{"gene":"EMSY","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2003,"finding":"EMSY binds directly to BRCA2 within a region encoded by exon 3, silences the transcriptional activation potential of BRCA2 exon 3, associates with chromatin regulators HP1beta and BS69, and localizes to sites of DNA repair following DNA damage.","method":"Co-immunoprecipitation, transcriptional reporter assays, protein interaction studies, and localization to DNA damage sites","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assays, functional transcriptional silencing demonstrated, replicated across multiple subsequent studies","pmids":["14651845"],"is_preprint":false},{"year":2006,"finding":"Crystal structure of the HP1beta chromo shadow domain (CSD) in complex with the N-terminal domain of EMSY at 1.8 Å resolution reveals that EMSY is bound by two HP1 CSD homodimers, and the binding sequences differ from the consensus HP1 binding motif PXVXL.","method":"X-ray crystallography at 1.8 Å resolution","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure with functional validation of an unusual binding mode","pmids":["16615912"],"is_preprint":false},{"year":2005,"finding":"Crystal structure of the ENT domain of EMSY at 2.0 Å resolution reveals a unique five-alpha-helix helical bundle. The ENT domain forms a homodimer via anti-parallel packing of the N-terminal alpha-helix, stabilized by hydrophobic residues, with a dissociation constant in the low micromolar range.","method":"X-ray crystallography at 2.0 Å resolution; biophysical characterization of dimerization","journal":"Journal of Molecular Biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus biophysical binding measurements in a focused structural study","pmids":["15978617"],"is_preprint":false},{"year":2005,"finding":"The HP1beta-binding motif adjacent to the ENT domain is necessary and sufficient for EMSY binding to the chromoshadow domain of HP1beta. Biophysical and NMR analyses show the main complex consists of one EMSY dimer sandwiched between two HP1-CSD dimers.","method":"Crystal structure at 2.0 Å, NMR, biophysical binding assays, mutagenesis of the binding motif","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure, NMR, and mutagenesis combined in a single study establish the binding determinants","pmids":["15947784"],"is_preprint":false},{"year":2012,"finding":"Akt1 (but not Akt2) phosphorylates EMSY at Ser209, relieving EMSY-mediated repression of interferon-stimulated genes (ISGs). EMSY binds directly to ISG promoters and represses them in a BRCA2-dependent manner; the Akt1/EMSY/ISG pathway is activated by viral infection and IFN and inhibits HSV-1 and VSV replication.","method":"In vitro kinase assay, ChIP showing EMSY binding to ISG promoters, overexpression/knockdown with ISG expression readouts, site-specific phosphorylation mapping","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay identifying phospho-site, ChIP, gain/loss-of-function, and antiviral functional readout in a single focused study","pmids":["22315412"],"is_preprint":false},{"year":2014,"finding":"EMSY is recruited to the miR-31 promoter by the DNA-binding transcription factor ETS-1, where it represses miR-31 transcription by delivering the H3K4me3 demethylase KDM5B/JARID1b/PLU-1, leading to loss of the antimetastatic miRNA and promoting cell migration, invasion, and colony formation.","method":"ChIP showing EMSY and KDM5B at the miR-31 promoter, co-immunoprecipitation of EMSY with ETS-1 and KDM5B, reporter assays, in vitro transformation and in vivo tumor/metastasis assays with EMSY overexpression","journal":"Molecular Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal ChIP, Co-IP of complex components, functional in vitro and in vivo readouts, multiple orthogonal methods","pmids":["24582497"],"is_preprint":false},{"year":2016,"finding":"EMSY forms a complex with the H3K4me3 demethylase KDM5A and SIN3B (Sin3/HDAC). The transcription factor ZNF131 is a substoichiometric interactor that recruits EMSY to active, H3K4me3-marked promoters. In most cases EMSY positively correlates with transcriptional activity of its target genes and stimulates cell proliferation.","method":"Quantitative interaction proteomics, ChIP-sequencing, EMSY