{"gene":"UHRF1","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2007,"finding":"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.","method":"Co-immunoprecipitation, live-cell imaging, genetic knockout (ESCs and embryos), biochemical fractionation","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic KO with defined methylation phenotype, replicated across multiple labs subsequently","pmids":["17994007"],"is_preprint":false},{"year":2004,"finding":"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.","method":"In vitro methyl-CpG binding assay, Co-immunoprecipitation, chromatin immunoprecipitation","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and ChIP, single lab, two orthogonal methods","pmids":["15361834"],"is_preprint":false},{"year":2004,"finding":"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.","method":"In vitro ubiquitin ligase assay, Co-immunoprecipitation, domain mutagenesis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of E3 ligase activity with mutagenesis, single lab with multiple orthogonal methods","pmids":["14993284"],"is_preprint":false},{"year":2007,"finding":"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.","method":"In vitro biochemical binding assay, immunofluorescence, RNAi knockdown with heterochromatin phenotype","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding assay plus cellular localization and knockdown phenotype, single lab","pmids":["17967883"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Co-immunoprecipitation, fluorescent reporter silencing assay in ESCs, genetic perturbation","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and functional silencing assay, single lab, two orthogonal methods","pmids":["19798101"],"is_preprint":false},{"year":2009,"finding":"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.","method":"In vitro binding assay, mutagenesis, live-cell FRAP","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro binding with mutagenesis and live-cell kinetics, single lab with multiple orthogonal methods","pmids":["20026581"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Xenopus egg extract reconstitution, in vitro binding assay, RING mutant transfection in mammalian cells, mass spectrometry","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical reconstitution in Xenopus extracts plus mutagenesis plus cellular validation, replicated by subsequent studies","pmids":["24013172"],"is_preprint":false},{"year":2016,"finding":"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.","method":"In vitro ubiquitylation assay, mutagenesis, biochemical binding assays, structural analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mutagenesis and structural validation, single study with multiple orthogonal methods","pmids":["27595565"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Co-immunoprecipitation, phosphomutant analysis, ubiquitination assay, laser-induced DSB recruitment assay, epistasis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, phosphomutant rescue, single lab with multiple orthogonal methods","pmids":["26727879"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Conditional genetic deletion, ChIP, retrotransposon expression analysis, co-immunoprecipitation","journal":"Cell stem cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with double KO plus ChIP, single lab","pmids":["27151458"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Crystal structure determination, in vitro binding assay, mutagenesis, immunofluorescence, DNA methylation analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus mutagenesis plus cellular validation, single lab with multiple orthogonal methods","pmids":["29471350"],"is_preprint":false},{"year":2019,"finding":"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.","method":"In vitro methylation assay, co-immunoprecipitation, ubiquitination assay, genetic perturbation, genome-wide methylation analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro methylation assay, co-IP, and methylation analysis, single lab","pmids":["31400111"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Affinity purification of ICL-binding activities, Co-immunoprecipitation, cell sensitivity assay, genetic epistasis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — affinity purification plus Co-IP plus genetic epistasis, single lab","pmids":["25818288"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Immunofluorescence, RNAi knockdown, ChIP for histone acetylation, RT-PCR for satellite RNA","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with multiple phenotypic readouts, single lab","pmids":["17182844"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Domain deletion/mutation transfection with live-cell imaging, in vitro restriction enzyme accessibility assay","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutagenesis with cellular and in vitro assays, single lab","pmids":["18508923"],"is_preprint":false},{"year":2004,"finding":"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.","method":"In vitro kinase assay, site-directed mutagenesis, reporter gene assay, FACS cell cycle analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with mutagenesis and functional reporter, single lab","pmids":["15178447"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Co-immunoprecipitation, immunofluorescence