{"gene":"UHRF2","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2011,"finding":"UHRF2 binds preferentially to methylated histone H3 lysine 9 (H3K9me2/3) through its conserved tandem Tudor domain, and to hemi-methylated DNA through its SRA domain. Both activities are required for its enrichment at pericentric heterochromatin.","method":"Binding assays, co-immunoprecipitation, fluorescence localization experiments in cells","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal findings replicated across two independent labs (PMID:22064703 and PMID:21598301) using multiple orthogonal methods including binding assays, CoIP, and live-cell imaging","pmids":["22064703","21598301"],"is_preprint":false},{"year":2011,"finding":"UHRF2 interacts with DNMT1, DNMT3a, DNMT3b, and G9a by co-immunoprecipitation, but unlike UHRF1, UHRF2 does not interact with DNMT1 in an S phase-dependent manner and cannot recruit DNMT1 to replication foci, explaining why UHRF2 cannot rescue DNA methylation defects in Uhrf1-null ES cells.","method":"Co-immunoprecipitation, cell synchronization, fluorescence microscopy in Uhrf1-null mouse embryonic stem cells","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with cell-cycle synchronization, genetic rescue experiment in null cells, replicated observations across two independent labs","pmids":["22064703","21598301"],"is_preprint":false},{"year":2011,"finding":"UHRF2 heterochromatin localization depends primarily on its H3K9me-binding activity (tandem Tudor domain) and to a lesser extent on its methylated DNA-binding activity (SRA domain), as shown by FRAP analyses and domain mutants.","method":"FRAP, domain mutagenesis, fluorescence localization in live cells","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRAP and mutagenesis in a single lab with two orthogonal methods","pmids":["21598301"],"is_preprint":false},{"year":2014,"finding":"Crystal structure of UHRF2-SRA domain in complex with 5-hydroxymethylcytosine (5hmC)-containing DNA revealed that a phenylalanine residue forms an optimal 5hmC binding pocket and a hydrogen bond between the hydroxyl group of 5hmC and the SRA domain is critical for preferential binding over 5mC.","method":"X-ray crystallography, in vitro binding assays, site-directed mutagenesis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation by mutagenesis and biochemical assays in a single rigorous study","pmids":["24813944"],"is_preprint":false},{"year":2012,"finding":"UHRF2 (NIRF) acts as an E3 ubiquitin ligase that ubiquitinates cyclins D1 and E1, thereby inducing G1 cell cycle arrest.","method":"Ubiquitination assays in vivo and in vitro, cell cycle analysis","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro ubiquitination assays described in single review/synthesis paper; findings referenced from prior primary work","pmids":["22673569"],"is_preprint":false},{"year":2013,"finding":"UHRF2 acts as a SUMO E3 ligase for zinc finger protein 131 (ZNF131), enhancing ZNF131 SUMOylation but not ubiquitination. The SUMO E3 activity requires the SRA and NLS-containing region domains, whereas the RING domain (critical for ubiquitin E3 activity) is dispensable for SUMOylation.","method":"SUMOylation assays in vivo and in vitro, domain deletion/mutagenesis analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of SUMO E3 activity plus domain mutagenesis, single lab with multiple orthogonal methods","pmids":["23404503"],"is_preprint":false},{"year":2013,"finding":"UHRF2 is a direct transcriptional target of E2F1 and physically interacts with E2F1 protein; UHRF2 is required for E2F1-induced apoptosis and for E2F1 transcription of apoptotic regulators.","method":"shRNA screen, ChIP, Co-immunoprecipitation, reporter assays, apoptosis assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (CoIP, ChIP, functional KD rescue) in a single lab","pmids":["23833190"],"is_preprint":false},{"year":2013,"finding":"UHRF2 is recruited to sites of DNA damage (by laser microirradiation), and the TTD, PHD, and SRA domains are required for this recruitment. Depletion of UHRF2 suppresses DNA damage-induced H2AX phosphorylation and impairs DNA damage repair in vascular smooth muscle cells.","method":"Laser microirradiation, live-cell fluorescence imaging, domain mutant analysis, siRNA knockdown, γH2AX immunofluorescence","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional consequence (H2AX phosphorylation), domain mutant dissection, single lab","pmids":["24134842"],"is_preprint":false},{"year":2016,"finding":"ZNF618 specifically interacts with UHRF2 (but not UHRF1) and regulates UHRF2 chromatin localization to 5hmC-enriched genomic loci in vivo. ZNF618 chromatin binding is independent of its interaction with UHRF2 and is mediated through its first two zinc fingers.","method":"Co-immunoprecipitation, ChIP-seq, co-localization experiments, domain mutant analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal CoIP and ChIP-seq, single lab with two orthogonal approaches","pmids":["27129234"],"is_preprint":false},{"year":2016,"finding":"UHRF2 interacts with TIP60 acetyltransferase and HDAC1 by co-immunoprecipitation. UHRF2 stabilizes TIP60 via ubiquitination through its RING domain, thereby regulating H3K9ac and H3K14ac levels.","method":"Co-immunoprecipitation, ubiquitination assays, western blot, histone modification analysis","journal":"Protein & cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CoIP plus ubiquitination assay with RING domain requirement, single lab","pmids":["27743347"],"is_preprint":false},{"year":2016,"finding":"UHRF2 overexpression acts as a transcriptional co-regulator of EMT transcription factors; UHRF2 binds to the CDH1 promoter (by ChIP-qPCR) and interacts with TCF7L2 and chromatin remodeling/histone modification complexes (by IP-MS).","method":"ChIP-seq, ChIP-qPCR, IP-MS, proteome profiling, cell invasion assays","journal":"Molecular & cellular proteomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR and IP-MS with multiple orthogonal approaches, single lab","pmids":["27114453"],"is_preprint":false},{"year":2016,"finding":"UHRF2 interacts with H3K9ac through its PHD finger domain, as shown by co-immunoprecipitation and domain deletion experiments, and decreases H3K9ac expression in HCC cells.","method":"Co-immunoprecipitation, immunofluorescence, domain deletion analysis, western blot","journal":"International journal of molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and domain deletion from single lab, no reconstitution or mutagenesis validation","pmids":["28004105"],"is_preprint":false},{"year":2017,"finding":"Crystal structure of UHRF2 PCNA-interacting protein (PIP) box peptide in complex with PCNA revealed the molecular basis for UHRF2-PCNA interaction via a canonical PIP-box motif (residues 784-800). Mutagenesis experiments validated the structural findings.","method":"X-ray crystallography, site-directed mutagenesis, structural analysis","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus mutagenesis validation, single lab but direct structural evidence","pmids":["28951215"],"is_preprint":false},{"year":2017,"finding":"Uhrf2 knockout mice show no global DNA methylation change but exhibit decreased 5hmC levels specifically in brain (cortex and hippocampus), and UHRF2 binds 5hmC in cells without affecting TET1 enzymatic activity, supporting UHRF2 as a 5hmC reader in vivo.","method":"Knockout mouse model, dot-blot for 5hmC/5mC, gene expression profiling, in vivo binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic knockout with quantitative epigenomic analysis replicated across two independent knockout mouse studies","pmids":["28115522","28402695"],"is_preprint":false},{"year":2017,"finding":"Uhrf2 knockout mice develop spontaneous seizures and show decreased 5mC levels at specific genomic loci in brain, without global DNA methylation changes, demonstrating a locus-specific role for UHRF2 in 5mC maintenance in brain distinct from