knockout cell line with rescue experiments","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — quantitative MS interactomics, ChIP-seq, and genetic KO with rescue in a single focused study","pmids":["26841866"],"is_preprint":false},{"year":2011,"finding":"EMSY overexpression represses BRCA2/RAD51-dependent homologous recombination repair independently of transcriptional repression. Because EMSY, RPA and PALB2 all bind the same BRCA2 region, EMSY overexpression likely overrides RPA and PALB2 at DNA-damage sites, crippling the BRCA2/RAD51 complex.","method":"Direct-repeat GFP recombination/repair assay, overexpression of EMSY with quantification of recombination frequency","journal":"Molecular Genetics and Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — defined cellular HR assay with clear phenotype, single lab, single method","pmids":["21409565"],"is_preprint":false},{"year":2017,"finding":"EMSY overexpression impairs homologous recombination repair. Protein kinase A (PKA) directly phosphorylates EMSY at threonine 207 (T207), and this phospho-site is required for EMSY-driven suppression of DNA damage repair in a BRCA2-independent manner.","method":"DR-GFP and RAD51 foci formation assays, in vitro kinase assay with PKA, immunoprecipitation experiments","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 1–2 / Weak — in vitro kinase assay identifying phospho-site plus functional DR-GFP assay, single lab","pmids":["28099152"],"is_preprint":false},{"year":2021,"finding":"KEAP1 targets EMSY for ubiquitin-mediated degradation; loss of KEAP1 in NSCLC stabilizes EMSY protein, producing homologous recombination repair defects (BRCAness phenotype) and sensitivity to PARP inhibitors. EMSY accumulation also suppresses the type I interferon response and impairs innate immune signaling, fostering cancer immune evasion.","method":"Genetic loss-of-function of KEAP1, ubiquitin-mediated degradation assays, HRR assays, PARP inhibitor sensitivity assays, interferon response gene expression, STING agonist rescue experiments","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (protein stability, HRR assay, immune signaling), published in Cell with genetic and pharmacological validation","pmids":["34963055"],"is_preprint":false},{"year":2005,"finding":"Overexpression of a truncated EMSY (including its BRCA2-interacting domain) in human telomerase-immortalized breast epithelial cells induces structural chromosomal abnormalities and increases chromosome breaks after mitomycin C treatment, mimicking the chromosomal instability associated with BRCA2 loss.","method":"Lentiviral overexpression, metaphase chromosome analysis, mitomycin C challenge","journal":"Journal of the National Cancer Institute","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — defined cellular phenotype (chromosomal instability) with a specific reagent, single lab","pmids":["16145051"],"is_preprint":false},{"year":2014,"finding":"EMSY interacts with beta-catenin and activates beta-catenin/TCF signaling in ovarian cancer cells, promoting cell growth and migration; knockdown of EMSY inhibits growth, migration, and tumorigenesis in vitro and in vivo.","method":"Co-immunoprecipitation of EMSY with beta-catenin, TCF reporter assays, siRNA knockdown, xenograft tumor assays","journal":"Tumour Biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — Co-IP and reporter assay with in vivo validation, single lab","pmids":["25510665"],"is_preprint":false},{"year":2025,"finding":"EMSY interacts with beta-catenin and promotes LDHA transcriptional activation, enhancing glycolysis (lactate production) in ovarian cancer cells; knockdown of EMSY inhibits beta-catenin-driven LDHA transcription.","method":"Co-immunoprecipitation of EMSY with beta-catenin, LDHA knockdown rescue, lactate production assays, glycolysis inhibition experiments","journal":"European Journal of Medical Research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — Co-IP plus functional metabolic assay and knockdown rescue, single lab","pmids":["41023769"],"is_preprint":false},{"year":2024,"finding":"EMSY competitively binds to the Jmjc domain of KDM5B, inhibiting its enzyme activity, thereby reshaping methionine metabolism