co-localization, RING finger mutant analysis","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and co-localization, single lab, single method per claim","pmids":["18692478"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Fluorescent nucleobase surrogate incorporation, stopped-flow kinetics, fluorescence spectroscopy","journal":"Journal of the American Chemical Society","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — real-time kinetic assay with two independent fluorescent probes, single lab","pmids":["28112929"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Domain mutation transfection, genome-wide methylation analysis, gene expression assays, functional oncogenic assays","journal":"Cancer cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutagenesis with genome-wide methylation and expression readouts, single lab","pmids":["30956060"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Conditional KO, Co-immunoprecipitation, ChIP for histone modifications, bisulfite sequencing","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with multiple molecular readouts plus Co-IP, single lab","pmids":["31624244"],"is_preprint":false},{"year":2020,"finding":"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.","method":"In vitro acetylation assay, DNA binding assay, acetyl-mimetic/acetyl-deficient mutant analysis, genome-wide methylation analysis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro acetylation and binding assays with mutagenesis and genome-wide methylation, single lab","pmids":["32726623"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Structural analysis (NMR/crystallography implied), in vitro binding assay, ubiquitylation assay, cellular localization","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — structural analysis combined with biochemical and cellular assays, single lab","pmids":["32609811"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation, in vitro kinase/phosphatase assay, genetic KO with metabolic phenotyping, hepatic overexpression","journal":"Cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus phosphatase assay plus in vivo KO rescue, single lab with multiple methods","pmids":["34561619"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Co-immunoprecipitation, domain mutagenesis, genetic KO with gene expression analysis, rescue experiments","journal":"Cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with SRA domain mutagenesis plus functional rescue, single lab","pmids":["36302855"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Auxin-inducible degron depletion, proteomics, genome-wide methylation analysis, genetic epistasis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — degron alleles (clean acute depletion), proteomics, bioinformatics and genetics, multiple orthogonal approaches","pmids":["38580649"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Genome-wide ChIP-seq, biochemical ubiquitylation assay, genetic disruption of UHRF1 RING domain, epistasis analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro ubiquitylation assay plus genome-wide mapping plus domain mutagenesis, single lab with multiple orthogonal methods","pmids":["39631394"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Integrative epigenomics (bisulfite sequencing), biochemical assays, UIM mutant analysis, DNMT1 depletion/recovery experiments","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide methylation plus biochemical assays, single lab","pmids":["39607687"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Oligonucleotide affinity chromatography, LC-MS, Co-immunoprecipitation, shRNA knockdown, reporter assay","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — affinity chromatography/MS identification plus knockdown functional assay, single lab with two methods","pmids":["26752645"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Conditional KO, bisulfite sequencing, gene expression analysis, cell cycle analysis","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with methylation and expression readouts at specific target genes, single lab","pmids":["29618490"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Oocyte-specific KO, nuclear transfer epistasis, proteomic analysis, immunofluorescence","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with nuclear transfer rescue experiment plus proteomics, single lab","pmids":["37225425"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-immunoprecipitation, in vitro kinase assay, phosphomutant analysis, proteasome inhibitor assay","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with phosphomutant and protein interaction analysis, single lab","pmids":["36593255"],"is_preprint":false},{"year":2023,"finding":"Diosgenin directly binds UHRF1 protein and induces its proteasomal degradation by reducing the interaction between UHRF1 and deubiquitinase USP7.","method":"Molecular docking, Co-immunoprecipitation, proteasome inhibitor assay, ubiquitination assay","journal":"European journal of pharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and degradation assay, partially supported by computational docking, single lab","pmids":["36681316"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Immunofluorescence, co-immunoprecipitation, phosphomutant