biochemical and biophysical research communications 14 32312517
2020 Alternative splicing and allosteric regulation modulate the chromatin binding of UHRF1. Nucleic acids research 14 32609811
2014 Characterization of Np95 expression in mouse brain from embryo to adult: A novel marker for proliferating neural stem/precursor cells. Neurogenesis (Austin, Tex.) 14 27504471
2006 Modulating ICBP90 to suppress human ribonucleotide reductase M2 induction restores sensitivity to hydroxyurea cytotoxicity. Anticancer research 14 16886595
2024 UHRF1 ubiquitin ligase activity supports the maintenance of low-density CpG methylation. Nucleic acids research 13 39607687

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