and promoting cancer stem cell self-renewal and tumorigenesis in an H3K4 methylation-dependent manner in triple-negative breast cancer.","method":"Multiomics integration, co-immunoprecipitation of EMSY with KDM5B Jmjc domain, H3K4 methylation assays, methionine deprivation and PARP inhibitor functional assays","journal":"Cell Reports Medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — Co-IP and methylation assays with functional readouts, single lab","pmids":["38290515"],"is_preprint":false},{"year":2010,"finding":"Loss-of-function of EMSY in Xenopus tropicalis via antisense morpholino oligonucleotides impairs gastrulation movements, disrupts dorsal structures, downregulates regional markers (Xbra, Chd, Gsc, Shh, Sox3, Sox17), and upregulates p53 expression and Bax/apoptosis, demonstrating an essential developmental role.","method":"Antisense morpholino knockdown in Xenopus embryos, in situ hybridization for regional markers, p53/Bax expression analysis","journal":"New Biotechnology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — morpholino loss-of-function with multiple molecular marker readouts, single lab, ortholog study","pmids":["21056705"],"is_preprint":false},{"year":2019,"finding":"siRNA knockdown of EMSY in skin organotypic culture enhances barrier function, increasing expression of filaggrin, filaggrin-2, and long-chain ceramides; conversely, EMSY overexpression in keratinocytes reduces markers of barrier formation, demonstrating that EMSY transcriptionally represses genes required for skin barrier assembly.","method":"siRNA knockdown in organotypic skin culture, mass spectrometry proteomics, lipid analysis, electron microscopy, immunohistochemistry","journal":"The Journal of Allergy and Clinical Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (proteomics, lipid analysis, EM) in a single focused study with both KD and OE","pmids":["31158401"],"is_preprint":false}],"current_model":"EMSY is a nuclear protein that binds BRCA2 exon 3 to silence its transcriptional activation potential and impair homologous recombination repair (causing BRCAness), associates with HP1beta (via a structurally defined non-canonical motif), and assembles into a KDM5A/SIN3B repressor complex recruited to active promoters by ZNF131; it is phosphorylated by Akt1 at Ser209 and by PKA at Thr207 to modulate its repressive functions, suppresses the type I interferon response, promotes beta-catenin/TCF signaling and glycolysis, and is subject to KEAP1-mediated ubiquitin degradation whose loss stabilizes EMSY and drives immune evasion in cancer."},"narrative":{"mechanistic_narrative":"EMSY is a nuclear chromatin-associated protein that couples transcriptional repression to the control of genome stability, functioning as a central effector of the \"BRCAness\" phenotype [PMID:14651845, PMID:34963055]. It binds directly to the BRCA2 region encoded by exon 3, silencing the transcriptional activation potential of that domain, and localizes to sites of DNA damage [PMID:14651845]; through this interaction EMSY overexpression cripples BRCA2/RAD51-dependent homologous recombination repair independently of transcription, plausibly by displacing RPA and PALB2 from a shared BRCA2 surface, and produces chromosomal instability resembling BRCA2 loss [PMID:21409565, PMID:16145051]. EMSY engages the chromatin machinery through an N-terminal ENT domain that homodimerizes and an adjacent non-canonical motif that binds two HP1beta chromoshadow-domain dimers, assembling a defined EMSY-HP1beta architecture [PMID:16615912, PMID:15978617, PMID:15947784]. It nucleates H3K4me3-demethylase repressor complexes — recruiting KDM5B via ETS-1 to silence the antimetastatic miR-31 [PMID:24582497], and assembling with KDM5A and SIN3B and being targeted to active, H3K4me3-marked promoters by ZNF131 [PMID:26841866] — and competitively inhibits KDM5B catalytic activity to reshape methionine metabolism and stem-cell self-renewal [PMID:38290515]. EMSY-mediated repression is gated by phosphorylation: Akt1 phosphorylates Ser209 to relieve repression of interferon-stimulated genes and enable an antiviral response, while PKA phosphorylates Thr207 to drive suppression of DNA repair [PMID:22315412, PMID:28099152]. EMSY