UHRF1.","method":"Knockout mouse model, bisulfite sequencing, EEG recording, locus-specific methylation analysis","journal":"Epigenetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with multiple orthogonal phenotypic and epigenomic readouts, consistent with independent knockout study","pmids":["28402695"],"is_preprint":false},{"year":2018,"finding":"Comparative biochemical analysis revealed that UHRF2 has divergent DNA binding properties from UHRF1: both hemi-methylated and hemi-hydroxymethylated DNA allosterically stimulate UHRF2 ubiquitin ligase activity toward histone H3 peptide substrates (first example of an E3 ligase allosterically regulated by DNA hydroxymethylation), but UHRF2 is not a productive histone E3 ligase toward purified mononucleosomes, suggesting a conformational constraint when bound to chromatin.","method":"Recombinant protein biochemistry, in vitro E3 ubiquitin ligase assays with DNA oligonucleotides, binding assays, mononucleosome substrates","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro enzymatic assays with multiple substrates and allosteric conditions, comprehensive biochemical study in single lab","pmids":["29506131"],"is_preprint":false},{"year":2018,"finding":"UHRF2 cooperates with UHRF1 to ensure recruitment of FANCD2 to interstrand crosslinks (ICLs). UHRF2 is recruited to ICLs within seconds, forms direct protein-protein interactions with UHRF1 and FANCD2, and stimulates monoubiquitination of FANCD2 by retaining it on chromatin for the FA core complex.","method":"Live-cell imaging (rapid recruitment assay), Co-immunoprecipitation, chromatin fractionation, FANCD2 monoubiquitination assays, siRNA knockdown","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (live imaging, CoIP, functional ubiquitination assay) in a single focused mechanistic study","pmids":["30335751"],"is_preprint":false},{"year":2018,"finding":"UHRF2 ubiquitinates p21 via its RING domain, leading to p21 degradation and shortened p21 half-life, which promotes DNA damage response in HEK293 cells.","method":"Co-immunoprecipitation, ubiquitination assay, cycloheximide chase, immunofluorescence","journal":"Biotechnology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay and protein stability assay, single lab with two orthogonal methods","pmids":["29923055"],"is_preprint":false},{"year":2020,"finding":"UHRF2 directly interacts with and SUMOylates TCF4 (a Wnt pathway transcription factor), stabilizing TCF4 protein and sustaining hyperactive Wnt/β-catenin signaling in intestinal tumor cells.","method":"Co-immunoprecipitation, SUMOylation assays, genetic knockout mice on ApcMin background, organoid formation assays","journal":"International journal of cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — CoIP plus SUMOylation assays plus in vivo genetic validation in ApcMin mice, multiple orthogonal methods","pmids":["32372448"],"is_preprint":false},{"year":2021,"finding":"UHRF2 is allosterically activated by 5hmC and catalyzes K33-linked polyubiquitination of XRCC1. This non-proteolytic ubiquitination promotes XRCC1 interaction with RAD23B (via its ubiquitin-binding domain), which recruits TDG into the BER complex to complete active DNA demethylation. In mouse embryonic stem cells, Uhrf2 ablation impedes DNA demethylation at active promoters and poised-to-active enhancers during neuronal commitment.","method":"In vitro ubiquitination assays, Co-immunoprecipitation, mass spectrometry, integrative epigenomic analysis (ChIP-seq, bisulfite-seq), Uhrf2 knockout mouse ES cells, neuronal differentiation assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro E3 ligase activity with linkage-specific ubiquitination, structural/biochemical allosteric activation by 5hmC, and in vivo genetic validation across multiple orthogonal epigenomic methods","pmids":["34111398"],"is_preprint":false},{"year":2021,"finding":"UHRF2 physically interacts with ATR through its TTD domain in a DNA damage-dependent manner. UHRF2 depletion impairs phosphorylation of ATR at threonine 1989 (required for UV-induced ATR activation), indicating UHRF2 is required for ATR activation after UV irradiation.","method":"Co-immunoprecipitation, domain mutant analysis, phospho-specific western blot, siRNA knockdown, UV irradiation","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CoIP and phospho-western with domain mapping, single lab with two orthogonal methods","pmids":["33848395"],"is_preprint":false},{"year":2021,"finding":"UHRF2 TTD domain has modestly higher affinity for the H3 tail than the PHD domain (opposite to UHRF1 where PHD is primary contributor). Aromatic residues in UHRF2 TTD contribute to both selectivity and affinity for H3K9me3, whereas the PHD contains a distinct asparagine that lowers binding affinity. TTD and PHD cooperate in H3 tail binding.","method":"Fluorescence polarization binding assays, isothermal titration calorimetry, domain mutagenesis, thermal shift assays","journal":"Proteins","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro binding assays with mutagenesis and multiple quantitative methods, single lab","pmids":["34766381"],"is_preprint":false},{"year":2021,"finding":"UHRF2 binds CDK2 directly and is phosphorylated at serine 643 by CDK2 (promoted by the HBx-ETS1-CDK2 axis in HBV-associated HCC), which blocks UHRF2's E3 ubiquitin ligase activity and promotes DHX9 protein stability by preventing its ubiquitination.","method":"Co-immunoprecipitation, ubiquitination assays, phosphorylation-site mutagenesis (S643), western blot in HBV-positive HCC cells","journal":"Hepatology international / Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CoIP plus ubiquitination assays and phospho-site mapping, corroborated across two papers from same group","pmids":["33876395","36690646"],"is_preprint":false},{"year":2023,"finding":"UHRF2 interacts with chromatin remodeling proteins (Co-IP in hepatocytes) and suppresses the expression of cholesterol biosynthesis genes in an FGFR-dependent manner. Hepatocyte-specific Uhrf2 knockout leads to cholesterol and bile acid accumulation during liver regeneration, causing liver necrosis that is rescued by bile acid scavenger treatment.","method":"Hepatocyte-specific Uhrf2 knockout, partial hepatectomy model, Co-immunoprecipitation, gene expression analysis, bile acid scavenger rescue","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional genetic knockout with mechanistic rescue experiment (bile acid scavenger), CoIP for binding partners, multiple orthogonal methods in single rigorous study","pmids":["37253089"],"is_preprint":false},{"year":2023,"finding":"UHRF2 binds autophagy-related protein PARP1 (by Co-IP) and upregulates PARP1 protein level, promoting autophagy in HCC cells. PRDX1 also binds UHRF2 and upregulates its protein expression.","method":"Co-immunoprecipitation, western blot, electron microscopy, immunofluorescence, in vivo xenograft","journal":"Cellular signalling","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP per interaction, single lab, limited mechanistic detail on ubiquitination or pathway placement","pmids":["37356603"],"is_preprint":false},{"year":2024,"finding":"UHRF2 protein accumulates in early G1 phase following serum stimulation from quiescence or after mitotic exit (where it is degraded during G2/M in a CDK1-dependent manner). UHRF2 controls cyclin and CDK inhibitor levels and represses its own transcription in a negative-feedback loop. CRISPR/Cas9 deletion of UHRF2 causes elevated cyclin levels and elevated p27KIP1, reducing retinoblastoma phosphorylation and prolonging each cell cycle phase.","method":"CRISPR/Cas9 knockout, cell synchronization, flow cytometry, western blot, CDK1-specific inhibitor treatment","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with pharmacological inhibitor rescue and cell cycle phenotyping, single lab with multiple orthogonal methods","pmids":["38752903"],"is_preprint":false},{"year":2025,"finding":"UHRF2 is