analysis, MHC-I ubiquitination assay, genetic KO with immune assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, phosphomutant with functional immune readout, single lab","pmids":["39362877"],"is_preprint":false}],"current_model":"UHRF1 (Np95/ICBP90) is a multi-domain epigenetic regulator that reads hemi-methylated DNA (via SRA), H3K9me3 (via TTD), and unmodified H3 tail (via PHD), and writes H3K18/K23 ubiquitin marks (via RING E3 ligase) to recruit DNMT1 to replication forks for maintenance DNA methylation; it also stimulates de novo methyltransferases DNMT3A/B, antagonizes TET2-mediated demethylation, recruits HDAC1 and histone methyltransferases (G9a, SUV39H1/H2) to silence tumor suppressor genes, participates in DNA double-strand break repair by mediating K63-linked ubiquitination of RIF1 downstream of BRCA1, serves as a lesion-recognition factor and nuclease scaffold for interstrand crosslink repair, is regulated post-translationally by PKA (S298 phosphorylation), SET8 methylation (K385), AKT1 phosphorylation (T210), and PCAF/HDAC1 acetylation (K490), and additionally suppresses AMPK activity by bridging PP2A to dephosphorylate AMPK in the nucleus."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2004,"claim":"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","pmids":["15361834","14993284"],"confidence":"High","gaps":["Histone substrate residues not yet mapped","Functional link between reading and ligase activity unresolved","PKA-regulated promoter role (idx15) characterized only for topoisomerase IIalpha"]},{"year":2007,"claim":"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","pmids":["17994007","17967883"],"confidence":"High","gaps":["Mechanism linking histone-mark reading to DNMT1 recruitment not yet defined","Relative contribution of DNA versus histone reading unclear"]},{"year":2009,"claim":"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","pmids":["19798101"],"confidence":"Medium","gaps":["Direct stimulation of DNMT3 catalysis not demonstrated here","Domain mediating DNMT3 contact unknown"]},{"year":2013,"claim":"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","pmids":["24013172"],"confidence":"High","gaps":["Allosteric trigger for ligase activation not yet defined","Structural basis of DNMT1-ubiquitin recognition unresolved"]},{"year":2016,"claim":"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","pmids":["27595565"],"confidence":"High","gaps":["Conformational intermediates not visualized","In vivo relevance of cooperativity vs. fixed-domain models partly open"]},{"year":2016,"claim":"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","pmids":["26727879","27151458"],"confidence":"Medium","gaps":["RIF1 ubiquitylation site not mapped","Single-lab DSB recruitment without reciprocal validation","Generality of SETDB1 antagonism beyond IAPs unclear"]},{"year":2017,"claim":"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","pmids":["28112929"],"confidence":"Medium","gaps":["Link between residence time and in vivo DNMT1 loading inferred, not measured directly","Single-lab kinetic system"]},{"year":2018,"claim":"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","pmids":["29471350"],"confidence":"High","gaps":["Stoichiometry of dual interaction unknown","Temporal order of UBL binding vs. ubiquitin reading unresolved"]},{"year":2019,"claim":"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","pmids":["30956060","31400111"],"confidence":"Medium","gaps":["Reconciliation with ligase-dependent maintenance models (idx6) not addressed","Single-lab domain dissection"]},{"year":2020,"claim":"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","pmids":["32726623","32609811"],"confidence":"Medium","gaps":["In vivo dynamics of K490 acetylation not quantified","Human relevance of murine V1 splice module unclear"]},{"year":2021,"claim":"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","pmids":["34561619"],"confidence":"Medium","gaps":["Structural basis of PP2A-AMPK bridging unknown","Single-lab finding"]},{"year":2023,"claim":"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","pmids":["38580649","36593255"],"confidence":"High","gaps":["Mechanism of DNMT3/TET2 modulation not biochemically resolved","Interplay of T210 phosphorylation with K385 methylation degradation pathway unaddressed"]},{"year":2024,"claim":"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","pmids":["39631394","39607687"],"confidence":"High","gaps":["Quantitative partitioning of ligase- vs reader-dependent maintenance across the genome incomplete","Trigger selecting K18 vs K23 ubiquitylation unclear"]},{"year":2024,"claim":"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","pmids":["39362877"],"confidence":"Medium","gaps":["Phosphorylation site and responsible kinase not fully defined","Single-lab finding without reciprocal