protein levels are restrained by KEAP1-directed ubiquitin-mediated degradation; KEAP1 loss stabilizes EMSY, generating HR-repair defects, PARP-inhibitor sensitivity, and suppression of the type I interferon response that fosters cancer immune evasion [PMID:34963055]. EMSY additionally interacts with beta-catenin to activate TCF signaling and LDHA-driven glycolysis [PMID:25510665, PMID:41023769], and is required for normal vertebrate development and for restraint of the skin barrier program [PMID:21056705, PMID:31158401].","teleology":[{"year":2003,"claim":"Established EMSY as a BRCA2-binding nuclear protein, framing how a non-mutated BRCA2 pathway could be inactivated and linking EMSY to both transcription and DNA repair.","evidence":"Co-IP, transcriptional reporter assays, and localization to DNA damage sites","pmids":["14651845"],"confidence":"High","gaps":["Did not define the structural basis of any interaction","Did not establish whether repression and repair functions are separable"]},{"year":2005,"claim":"Resolved the architecture of EMSY's N-terminal module, showing the ENT domain forms a low-micromolar homodimer and that an adjacent motif binds HP1beta, defining how EMSY docks onto chromatin machinery.","evidence":"X-ray crystallography (2.0 Å), NMR, biophysical and mutagenesis analyses of ENT dimerization and HP1beta-CSD binding","pmids":["15978617","15947784"],"confidence":"High","gaps":["Did not connect the structural module to a transcriptional or repair output in cells","Functional consequence of dimerization untested in vivo"]},{"year":2005,"claim":"Showed that a BRCA2-interacting EMSY fragment is sufficient to induce chromosomal instability, providing the first phenotypic link between EMSY overexpression and a BRCA2-loss-like state.","evidence":"Lentiviral overexpression of truncated EMSY, metaphase analysis, mitomycin C challenge in breast epithelial cells","pmids":["16145051"],"confidence":"Medium","gaps":["Used a truncated construct, not full-length protein","Single lab; mechanism of instability not resolved"]},{"year":2006,"claim":"Determined the high-resolution structure of the EMSY-HP1beta CSD complex, revealing a 2:2 binding mode that diverges from the canonical PXVXL motif.","evidence":"X-ray crystallography at 1.8 Å","pmids":["16615912"],"confidence":"High","gaps":["Cellular consequence of the non-canonical mode not tested","Stoichiometry with full repressor complexes unaddressed"]},{"year":2011,"claim":"Separated EMSY's repair function from its transcriptional function, showing overexpression suppresses BRCA2/RAD51 HR repair, likely by competing with RPA and PALB2 at a shared BRCA2 surface.","evidence":"DR-GFP recombination assay with EMSY overexpression","pmids":["21409565"],"confidence":"Medium","gaps":["Competition with RPA/PALB2 inferred, not directly demonstrated","Single method, single lab"]},{"year":2012,"claim":"Identified Akt1-specific phosphorylation of EMSY at Ser209 as a switch that relieves repression of interferon-stimulated genes, embedding EMSY in antiviral signaling.","evidence":"In vitro kinase assay, ChIP at ISG promoters, gain/loss-of-function with antiviral readouts against HSV-1 and VSV","pmids":["22315412"],"confidence":"High","gaps":["In vivo relevance of Ser209 phosphorylation not established","How phosphorylation alters chromatin binding mechanistically unclear"]},{"year":2014,"claim":"Defined EMSY as a recruitable corepressor that delivers an H3K4me3 demethylase to specific promoters and links it to beta-catenin oncogenic signaling.","evidence":"ChIP and Co-IP placing EMSY/KDM5B at the miR-31 promoter via ETS-1; Co-IP with beta-catenin, TCF reporter, knockdown and xenograft assays","pmids":["24582497","25510665"],"confidence":"Medium","gaps":["beta-catenin interaction shown by Co-IP without structural mapping","Generality of ETS-1/KDM5B recruitment beyond miR-31 untested"]},{"year":2016,"claim":"Mapped EMSY's native repressor complex (KDM5A/SIN3B) and its recruitment by ZNF131 to active promoters, refining EMSY as a chromatin regulator that frequently correlates with target gene activity.","evidence":"Quantitative interaction proteomics, ChIP-seq, and EMSY knockout with