required for resistance to DNA methylation reprogramming at retrotransposons in primordial germ cells (PGCs). Uhrf2 knockout PGCs show loss of retrotransposon DNA methylation and precocious demethylation of germline genes, leading to meiotic gene overexpression in females, impaired oocyte development, female-specific reduced fertility, and incomplete remethylation of retrotransposons during spermatogenesis. This function in the germline is distinct from somatic cells.","method":"Knockout mouse model, whole-genome bisulfite sequencing, RNA-seq, fertility assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional/constitutive knockout with genome-wide epigenomic profiling, multiple orthogonal functional readouts in a single rigorous study","pmids":["40783491"],"is_preprint":false},{"year":2026,"finding":"During viral infection, nuclear-translocated TBK1 is hijacked by UHRF2 at IFN-I gene loci. UHRF2 physically interacts with HDAC1 and catalyzes atypical K29-linked polyubiquitination of HDAC1, stabilizing it. The UHRF2-HDAC1 complex erases H4K12 lactylation at IFN-I loci, silencing type I interferon transcription. IFN-I signaling feedback transiently downregulates UHRF2 expression to allow initial antiviral response.","method":"Co-immunoprecipitation, ubiquitination assays (linkage-specific), ChIP, H4K12la chromatin analysis, Uhrf2 knockout mouse model with viral challenge","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple CoIP and ubiquitination assays with linkage specificity and in vivo mouse validation, single lab","pmids":["42212328"],"is_preprint":false}],"current_model":"UHRF2 is a multi-domain nuclear E3 ubiquitin ligase (and SUMO E3 ligase) that reads 5-hydroxymethylcytosine (5hmC) via its SRA domain, binds H3K9me2/3 via its tandem Tudor domain, and integrates epigenetic signals at heterochromatin; it is allosterically activated by 5hmC to catalyze K33-linked polyubiquitination of XRCC1 (promoting TDG-RAD23B-BER-dependent active DNA demethylation), ubiquitinates cyclins D1/E1 and p21 to regulate cell cycle progression, stabilizes TIP60 and TCF4 via ubiquitination/SUMOylation to modulate histone acetylation and Wnt signaling, cooperates with UHRF1 to recruit FANCD2 to interstrand crosslinks, activates ATR after UV damage via its TTD domain, suppresses cholesterol biosynthesis gene expression in hepatocytes, mediates K29-linked ubiquitination of HDAC1 to epigenetically silence type I interferon genes, and maintains locus-specific DNA methylation and retrotransposon methylation in the germline—though unlike its paralog UHRF1, it cannot support global DNA methylation maintenance due to its inability to interact with DNMT1 in an S phase-dependent manner."},"narrative":{"mechanistic_narrative":"UHRF2 is a multi-domain nuclear E3 ubiquitin ligase and epigenetic reader that integrates histone and DNA modification signals at chromatin to govern DNA methylation dynamics, the cell cycle, and DNA damage responses [PMID:22064703, PMID:21598301, PMID:34111398]. It engages chromatin through a tandem Tudor domain that binds H3K9me2/3, an SRA domain that reads DNA modifications, and a PHD finger, with heterochromatin enrichment driven principally by H3K9me recognition [PMID:22064703, PMID:21598301]; structural work showed its SRA domain forms a dedicated pocket that hydrogen-bonds the 5-hydroxymethylcytosine hydroxyl group, conferring preferential 5hmC over 5mC binding [PMID:24813944], and in vivo it acts as a 5hmC reader without altering TET enzymatic activity [PMID:28115522, PMID:28402695]. Recognition of hemi-methylated or hemi-hydroxymethylated DNA allosterically activates its RING-dependent ubiquitin ligase activity [PMID:29506131], and 5hmC-stimulated UHRF2 catalyzes non-proteolytic K33-linked polyubiquitination of XRCC1, which recruits RAD23B and TDG to drive TDG-BER-dependent active DNA demethylation at promoters and enhancers during neuronal commitment [PMID:34111398]. Despite interacting with DNMT1/3a/3b and G9a, UHRF2 cannot bind DNMT1 in an S-phase-dependent manner or maintain global methylation, and its physiological roles are locus-specific: knockout mice retain global methylation but lose brain 5hmC and locus-specific 5mC and develop seizures [PMID:22064703, PMID:21598301, PMID:28115522, PMID:28402695], while in primordial germ cells UHRF2 protects retrotransposon methylation and restrains precocious germline demethylation [PMID:40783491]. Beyond methylation, UHRF2 regulates the cell cycle by ubiquitinating cyclins D1/E1 and p21 and controlling CDK-inhibitor levels [PMID:22673569, PMID:29923055, PMID:38752903], cooperates with UHRF1 to retain FANCD2 at interstrand crosslinks and promote its monoubiquitination [PMID:30335751], and is required for UV-induced ATR activation via its TTD domain [PMID:33848395]. It additionally functions as a SUMO E3 ligase and chromatin co-regulator—SUMOylating TCF4 to sustain Wnt signaling, stabilizing TIP60 to modulate histone acetylation, and forming a complex with HDAC1 that, via atypical K29-linked ubiquitination, silences type I interferon genes during viral infection [PMID:23404503, PMID:27743347, PMID:32372448, PMID:42212328].","teleology":[{"year":2011,"claim":"Established how UHRF2 is targeted to chromatin, answering whether it reads histone and DNA marks like its paralog and why it nonetheless cannot substitute for UHRF1.","evidence":"Binding assays, Co-IP, live-cell imaging and FRAP with domain mutants in cells, including Uhrf1-null mouse ES cells","pmids":["22064703","21598301"],"confidence":"High","gaps":["Did not define the catalytic output of chromatin engagement","Structural basis of mark recognition not resolved at this stage"]},{"year":2014,"claim":"Defined the molecular basis for UHRF2's selective recognition of 5hmC, distinguishing its reader specificity from 5mC binding.","evidence":"X-ray crystallography of SRA-5hmC DNA complex with binding assays and mutagenesis","pmids":["24813944"],"confidence":"High","gaps":["Did not connect 5hmC reading to a catalytic or cellular output","In vivo relevance of the pocket not tested here"]},{"year":2012,"claim":"Identified UHRF2 as an E3 ubiquitin ligase acting on cell cycle regulators, linking it to G1 control.","evidence":"In vivo and in vitro ubiquitination assays with cell cycle analysis","pmids":["22673569"],"confidence":"Medium","gaps":["Ubiquitin chain linkage and degradation outcome not characterized","Reported in a synthesis paper rather than fully primary form"]},{"year":2013,"claim":"Revealed that UHRF2 possesses SUMO E3 activity distinct from its ubiquitin ligase function, broadening its enzymatic repertoire.","evidence":"In vitro and in vivo SUMOylation assays with domain deletion mapping on ZNF131","pmids":["23404503"],"confidence":"High","gaps":["Biological consequence of ZNF131 SUMOylation unresolved","Domain requirements for SUMO vs ubiquitin activity not structurally explained"]},{"year":2013,"claim":"Placed UHRF2 in the E2F1 apoptotic program and at DNA damage sites, implicating it in damage signaling.","evidence":"shRNA screen, ChIP, Co-IP, reporter and apoptosis assays; laser microirradiation with domain mutants and γH2AX readouts","pmids":["23833190","24134842"],"confidence":"Medium","gaps":["Direct enzymatic targets at damage sites not identified","Mechanism linking recruitment to H2AX phosphorylation unresolved"]},{"year":2016,"claim":"Identified protein partners and chromatin-modifying complexes that direct UHRF2 to specific loci and let it modulate histone acetylation and EMT/Wnt programs.","evidence":"Co-IP, ChIP-seq/ChIP-qPCR, IP-MS and ubiquitination assays across multiple cell systems (ZNF618, TIP60/HDAC1, TCF7L2)","pmids":["27129234","27743347","27114453"],"confidence":"Medium","gaps":["Causal hierarchy between locus targeting and transcriptional output unclear","TIP60 stabilization mechanism not structurally defined"]},{"year":2017,"claim":"Used genetic and structural approaches to establish UHRF2 