validation"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[2,6,7,8,10,25,32]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,6,7,8,25,32]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,1,5,12,17,20]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[3,5,21]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,15,23,27]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,6,10,22]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,6,13,22]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,3,13,14]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[22,29,32]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,6,18,25]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,18,23,27]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[8,12]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[15,28]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[11,30,32]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[32]}],"complexes":["pericentric heterochromatin duplication body (pHDB)"],"partners":["DNMT1","DNMT3A","DNMT3B","HDAC1","BRCA1","RIF1","USP7","SAP30"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96T88","full_name":"E3 ubiquitin-protein ligase UHRF1","aliases":["Inverted CCAAT box-binding protein of 90 kDa","Nuclear zinc finger protein Np95","HuNp95","Nuclear protein 95","hNp95","RING finger protein 106","Transcription factor ICBP90","Ubiquitin-like PHD and RING finger domain-containing protein 1","hUHRF1"],"length_aa":793,"mass_kda":89.8,"function":"E3 ubiquitin-protein ligase that acts as a key epigenetic regulator by bridging DNA methylation and chromatin modification (PubMed:10646863, PubMed:15009091, PubMed:19056828, PubMed:23022729, PubMed:24013172, PubMed:27595565, PubMed:30104358, PubMed:30392929, PubMed:30392931, PubMed:39607687). Plays a key role in DNA methylation inheritance by promoting recruitment of DNMT1 to hemimethylated DNA and ensure faithful propagation of the DNA methylation patterns through DNA replication (PubMed:23022729, PubMed:24013172, PubMed:27595565, PubMed:30104358, PubMed:30392929, PubMed:30392931, PubMed:39607687). Acts both as a histone reader and writer: specifically recognizes and binds (1) hemimethylated DNA at replication forks and (2) histone H3 trimethylated at 'Lys-9' and unmethylated at 'Arg-2' (H3K9me3 and H3R2me0, respectively), thereby activating its E3 ubiquitin-protein ligase activity (PubMed:15361834, PubMed:17673620, PubMed:17967883, PubMed:18772889, PubMed:21745816, PubMed:21777816, PubMed:22100450, PubMed:22837395, PubMed:23022729, PubMed:27595565, PubMed:30104358). UHRF1 then mediates histone H3 'Lys-18' monoubiquitination (H3K18ub), a docking site for DNMT1, leading to DNMT1 recruitment and replication-coupled DNA methylation maintenance (PubMed:27595565). Also mediates histone H3 'Lys-14' and 'Lys-23' ubiquitination (H3K14ub and H3K23ub) at lower level (PubMed:24013172, PubMed:27595565). Histone ubiquitin ligase activity also stimulates the methyltransferase activity of SUV39H1 and/or SUV39H2, promoting accumulation of H3K9me3 histone mark to reinformce heterochromatin state (PubMed:39631394). Enriched in pericentric heterochromatin where it recruits different chromatin modifiers required for this chromatin replication. Also localizes to euchromatic regions where it negatively regulates transcription possibly by impacting DNA methylation and histone modifications (PubMed:21777816). Plays a role in DNA repair by cooperating with UHRF2 to ensure recruitment of FANCD2 to interstrand cross-links (ICLs) leading to FANCD2 activation (PubMed:30335751). Also ubiquitinates non-histone proteins, such as histone H3, KIF11 and PML (PubMed:22945642, PubMed:37728657). Acts as a critical player of proper spindle architecture by catalyzing the 'Lys-63'-linked ubiquitination of KIF11, thereby controlling KIF11 localization on the spindle (PubMed:37728657)","subcellular_location":"Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q96T88/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/UHRF1","classification":"Common Essential","n_dependent_lines":31,"n_total_lines":74,"dependency_fraction":0.4189189189189189},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"H2AFZ","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HMGA1","stoichiometry":0.2},{"gene":"NUCKS1","stoichiometry":0.2},{"gene":"PARP1","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/UHRF1","total_profiled":1310},"omim":[{"mim_id":"619811","title":"UHRF1-BINDING PROTEIN 1-LIKE; UHRF1BP1L","url":"https://www.omim.org/entry/619811"},{"mim_id":"619570","title":"UHRF1-BINDING PROTEIN 1; UHRF1BP1","url":"https://www.omim.org/entry/619570"},{"mim_id":"617077","title":"ZINC FINGER PROTEIN 618; ZNF618","url":"https://www.omim.org/entry/617077"},{"mim_id":"615211","title":"UBIQUITIN-LIKE PROTEIN CONTAINING PHD AND RING FINGER DOMAINS 2, E3 UBIQUITIN PROTEIN LIGASE; UHRF2","url":"https://www.omim.org/entry/615211"},{"mim_id":"612915","title":"MEDIATOR COMPLEX SUBUNIT 20; MED20","url":"https://www.omim.org/entry/612915"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":25.5},{"tissue":"lymphoid tissue","ntpm":62.6}],"url":"https://www.proteinatlas.org/search/UHRF1"},"hgnc":{"alias_symbol":["ICBP90","Np95","FLJ21925","RNF106","TDRD22"],"prev_symbol":[]},"alphafold":{"accession":"Q96T88","domains":[{"cath_id":"3.10.20.90","chopping":"4-74","consensus_level":"high","plddt":87.2438,"start":4,"end":74},{"cath_id":"2.30.30.30","chopping":"215-280","consensus_level":"medium","plddt":92.6877,"start":215,"end":280},{"cath_id":"2.30.280.10","chopping":"429-483_495-602","consensus_level":"high","plddt":95.0269,"start":429,"end":602},{"cath_id":"3.30.40.10","chopping":"679-786","consensus_level":"high","plddt":90.0677,"start":679,"end":786}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96T88","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96T88-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96T88-F1-predicted_aligned_error_v6.png","plddt_mean":79.