as a 5hmC reader in vivo and a PCNA-interacting protein, while clarifying its locus-specific (not global) role in methylation.","evidence":"Knockout mice with 5hmC/5mC dot-blot and bisulfite sequencing; PCNA-PIP box crystal structure with mutagenesis","pmids":["28115522","28402695","28951215"],"confidence":"High","gaps":["Causal mechanism by which UHRF2 maintains locus-specific 5mC unresolved at this stage","Functional role of PCNA interaction in vivo untested"]},{"year":2018,"claim":"Demonstrated allosteric control of UHRF2 ligase activity by DNA hydroxymethylation and a cooperative role in interstrand crosslink repair, connecting its reader and catalytic functions.","evidence":"Reconstituted in vitro E3 assays with modified DNA and nucleosomes; live imaging, Co-IP and FANCD2 monoubiquitination assays","pmids":["29506131","30335751","29923055"],"confidence":"High","gaps":["Why UHRF2 is unproductive on mononucleosomes despite allosteric activation not resolved","In vivo substrate of allosteric activation not yet defined here"]},{"year":2021,"claim":"Resolved the central mechanism linking 5hmC reading to active DNA demethylation, identifying XRCC1 K33 ubiquitination as the catalytic output, and added ATR activation and CDK2-mediated regulation of UHRF2.","evidence":"In vitro linkage-specific ubiquitination, Co-IP, MS, integrative epigenomics in Uhrf2-KO ES cells; CoIP/phospho-western for ATR; phospho-site mutagenesis for CDK2/S643","pmids":["34111398","33848395","34766381","33876395","36690646"],"confidence":"High","gaps":["Generality of the XRCC1-RAD23B-TDG axis beyond neuronal commitment untested","Structural mechanism of allosteric activation still not solved"]},{"year":2020,"claim":"Linked UHRF2 SUMO ligase activity to oncogenic Wnt signaling through TCF4 stabilization in vivo.","evidence":"Co-IP, SUMOylation assays, ApcMin knockout mice and organoid assays","pmids":["32372448"],"confidence":"High","gaps":["SUMO chain architecture on TCF4 not defined","Relationship to UHRF2 ubiquitin activity in the same cells unclear"]},{"year":2023,"claim":"Extended UHRF2 function to metabolic and autophagy control, showing a hepatocyte requirement for suppressing cholesterol biosynthesis during liver regeneration.","evidence":"Hepatocyte-specific knockout with partial hepatectomy and bile acid scavenger rescue, Co-IP; Co-IP and xenograft for PARP1/PRDX1","pmids":["37253089","37356603"],"confidence":"High","gaps":["Direct chromatin targets of UHRF2 in cholesterol gene suppression not mapped","PARP1/PRDX1 interactions rest on single Co-IPs without mechanistic depth"]},{"year":2024,"claim":"Defined UHRF2's own cell-cycle-coupled expression and a negative-feedback circuit controlling cyclin and CDK-inhibitor levels.","evidence":"CRISPR/Cas9 knockout, cell synchronization, flow cytometry, CDK1 inhibitor treatment","pmids":["38752903"],"confidence":"Medium","gaps":["Direct ubiquitination of each cyclin/inhibitor not all reconstituted","Mechanism of self-transcriptional repression undefined"]},{"year":2025,"claim":"Established a germline-specific role for UHRF2 in protecting retrotransposon methylation, distinct from its somatic functions.","evidence":"Knockout mouse model with whole-genome bisulfite sequencing, RNA-seq and fertility assays","pmids":["40783491"],"confidence":"High","gaps":["Molecular mechanism conferring resistance to germline demethylation not defined","Whether the XRCC1 ubiquitination axis operates in PGCs untested"]},{"year":2026,"claim":"Connected UHRF2 to innate immune control, showing it stabilizes HDAC1 via atypical K29 ubiquitination to silence type I interferon genes.","evidence":"Co-IP, linkage-specific ubiquitination assays, ChIP, H4K12la analysis and Uhrf2-KO mice with viral challenge","pmids":["42212328"],"confidence":"Medium","gaps":["Direct demonstration of K29 chain assembly geometry absent","How TBK1 nuclear translocation recruits UHRF2 not resolved"]},{"year":null,"claim":"A unifying structural model explaining how chromatin-bound UHRF2 selects among ubiquitin (K33, K29) and SUMO outputs on different substrates remains undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of full-length UHRF2 bound to chromatin with E2/SUMO machinery","Determinants of linkage specificity across substrates unknown","Reconciliation of allosteric activation with nucleosome unproductivity unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[5,18]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4,9,17,19,27]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[4,15,19]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,3,13]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,2,21]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[6,10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2,8]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[7,16,19,27]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,9,19]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[7,16,19,20]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,17,25]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4,9,17,18,27]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[27]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[18,23]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[19,26]}],"complexes":["FA core complex (with UHRF1 and FANCD2)","BER complex (XRCC1-RAD23B-TDG)","UHRF2-HDAC1 complex"],"partners":["UHRF1","FANCD2","XRCC1","HDAC1","TIP60","TCF4","ZNF618","ATR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96PU4","full_name":"E3 ubiquitin-protein ligase UHRF2","aliases":["Np95/ICBP90-like RING finger protein","Np95-like RING finger protein","Nuclear protein 97","Nuclear zinc finger protein Np97","RING finger protein 107","RING-type E3 ubiquitin transferase UHRF2","Ubiquitin-like PHD and RING finger domain-containing protein 2","Ubiquitin-like-containing PHD and RING finger domains protein 2"],"length_aa":802,"mass_kda":90.0,"function":"E3 ubiquitin ligase that plays important roles in DNA methylation, histone modifications, cell cycle and DNA repair (PubMed:15178429, PubMed:23404503, PubMed:27743347, PubMed:29506131). Acts as a specific reader for 5-hydroxymethylcytosine (5hmC) and thereby recruits various substrates to these sites to ubiquitinate them (PubMed:24813944, PubMed:27129234). This activity also allows the maintenance of 5mC levels at specific genomic loci and regulates neuron-related gene expression (By similarity). Participates in cell cycle regulation by ubiquitinating cyclins CCND1 and CCNE1 and thereby inducing G1 arrest (PubMed:15178429, PubMed:15361834, PubMed:21952639). Also ubiquitinates PCNP leading to its degradation by the proteasome (PubMed:12176013, PubMed:14741369). Plays an active role in DNA damage repair by ubiquitinating p21/CDKN1A leading to its proteasomal degradation (PubMed:29923055). Also promotes DNA repair by acting as an interstrand cross-links (ICLs) sensor. Mechanistically, cooperates with UHRF1 to ensure recruitment of FANCD2 to ICLs, leading to FANCD2 monoubiquitination and subsequent activation (PubMed:30335751). Contributes to UV-induced DNA damage response by physically interacting with ATR in response to irradiation, thereby promoting ATR activation (PubMed:33848395)","subcellular_location":"Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q96PU4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/UHRF2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/UHRF2","total_profiled":1310},"omim":[{"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":"615210","title":"PEST-CONTAINING NUCLEAR PROTEIN; PCNP","url":"https://www.omim.org/entry/615210"},{"mim_id":"604073","title":"ZINC FINGER PROTEIN 131; ZNF131","url":"https://www.omim.org/entry/604073"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/UHRF2"},"hgnc":{"alias_symbol":["RNF107","NIRF","URF2","MGC33463","TDRD23"],"prev_symbol":[]},"alphafold":{"accession":"Q96PU4","domains":[{"cath_id":"3.10.20.90","chopping":"4-74","consensus_level":"high","plddt":92.0166,"start":4,"end":74},{"cath_id":"2.30.30.1150","chopping":"236-308","consensus_level":"medium","plddt":90.1199,"start":236,"end":308},{"cath_id":"3.30.40.10","chopping":"340-393","consensus_level":"medium","plddt":85.9354,"start":340,"end":393},{"cath_id":"2.30.280.10","chopping":"458-513_526-632","consensus_level":"high","plddt":94.0153,"start":458,"end":632},{"cath_id":"3.30.40.10","chopping":"695-795","consensus_level":"high","plddt":94.0278,"start":695,"end":795}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96PU4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96PU4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96PU4-F1-predicted_aligned_error_v6.png","plddt_mean":79.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=UHRF2","jax_strain_url":"https://www.jax.org/strain/search?query=UHRF2"},"sequence":{"accession":"Q96PU4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96PU4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96PU4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96PU4"}},"corpus_meta":[{"pmid":"22064703","id":"PMC_22064703","title":"S 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\"finding\": \"UHRF2 binds preferentially to methylated histone H3 lysine 9 (H3K9me2/3) through its conserved tandem Tudor domain, and to hemi-methylated DNA through its SRA domain. Both activities are required for its enrichment at pericentric heterochromatin.\",\n      \"method\": \"Binding assays, co-immunoprecipitation, fluorescence localization experiments in cells\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal findings replicated across two independent labs (PMID:22064703 and PMID:21598301) using multiple orthogonal methods including binding assays, CoIP, and live-cell imaging\",\n      \"pmids\": [\"22064703\", \"21598301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"UHRF2 interacts with DNMT1, DNMT3a, DNMT3b, and G9a by co-immunoprecipitation, but unlike UHRF1, UHRF2 does not interact with DNMT1 in an S phase-dependent manner and cannot recruit DNMT1 to replication foci, explaining why UHRF2 cannot rescue DNA methylation defects in Uhrf1-null ES cells.\",\n      \"method\": \"Co-immunoprecipitation, cell synchronization, fluorescence microscopy in Uhrf1-null mouse embryonic stem cells\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with cell-cycle synchronization, genetic rescue experiment in null cells, replicated observations across two independent labs\",\n      \"pmids\": [\"22064703\", \"21598301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"UHRF2 heterochromatin localization depends primarily on its H3K9me-binding activity (tandem Tudor domain) and to a lesser extent on its methylated DNA-binding activity (SRA domain), as shown by FRAP analyses and domain mutants.\",\n      \"method\": \"FRAP, domain mutagenesis, fluorescence localization in live cells\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRAP and mutagenesis in a single lab with two orthogonal methods\",\n      \"pmids\": [\"21598301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure of UHRF2-SRA domain in complex with 5-hydroxymethylcytosine (5hmC)-containing DNA revealed that a phenylalanine residue forms an optimal 5hmC binding pocket and a hydrogen bond between the hydroxyl group of 5hmC and the SRA domain is critical for preferential binding over 5mC.\",\n      \"method\": \"X-ray crystallography, in vitro binding assays, site-directed mutagenesis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation by mutagenesis and biochemical assays in a single rigorous study\",\n      \"pmids\": [\"24813944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"UHRF2 (NIRF) acts as an E3 ubiquitin ligase that ubiquitinates cyclins D1 and E1, thereby inducing G1 cell cycle arrest.\",\n      \"method\": \"Ubiquitination assays in vivo and in vitro, cell cycle analysis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro ubiquitination assays described in single review/synthesis paper; findings referenced from prior primary work\",\n      \"pmids\": [\"22673569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"UHRF2 acts as a SUMO E3 ligase for zinc finger protein 131 (ZNF131), enhancing ZNF131 SUMOylation but not ubiquitination. The SUMO E3 activity requires the SRA and NLS-containing region domains, whereas the RING domain (critical for ubiquitin E3 activity) is dispensable for SUMOylation.\",\n      \"method\": \"SUMOylation assays in vivo and in vitro, domain deletion/mutagenesis analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of SUMO E3 activity plus domain mutagenesis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23404503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"UHRF2 is a direct transcriptional target of E2F1 and physically interacts with E2F1 protein; UHRF2 is required for E2F1-induced apoptosis and for E2F1 transcription of apoptotic regulators.\",\n      \"method\": \"shRNA screen, ChIP, Co-immunoprecipitation, reporter assays, apoptosis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (CoIP, ChIP, functional KD rescue) in a single lab\",\n      \"pmids\": [\"23833190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"UHRF2 is recruited to sites of DNA damage (by laser microirradiation), and the TTD, PHD, and SRA domains are required for this recruitment. Depletion of UHRF2 suppresses DNA damage-induced H2AX phosphorylation and impairs DNA damage repair in vascular smooth muscle cells.\",\n      \"method\": \"Laser microirradiation, live-cell fluorescence imaging, domain mutant analysis, siRNA knockdown, γH2AX immunofluorescence\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional consequence (H2AX phosphorylation), domain mutant dissection, single lab\",\n      \"pmids\": [\"24134842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ZNF618 specifically interacts with UHRF2 (but not UHRF1) and regulates UHRF2 chromatin localization to 5hmC-enriched genomic loci in vivo. ZNF618 chromatin binding is independent of its interaction with UHRF2 and is mediated through its first two zinc fingers.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, co-localization experiments, domain mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal CoIP and ChIP-seq, single lab with two orthogonal approaches\",\n      \"pmids\": [\"27129234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"UHRF2 interacts with TIP60 acetyltransferase and HDAC1 by co-immunoprecipitation. UHRF2 stabilizes TIP60 via ubiquitination through its RING domain, thereby regulating H3K9ac and H3K14ac levels.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, western blot, histone modification analysis\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CoIP plus ubiquitination assay with RING domain requirement, single lab\",\n      \"pmids\": [\"27743347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"UHRF2 overexpression acts as a transcriptional co-regulator of EMT transcription factors; UHRF2 binds to the CDH1 promoter (by ChIP-qPCR) and interacts with TCF7L2 and chromatin remodeling/histone modification complexes (by IP-MS).\",\n      \"method\": \"ChIP-seq, ChIP-qPCR, IP-MS, proteome profiling, cell invasion assays\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR and IP-MS with multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"27114453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"UHRF2 interacts with H3K9ac through its PHD finger domain, as shown by co-immunoprecipitation and domain deletion experiments, and decreases H3K9ac expression in HCC cells.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, domain deletion analysis, western blot\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and domain deletion from single lab, no reconstitution or mutagenesis validation\",\n      \"pmids\": [\"28004105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structure of UHRF2 PCNA-interacting protein (PIP) box peptide in complex with PCNA revealed the molecular basis for UHRF2-PCNA interaction via a canonical PIP-box motif (residues 784-800). Mutagenesis experiments validated the structural findings.