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=UHRF1","jax_strain_url":"https://www.jax.org/strain/search?query=UHRF1"},"sequence":{"accession":"Q96T88","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96T88.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96T88/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96T88"}},"corpus_meta":[{"pmid":"17994007","id":"PMC_17994007","title":"The 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Np95-deficient ESCs and embryos lose global and local DNA methylation, establishing Np95 as essential for epigenetic inheritance of DNA methylation.\",\n      \"method\": \"Co-immunoprecipitation, live-cell imaging, genetic knockout (ESCs and embryos), biochemical fractionation\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic KO with defined methylation phenotype, replicated across multiple labs subsequently\",\n      \"pmids\": [\"17994007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro methyl-CpG binding assay, Co-immunoprecipitation, chromatin immunoprecipitation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and ChIP, single lab, two orthogonal methods\",\n      \"pmids\": [\"15361834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro ubiquitin ligase assay, Co-immunoprecipitation, domain mutagenesis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of E3 ligase activity with mutagenesis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"14993284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro biochemical binding assay, immunofluorescence, RNAi knockdown with heterochromatin phenotype\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding assay plus cellular localization and knockdown phenotype, single lab\",\n      \"pmids\": [\"17967883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, fluorescent reporter silencing assay in ESCs, genetic perturbation\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and functional silencing assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"19798101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro binding assay, mutagenesis, live-cell FRAP\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding with mutagenesis and live-cell kinetics, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"20026581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Xenopus egg extract reconstitution, in vitro binding assay, RING mutant transfection in mammalian cells, mass spectrometry\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical reconstitution in Xenopus extracts plus mutagenesis plus cellular validation, replicated by subsequent studies\",\n      \"pmids\": [\"24013172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro ubiquitylation assay, mutagenesis, biochemical binding assays, structural analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutagenesis and structural validation, single study with multiple orthogonal methods\",\n      \"pmids\": [\"27595565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, phosphomutant analysis, ubiquitination assay, laser-induced DSB recruitment assay, epistasis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, phosphomutant rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26727879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional genetic deletion, ChIP, retrotransposon expression analysis, co-immunoprecipitation\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with double KO plus ChIP, single lab\",\n      \"pmids\": [\"27151458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Crystal structure determination, in vitro binding assay, mutagenesis, immunofluorescence, DNA methylation analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus mutagenesis plus cellular validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29471350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro methylation assay, co-immunoprecipitation, ubiquitination assay, genetic perturbation, genome-wide methylation analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro methylation assay, co-IP, and methylation analysis, single lab\",\n      \"pmids\": [\"31400111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Affinity purification of ICL-binding activities, Co-immunoprecipitation, cell sensitivity assay, genetic epistasis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — affinity purification plus Co-IP plus genetic epistasis, single lab\",\n      \"pmids\": [\"25818288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Immunofluorescence, RNAi knockdown, ChIP for histone acetylation, RT-PCR for satellite RNA\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"17182844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Domain deletion/mutation transfection with live-cell imaging, in vitro restriction enzyme accessibility assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutagenesis with cellular and in vitro assays, single lab\",\n      \"pmids\": [\"18508923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis, reporter gene assay, FACS cell cycle analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with