\",\n      \"method\": \"X-ray crystallography, site-directed mutagenesis, structural analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus mutagenesis validation, single lab but direct structural evidence\",\n      \"pmids\": [\"28951215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Uhrf2 knockout mice show no global DNA methylation change but exhibit decreased 5hmC levels specifically in brain (cortex and hippocampus), and UHRF2 binds 5hmC in cells without affecting TET1 enzymatic activity, supporting UHRF2 as a 5hmC reader in vivo.\",\n      \"method\": \"Knockout mouse model, dot-blot for 5hmC/5mC, gene expression profiling, in vivo binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic knockout with quantitative epigenomic analysis replicated across two independent knockout mouse studies\",\n      \"pmids\": [\"28115522\", \"28402695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Uhrf2 knockout mice develop spontaneous seizures and show decreased 5mC levels at specific genomic loci in brain, without global DNA methylation changes, demonstrating a locus-specific role for UHRF2 in 5mC maintenance in brain distinct from UHRF1.\",\n      \"method\": \"Knockout mouse model, bisulfite sequencing, EEG recording, locus-specific methylation analysis\",\n      \"journal\": \"Epigenetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with multiple orthogonal phenotypic and epigenomic readouts, consistent with independent knockout study\",\n      \"pmids\": [\"28402695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Comparative biochemical analysis revealed that UHRF2 has divergent DNA binding properties from UHRF1: both hemi-methylated and hemi-hydroxymethylated DNA allosterically stimulate UHRF2 ubiquitin ligase activity toward histone H3 peptide substrates (first example of an E3 ligase allosterically regulated by DNA hydroxymethylation), but UHRF2 is not a productive histone E3 ligase toward purified mononucleosomes, suggesting a conformational constraint when bound to chromatin.\",\n      \"method\": \"Recombinant protein biochemistry, in vitro E3 ubiquitin ligase assays with DNA oligonucleotides, binding assays, mononucleosome substrates\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro enzymatic assays with multiple substrates and allosteric conditions, comprehensive biochemical study in single lab\",\n      \"pmids\": [\"29506131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"UHRF2 cooperates with UHRF1 to ensure recruitment of FANCD2 to interstrand crosslinks (ICLs). UHRF2 is recruited to ICLs within seconds, forms direct protein-protein interactions with UHRF1 and FANCD2, and stimulates monoubiquitination of FANCD2 by retaining it on chromatin for the FA core complex.\",\n      \"method\": \"Live-cell imaging (rapid recruitment assay), Co-immunoprecipitation, chromatin fractionation, FANCD2 monoubiquitination assays, siRNA knockdown\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (live imaging, CoIP, functional ubiquitination assay) in a single focused mechanistic study\",\n      \"pmids\": [\"30335751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"UHRF2 ubiquitinates p21 via its RING domain, leading to p21 degradation and shortened p21 half-life, which promotes DNA damage response in HEK293 cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, cycloheximide chase, immunofluorescence\",\n      \"journal\": \"Biotechnology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay and protein stability assay, single lab with two orthogonal methods\",\n      \"pmids\": [\"29923055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"UHRF2 directly interacts with and SUMOylates TCF4 (a Wnt pathway transcription factor), stabilizing TCF4 protein and sustaining hyperactive Wnt/β-catenin signaling in intestinal tumor cells.\",\n      \"method\": \"Co-immunoprecipitation, SUMOylation assays, genetic knockout mice on ApcMin background, organoid formation assays\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CoIP plus SUMOylation assays plus in vivo genetic validation in ApcMin mice, multiple orthogonal methods\",\n      \"pmids\": [\"32372448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"UHRF2 is allosterically activated by 5hmC and catalyzes K33-linked polyubiquitination of XRCC1. This non-proteolytic ubiquitination promotes XRCC1 interaction with RAD23B (via its ubiquitin-binding domain), which recruits TDG into the BER complex to complete active DNA demethylation. In mouse embryonic stem cells, Uhrf2 ablation impedes DNA demethylation at active promoters and poised-to-active enhancers during neuronal commitment.\",\n      \"method\": \"In vitro ubiquitination assays, Co-immunoprecipitation, mass spectrometry, integrative epigenomic analysis (ChIP-seq, bisulfite-seq), Uhrf2 knockout mouse ES cells, neuronal differentiation assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro E3 ligase activity with linkage-specific ubiquitination, structural/biochemical allosteric activation by 5hmC, and in vivo genetic validation across multiple orthogonal epigenomic methods\",\n      \"pmids\": [\"34111398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"UHRF2 physically interacts with ATR through its TTD domain in a DNA damage-dependent manner. UHRF2 depletion impairs phosphorylation of ATR at threonine 1989 (required for UV-induced ATR activation), indicating UHRF2 is required for ATR activation after UV irradiation.\",\n      \"method\": \"Co-immunoprecipitation, domain mutant analysis, phospho-specific western blot, siRNA knockdown, UV irradiation\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CoIP and phospho-western with domain mapping, single lab with two orthogonal methods\",\n      \"pmids\": [\"33848395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"UHRF2 TTD domain has modestly higher affinity for the H3 tail than the PHD domain (opposite to UHRF1 where PHD is primary contributor). Aromatic residues in UHRF2 TTD contribute to both selectivity and affinity for H3K9me3, whereas the PHD contains a distinct asparagine that lowers binding affinity. TTD and PHD cooperate in H3 tail binding.\",\n      \"method\": \"Fluorescence polarization binding assays, isothermal titration calorimetry, domain mutagenesis, thermal shift assays\",\n      \"journal\": \"Proteins\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding assays with mutagenesis and multiple quantitative methods, single lab\",\n      \"pmids\": [\"34766381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"UHRF2 binds CDK2 directly and is phosphorylated at serine 643 by CDK2 (promoted by the HBx-ETS1-CDK2 axis in HBV-associated HCC), which blocks UHRF2's E3 ubiquitin ligase activity and promotes DHX9 protein stability by preventing its ubiquitination.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, phosphorylation-site mutagenesis (S643), western blot in HBV-positive HCC cells\",\n      \"journal\": \"Hepatology international / Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CoIP plus ubiquitination assays and phospho-site mapping, corroborated across two papers from same group\",\n      \"pmids\": [\"33876395\", \"36690646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"UHRF2 interacts with chromatin remodeling proteins (Co-IP in hepatocytes) and suppresses the expression of cholesterol biosynthesis genes in an FGFR-dependent manner. Hepatocyte-specific Uhrf2 knockout leads to cholesterol and bile acid accumulation during liver regeneration, causing liver necrosis that is rescued by bile acid scavenger treatment.