mutagenesis and functional reporter, single lab\",\n      \"pmids\": [\"15178447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, RING finger mutant analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and co-localization, single lab, single method per claim\",\n      \"pmids\": [\"18692478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Fluorescent nucleobase surrogate incorporation, stopped-flow kinetics, fluorescence spectroscopy\",\n      \"journal\": \"Journal of the American Chemical Society\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — real-time kinetic assay with two independent fluorescent probes, single lab\",\n      \"pmids\": [\"28112929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Domain mutation transfection, genome-wide methylation analysis, gene expression assays, functional oncogenic assays\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutagenesis with genome-wide methylation and expression readouts, single lab\",\n      \"pmids\": [\"30956060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional KO, Co-immunoprecipitation, ChIP for histone modifications, bisulfite sequencing\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with multiple molecular readouts plus Co-IP, single lab\",\n      \"pmids\": [\"31624244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro acetylation assay, DNA binding assay, acetyl-mimetic/acetyl-deficient mutant analysis, genome-wide methylation analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro acetylation and binding assays with mutagenesis and genome-wide methylation, single lab\",\n      \"pmids\": [\"32726623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Structural analysis (NMR/crystallography implied), in vitro binding assay, ubiquitylation assay, cellular localization\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural analysis combined with biochemical and cellular assays, single lab\",\n      \"pmids\": [\"32609811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase/phosphatase assay, genetic KO with metabolic phenotyping, hepatic overexpression\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus phosphatase assay plus in vivo KO rescue, single lab with multiple methods\",\n      \"pmids\": [\"34561619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, domain mutagenesis, genetic KO with gene expression analysis, rescue experiments\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with SRA domain mutagenesis plus functional rescue, single lab\",\n      \"pmids\": [\"36302855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Auxin-inducible degron depletion, proteomics, genome-wide methylation analysis, genetic epistasis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — degron alleles (clean acute depletion), proteomics, bioinformatics and genetics, multiple orthogonal approaches\",\n      \"pmids\": [\"38580649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Genome-wide ChIP-seq, biochemical ubiquitylation assay, genetic disruption of UHRF1 RING domain, epistasis analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro ubiquitylation assay plus genome-wide mapping plus domain mutagenesis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39631394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Integrative epigenomics (bisulfite sequencing), biochemical assays, UIM mutant analysis, DNMT1 depletion/recovery experiments\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide methylation plus biochemical assays, single lab\",\n      \"pmids\": [\"39607687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Oligonucleotide affinity chromatography, LC-MS, Co-immunoprecipitation, shRNA knockdown, reporter assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — affinity chromatography/MS identification plus knockdown functional assay, single lab with two methods\",\n      \"pmids\": [\"26752645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional KO, bisulfite sequencing, gene expression analysis, cell cycle analysis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with methylation and expression readouts at specific target genes, single lab\",\n      \"pmids\": [\"29618490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Oocyte-specific KO, nuclear transfer epistasis, proteomic analysis, immunofluorescence\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with nuclear transfer rescue experiment plus proteomics, single lab\",\n      \"pmids\": [\"37225425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, phosphomutant analysis, proteasome inhibitor assay\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with phosphomutant and protein interaction analysis, single lab\",\n      \"pmids\": [\"36593255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Diosgenin directly binds UHRF1 protein and induces its proteasomal degradation by reducing the interaction between UHRF1 and deubiquitinase USP7.\",\n      \"method\": \"Molecular docking, Co-immunoprecipitation, proteasome inhibitor assay, ubiquitination assay\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and degradation assay, partially supported by computational docking, single lab\",\n      \"pmids\": [\"36681316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Immunofluorescence, co-immunoprecipitation, phosphomutant analysis, MHC-I ubiquitination assay, genetic KO with immune assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, phosphomutant with functional immune readout, single lab\",\n      \"pmids\": [\"39362877\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UHRF1 (Np95/ICBP90) is a multi-domain epigenetic regulator that reads hemi-methylated DNA (via SRA), H3K9me3 (via TTD), and unmodified H3 tail (via PHD), and writes H3K18/K23 ubiquitin marks (via RING E3 ligase) to recruit DNMT1 to replication forks for maintenance DNA methylation; it also stimulates de novo methyltransferases DNMT3A/B, antagonizes TET2-mediated demethylation, recruits HDAC1 and histone methyltransferases (G9a, SUV39H1/H2) to silence tumor suppressor genes, participates in DNA double-strand break repair by mediating K63-linked ubiquitination of RIF1 downstream of BRCA1, serves as a lesion-recognition factor and nuclease scaffold for interstrand crosslink repair, is regulated post-translationally by PKA (S298 phosphorylation), SET8 methylation (K385), AKT1 phosphorylation (T210), and PCAF/HDAC1 acetylation (K490), and additionally suppresses AMPK activity by bridging PP2A to dephosphorylate AMPK in the nucleus.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #6]. 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 [#0, #17], while the tandem Tudor domain reads H3K9me3 through an aromatic cage and the PHD finger contributes H3-tail recognition [#5]. 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 [#6, #7, #10, #26]. 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 [#24], and its RING-catalyzed H3K18ub enhances SUV39H1/H2 to nucleate H3K9me3 domains that silence tumor suppressor promoters [#25]. UHRF1 reader activities sustain cancer-specific DNA hypermethylation and tumor suppressor silencing [#18], and it represses target genes through partners including HDAC1 and the Sin3A component SAP30 [#1, #23]. Activity is tuned post-translationally by PKA phosphorylation at S298 [#15], SET8 methylation at K385 driving its degradation [#11], AKT1 phosphorylation at T210 stabilizing it via USP7 [#30], and PCAF/HDAC1 acetylation at K490 controlling hemi-methylated DNA binding [#20]. UHRF1 additionally functions in genome maintenance—recruited to double-strand breaks by BRCA1 to K63-ubiquitylate RIF1 and promote homologous recombination [#8], and binding interstrand-crosslink DNA to recruit ERCC1 and MUS81 nucleases [#12]—and has nuclear-independent roles, including cytoplasmic suppression of AMPK via PP2A bridging [#22] and TGF-\\u03b2-induced cytoplasmic degradation of MHC-I [#32].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro methyl-CpG binding, Co-IP and ChIP, plus in vitro ubiquitin ligase assays with domain mutagenesis\",\n      \"pmids\": [\"15361834\", \"14993284\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Histone substrate residues not yet mapped\", \"Functional link between reading and ligase activity unresolved\", \"PKA-regulated promoter role (idx15) characterized only for topoisomerase IIalpha\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, live-cell imaging and genetic knockout in ESCs and embryos; in vitro H3K9me binding via PHD/SRA\",\n      \"pmids\": [\"17994007\", \"17967883\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking histone-mark reading to DNMT1 recruitment not yet defined\", \"Relative contribution of DNA versus histone reading unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended UHRF1 function beyond DNMT1 to de novo methyltransferases, showing it interacts with DNMT3A/3B and drives silencing preceding DNA methylation.\",\n      \"evidence\": \"Co-IP and fluorescent reporter silencing assay in ESCs with genetic perturbation\",\n      \"pmids\": [\"19798101\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct stimulation of DNMT3 catalysis not demonstrated here\", \"Domain mediating DNMT3 contact unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified H3K23 ubiquitylation as the mechanistic link by which UHRF1 RING activity recruits DNMT1, resolving how reading is coupled to methylation maintenance.\",\n      \"evidence\": \"Xenopus egg extract reconstitution, in vitro DNMT1-ubiquitylated H3 binding, RING mutant cellular validation, mass spectrometry\",\n      \"pmids\": [\"24013172\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Allosteric trigger for ligase activation not yet defined\", \"Structural basis of DNMT1-ubiquitin recognition unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the allosteric logic of UHRF1: hemi-methylated DNA binding activates H3-tail ubiquitylation via reciprocal cooperativity between reader domains.\",\n      \"evidence\": \"In vitro ubiquitylation and binding assays with mutagenesis and structural analysis\",\n      \"pmids\": [\"27595565\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational intermediates not visualized\", \"In vivo relevance of cooperativity vs. fixed-domain models partly open\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, phosphomutant and ubiquitination assays, laser DSB recruitment; conditional deletion with ChIP and retrotransposon analysis\",\n      \"pmids\": [\"26727879\", \"27151458\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RIF1 ubiquitylation site not mapped\", \"Single-lab DSB recruitment without reciprocal validation\", \"Generality of SETDB1 antagonism beyond IAPs unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided a kinetic mechanism for DNMT1 recruitment fidelity: SRA base-flipping of methylated cytosine is slow and prolongs CpG residence time.