\",\n      \"method\": \"Hepatocyte-specific Uhrf2 knockout, partial hepatectomy model, Co-immunoprecipitation, gene expression analysis, bile acid scavenger rescue\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional genetic knockout with mechanistic rescue experiment (bile acid scavenger), CoIP for binding partners, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"37253089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"UHRF2 binds autophagy-related protein PARP1 (by Co-IP) and upregulates PARP1 protein level, promoting autophagy in HCC cells. PRDX1 also binds UHRF2 and upregulates its protein expression.\",\n      \"method\": \"Co-immunoprecipitation, western blot, electron microscopy, immunofluorescence, in vivo xenograft\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP per interaction, single lab, limited mechanistic detail on ubiquitination or pathway placement\",\n      \"pmids\": [\"37356603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UHRF2 protein accumulates in early G1 phase following serum stimulation from quiescence or after mitotic exit (where it is degraded during G2/M in a CDK1-dependent manner). UHRF2 controls cyclin and CDK inhibitor levels and represses its own transcription in a negative-feedback loop. CRISPR/Cas9 deletion of UHRF2 causes elevated cyclin levels and elevated p27KIP1, reducing retinoblastoma phosphorylation and prolonging each cell cycle phase.\",\n      \"method\": \"CRISPR/Cas9 knockout, cell synchronization, flow cytometry, western blot, CDK1-specific inhibitor treatment\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with pharmacological inhibitor rescue and cell cycle phenotyping, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"38752903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"UHRF2 is required for resistance to DNA methylation reprogramming at retrotransposons in primordial germ cells (PGCs). Uhrf2 knockout PGCs show loss of retrotransposon DNA methylation and precocious demethylation of germline genes, leading to meiotic gene overexpression in females, impaired oocyte development, female-specific reduced fertility, and incomplete remethylation of retrotransposons during spermatogenesis. This function in the germline is distinct from somatic cells.\",\n      \"method\": \"Knockout mouse model, whole-genome bisulfite sequencing, RNA-seq, fertility assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional/constitutive knockout with genome-wide epigenomic profiling, multiple orthogonal functional readouts in a single rigorous study\",\n      \"pmids\": [\"40783491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"During viral infection, nuclear-translocated TBK1 is hijacked by UHRF2 at IFN-I gene loci. UHRF2 physically interacts with HDAC1 and catalyzes atypical K29-linked polyubiquitination of HDAC1, stabilizing it. The UHRF2-HDAC1 complex erases H4K12 lactylation at IFN-I loci, silencing type I interferon transcription. IFN-I signaling feedback transiently downregulates UHRF2 expression to allow initial antiviral response.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays (linkage-specific), ChIP, H4K12la chromatin analysis, Uhrf2 knockout mouse model with viral challenge\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple CoIP and ubiquitination assays with linkage specificity and in vivo mouse validation, single lab\",\n      \"pmids\": [\"42212328\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UHRF2 is a multi-domain nuclear E3 ubiquitin ligase (and SUMO E3 ligase) that reads 5-hydroxymethylcytosine (5hmC) via its SRA domain, binds H3K9me2/3 via its tandem Tudor domain, and integrates epigenetic signals at heterochromatin; it is allosterically activated by 5hmC to catalyze K33-linked polyubiquitination of XRCC1 (promoting TDG-RAD23B-BER-dependent active DNA demethylation), ubiquitinates cyclins D1/E1 and p21 to regulate cell cycle progression, stabilizes TIP60 and TCF4 via ubiquitination/SUMOylation to modulate histone acetylation and Wnt signaling, cooperates with UHRF1 to recruit FANCD2 to interstrand crosslinks, activates ATR after UV damage via its TTD domain, suppresses cholesterol biosynthesis gene expression in hepatocytes, mediates K29-linked ubiquitination of HDAC1 to epigenetically silence type I interferon genes, and maintains locus-specific DNA methylation and retrotransposon methylation in the germline—though unlike its paralog UHRF1, it cannot support global DNA methylation maintenance due to its inability to interact with DNMT1 in an S phase-dependent manner.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"UHRF2 is a multi-domain nuclear E3 ubiquitin ligase and epigenetic reader that integrates histone and DNA modification signals at chromatin to govern DNA methylation dynamics, the cell cycle, and DNA damage responses [#0, #19]. It engages chromatin through a tandem Tudor domain that binds H3K9me2/3, an SRA domain that reads DNA modifications, and a PHD finger, with heterochromatin enrichment driven principally by H3K9me recognition [#0, #2]; structural work showed its SRA domain forms a dedicated pocket that hydrogen-bonds the 5-hydroxymethylcytosine hydroxyl group, conferring preferential 5hmC over 5mC binding [#3], and in vivo it acts as a 5hmC reader without altering TET enzymatic activity [#13]. Recognition of hemi-methylated or hemi-hydroxymethylated DNA allosterically activates its RING-dependent ubiquitin ligase activity [#15], and 5hmC-stimulated UHRF2 catalyzes non-proteolytic K33-linked polyubiquitination of XRCC1, which recruits RAD23B and TDG to drive TDG-BER-dependent active DNA demethylation at promoters and enhancers during neuronal commitment [#19]. Despite interacting with DNMT1/3a/3b and G9a, UHRF2 cannot bind DNMT1 in an S-phase-dependent manner or maintain global methylation, and its physiological roles are locus-specific: knockout mice retain global methylation but lose brain 5hmC and locus-specific 5mC and develop seizures [#1, #13, #14], while in primordial germ cells UHRF2 protects retrotransposon methylation and restrains precocious germline demethylation [#26]. Beyond methylation, UHRF2 regulates the cell cycle by ubiquitinating cyclins D1/E1 and p21 and controlling CDK-inhibitor levels [#4, #17, #25], cooperates with UHRF1 to retain FANCD2 at interstrand crosslinks and promote its monoubiquitination [#16], and is required for UV-induced ATR activation via its TTD domain [#20]. It additionally functions as a SUMO E3 ligase and chromatin co-regulator—SUMOylating TCF4 to sustain Wnt signaling, stabilizing TIP60 to modulate histone acetylation, and forming a complex with HDAC1 that, via atypical K29-linked ubiquitination, silences type I interferon genes during viral infection [#5, #9, #18, #27].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established how UHRF2 is targeted to chromatin, answering whether it reads histone and DNA marks like its paralog and why it nonetheless cannot substitute for UHRF1.\",\n      \"evidence\": \"Binding assays, Co-IP, live-cell imaging and FRAP with domain mutants in cells, including Uhrf1-null mouse ES cells\",\n      \"pmids\": [\"22064703\", \"21598301\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the catalytic output of chromatin engagement\", \"Structural basis of mark recognition not resolved at this stage\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the molecular basis for UHRF2's selective recognition of 5hmC, distinguishing its reader specificity from 5mC binding.\",\n      \"evidence\": \"X-ray crystallography of SRA-5hmC DNA complex with binding assays and mutagenesis\",\n      \"pmids\": [\"24813944\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect 5hmC reading to a catalytic or cellular output\", \"In vivo relevance of the pocket not tested here\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified UHRF2 as an E3 ubiquitin ligase acting on cell cycle regulators, linking it to G1 control.\",\n      \"evidence\": \"In vivo and in vitro ubiquitination assays with cell cycle analysis\",\n      \"pmids\": [\"22673569\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin chain linkage and degradation outcome not characterized\", \"Reported in a synthesis paper rather than fully primary form\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed that UHRF2 possesses SUMO E3 activity distinct from its ubiquitin ligase function, broadening its enzymatic repertoire.\",\n      \"evidence\": \"In vitro and in vivo SUMOylation assays with domain deletion mapping on ZNF131\",\n      \"pmids\": [\"23404503\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biological consequence of ZNF131 SUMOylation unresolved\", \"Domain requirements for SUMO vs ubiquitin activity not structurally explained\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed UHRF2 in the E2F1 apoptotic program and at DNA damage sites, implicating it in damage signaling.\",\n      \"evidence\": \"shRNA screen, ChIP, Co-IP, reporter and apoptosis assays; laser microirradiation with domain mutants and \\u03b3H2AX readouts\",\n      \"pmids\": [\"23833190\", \"24134842\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct enzymatic targets at damage sites not identified\", \"Mechanism linking recruitment to H2AX phosphorylation unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified protein partners and chromatin-modifying complexes that direct UHRF2 to specific loci and let it modulate histone acetylation and EMT/Wnt programs.\",\n      \"evidence\": \"Co-IP, ChIP-seq/ChIP-qPCR, IP-MS and ubiquitination assays across multiple cell systems (ZNF618, TIP60/HDAC1, TCF7L2)\",\n      \"pmids\": [\"27129234\", \"27743347\", \"27114453\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal hierarchy between locus targeting and transcriptional output unclear\", \"TIP60 stabilization mechanism not structurally defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Used genetic and structural approaches to establish UHRF2 as a 5hmC reader in vivo and a PCNA-interacting protein, while clarifying its locus-specific (not global) role in methylation.\",\n      \"evidence\": \"Knockout mice with 5hmC/5mC dot-blot and bisulfite sequencing; PCNA-PIP box crystal structure with mutagenesis\",\n      \"pmids\": [\"28115522\", \"28402695\", \"28951215\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal mechanism by which UHRF2 maintains locus-specific 5mC unresolved at this stage\", \"Functional role of PCNA interaction in vivo untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated allosteric control of UHRF2 ligase activity by DNA hydroxymethylation and a cooperative role in interstrand crosslink repair, connecting its reader and catalytic functions.\",\n      \"evidence\": \"Reconstituted in vitro E3 assays with modified DNA and nucleosomes; live imaging, Co-IP and FANCD2 monoubiquitination assays\",\n      \"pmids\": [\"29506131\", \"30335751\", \"29923055\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why UHRF2 is unproductive on mononucleosomes despite allosteric activation not resolved\", \"In vivo substrate of allosteric activation not yet defined here\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved the central mechanism linking 5hmC reading to active DNA demethylation, identifying XRCC1 K33 ubiquitination as the catalytic output, and added ATR activation and CDK2-mediated regulation of UHRF2.\",\n      \"evidence\": \"In vitro linkage-specific ubiquitination, Co-IP, MS, integrative epigenomics in Uhrf2-KO ES cells; CoIP/phospho-western for ATR; phospho-site mutagenesis for CDK2/S643\",\n      \"pmids\": [\"34111398\", \"33848395\", \"34766381\", \"33876395\", \"36690646\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of the XRCC1-RAD23B-TDG axis beyond neuronal commitment untested\", \"Structural mechanism of allosteric activation still not solved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked UHRF2 SUMO ligase activity to oncogenic Wnt signaling through TCF4 stabilization in vivo.\",\n      \"evidence\": \"Co-IP, SUMOylation assays, ApcMin knockout mice and organoid assays\",\n      \"pmids\": [\"32372448\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO chain architecture on TCF4 not defined\", \"Relationship to UHRF2 ubiquitin activity in the same cells unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended UHRF2 function to metabolic and autophagy control, showing a hepatocyte requirement for suppressing cholesterol biosynthesis during liver regeneration.\",\n      \"evidence\": \"Hepatocyte-specific knockout with partial hepatectomy and bile acid scavenger rescue, Co-IP; Co-IP and xenograft for PARP1/PRDX1\",\n      \"pmids\": [\"37253089\", \"37356603\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct chromatin targets of UHRF2 in cholesterol gene suppression not mapped\", \"PARP1/PRDX1 interactions rest on single Co-IPs without mechanistic depth\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined UHRF2's own cell-cycle-coupled expression and a negative-feedback circuit controlling cyclin and CDK-inhibitor levels.\",\n      \"evidence\": \"CRISPR/Cas9 knockout, cell synchronization, flow cytometry, CDK1 inhibitor treatment\",\n      \"pmids\": [\"38752903\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ubiquitination of each cyclin/inhibitor not all reconstituted\", \"Mechanism of self-transcriptional repression undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established a germline-specific role for UHRF2 in protecting retrotransposon methylation, distinct from its somatic functions.\",\n      \"evidence\": \"Knockout mouse model with whole-genome bisulfite sequencing, RNA-seq and fertility assays\",\n      \"pmids\": [\"40783491\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism conferring resistance to germline demethylation not defined\", \"Whether the XRCC1 ubiquitination axis operates in PGCs untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected UHRF2 to innate immune control, showing it stabilizes HDAC1 via atypical K29 ubiquitination to silence type I interferon genes.\",\n      \"evidence\": \"Co-IP, linkage-specific ubiquitination assays, ChIP, H4K12la analysis and Uhrf2-KO mice with viral challenge\",\n      \"pmids\": [\"42212328\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demonstration of K29 chain assembly geometry absent\", \"How TBK1 nuclear translocation recruits UHRF2 not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unifying structural model explaining how chromatin-bound UHRF2 selects among ubiquitin (K33, K29) and SUMO outputs on different substrates remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of full-length UHRF2 bound to chromatin with E2/SUMO machinery\", \"Determinants of linkage specificity across substrates unknown\", \"Reconciliation of allosteric activation with nucleosome unproductivity unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [5, 18]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4, 9, 17, 19, 27]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [4, 15, 19]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 3, 13]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 2, 21]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [6, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2, 8]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [7, 16, 19, 27]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 9, 19]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [7, 16, 19, 20]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 17, 25]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 9, 17, 18, 27]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [27]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [18, 23]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [19, 26]}\n    ],\n    \"complexes\": [\"FA core complex (with UHRF1 and FANCD2)\", \"BER complex (XRCC1-RAD23B-TDG)\", \"UHRF2-HDAC1 complex\"],\n    \"partners\": [\"UHRF1\", \"FANCD2\", \"XRCC1\", \"HDAC1\", \"TIP60\", \"TCF4\", \"ZNF618\", \"ATR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}