\",\n      \"evidence\": \"Fluorescent nucleobase surrogate stopped-flow kinetics and fluorescence spectroscopy\",\n      \"pmids\": [\"28112929\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link between residence time and in vivo DNMT1 loading inferred, not measured directly\", \"Single-lab kinetic system\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved a second DNMT1-targeting input: a direct UHRF1 UBL–DNMT1 contact distinct from ubiquitin, acting together with H3K18/K23ub to localize DNMT1.\",\n      \"evidence\": \"Crystal structure of DNMT1 RFTS-ubiquitin complex, binding assays, mutagenesis, methylation analysis\",\n      \"pmids\": [\"29471350\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of dual interaction unknown\", \"Temporal order of UBL binding vs. ubiquitin reading unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"evidence\": \"Domain-mutation transfection with genome-wide methylation; in vitro methylation and ubiquitination assays with methylation analysis\",\n      \"pmids\": [\"30956060\", \"31400111\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation with ligase-dependent maintenance models (idx6) not addressed\", \"Single-lab domain dissection\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed acetylation (PCAF/HDAC1 at K490) and TTD-PHD linker splicing tune hemi-methylated DNA binding and H3K9me3 reading, adding layers of activity control.\",\n      \"evidence\": \"In vitro acetylation/binding assays with acetyl-mimetic mutants and genome-wide methylation; structural and biochemical analysis of splice variants\",\n      \"pmids\": [\"32726623\", \"32609811\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo dynamics of K490 acetylation not quantified\", \"Human relevance of murine V1 splice module unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Uncovered a non-epigenetic role: cytoplasmic/nuclear UHRF1 bridges PP2A to AMPK to suppress its activity, linking UHRF1 to metabolic signaling.\",\n      \"evidence\": \"Co-IP, in vitro phosphatase assay, genetic KO with metabolic phenotyping and hepatic overexpression\",\n      \"pmids\": [\"34561619\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of PP2A-AMPK bridging unknown\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established acute-depletion evidence that UHRF1 stimulates DNMT3A/3B and antagonizes TET2, and identified AKT1/USP7-dependent stabilization, broadening its methylation control and regulation.\",\n      \"evidence\": \"Auxin-inducible degron depletion with proteomics and methylation analysis; in vitro kinase assay with phosphomutant and interaction analysis\",\n      \"pmids\": [\"38580649\", \"36593255\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of DNMT3/TET2 modulation not biochemically resolved\", \"Interplay of T210 phosphorylation with K385 methylation degradation pathway unaddressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"Genome-wide ChIP-seq, in vitro ubiquitylation assays, RING and DNMT1 UIM mutant epistasis after DNMT1 depletion/recovery\",\n      \"pmids\": [\"39631394\", \"39607687\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative partitioning of ligase- vs reader-dependent maintenance across the genome incomplete\", \"Trigger selecting K18 vs K23 ubiquitylation unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a cytoplasmic immune-evasion function: TGF-beta-induced phosphorylation relocalizes UHRF1 to ubiquitylate and degrade MHC-I, suppressing antigen presentation.\",\n      \"evidence\": \"Immunofluorescence, Co-IP, phosphomutant analysis, MHC-I ubiquitination assay, genetic KO with immune readouts\",\n      \"pmids\": [\"39362877\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphorylation site and responsible kinase not fully defined\", \"Single-lab finding without reciprocal validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [2, 6, 7, 8, 10, 25, 32]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 6, 7, 8, 25, 32]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 1, 5, 12, 17, 20]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [3, 5, 21]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 15, 23, 27]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 6, 10, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 6, 13, 22]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 3, 13, 14]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [22, 29, 32]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 6, 18, 25]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 18, 23, 27]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [8, 12]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [15, 28]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [11, 30, 32]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [32]}\n    ],\n    \"complexes\": [\"pericentric heterochromatin duplication body (pHDB)\"],\n    \"partners\": [\"DNMT1\", \"DNMT3A\", \"DNMT3B\", \"HDAC1\", \"BRCA1\", \"RIF1\", \"USP7\", \"SAP30\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}