rescue","pmids":["26841866"],"confidence":"High","gaps":["Reconciliation of positive correlation with repressor recruitment incomplete","Substoichiometric ZNF131 role not structurally defined"]},{"year":2017,"claim":"Showed PKA phosphorylates EMSY at Thr207 to drive BRCA2-independent suppression of DNA repair, adding a second kinase input controlling EMSY's genome-stability function.","evidence":"DR-GFP and RAD51 foci assays, in vitro PKA kinase assay, immunoprecipitation","pmids":["28099152"],"confidence":"Medium","gaps":["Mechanism by which T207 phosphorylation alters repair unclear","Single lab; physiological PKA trigger not defined"]},{"year":2021,"claim":"Identified KEAP1 as the degron controlling EMSY abundance and showed that KEAP1 loss stabilizes EMSY to produce BRCAness, PARP-inhibitor sensitivity, and type I interferon suppression driving immune evasion.","evidence":"KEAP1 loss-of-function, ubiquitin-degradation assays, HRR and PARP-inhibitor sensitivity assays, interferon readouts, STING agonist rescue","pmids":["34963055"],"confidence":"High","gaps":["Degron motif on EMSY not mapped","Relationship between KEAP1-axis and kinase phospho-switches unresolved"]},{"year":2024,"claim":"Demonstrated that EMSY can act as a direct competitive inhibitor of KDM5B catalytic activity, linking its chromatin role to methionine metabolism and stem-cell self-renewal.","evidence":"Multiomics, Co-IP with KDM5B Jmjc domain, H3K4 methylation and methionine-deprivation functional assays","pmids":["38290515"],"confidence":"Medium","gaps":["Reconciliation with EMSY-KDM5A/SIN3B complex recruitment unclear","Single lab; structural basis of Jmjc competition not solved"]},{"year":2025,"claim":"Extended the EMSY/beta-catenin axis to metabolic reprogramming, showing EMSY promotes LDHA transcription and glycolysis in ovarian cancer.","evidence":"Co-IP with beta-catenin, LDHA knockdown rescue, lactate and glycolysis assays","pmids":["41023769"],"confidence":"Medium","gaps":["Direct vs indirect promoter occupancy at LDHA not established","Single lab"]},{"year":null,"claim":"How the multiple inputs converging on EMSY — KEAP1-mediated stability, Akt1/PKA phosphorylation, and partner choice between repressor complexes versus KDM5B inhibition — are integrated to select between DNA-repair suppression, interferon repression, and oncogenic transcription remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking phospho-switches to KEAP1 abundance control","Context-dependence across tissues and tumor types not systematically dissected","No structure of full-length EMSY in any functional complex"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,4,5,6,15]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[1,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,13]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,6]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,4,6]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,6]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0,7,9]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,5,6]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,3,5,6]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[11,12]}],"complexes":["EMSY-KDM5A-SIN3B repressor complex","EMSY-HP1beta chromoshadow complex"],"partners":["BRCA2","HP1BETA","KDM5B","KDM5A","SIN3B","ZNF131","ETS-1","CTNNB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7Z589","full_name":"BRCA2-interacting transcriptional repressor EMSY","aliases":[],"length_aa":1322,"mass_kda":141.5,"function":"Regulator which is able to repress transcription, possibly via its interaction with a multiprotein chromatin remodeling complex that modifies the chromatin (PubMed:14651845). Its interaction with BRCA2 suggests that it may play a central role in the DNA repair function of BRCA2 (PubMed:14651845). Mediates ligand-dependent transcriptional activation by nuclear hormone receptors (PubMed:19131338)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q7Z589/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EMSY","classification":"Not Classified","n_dependent_lines":43,"n_total_lines":1208,"dependency_fraction":0.03559602649006623},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/EMSY","total_profiled":1310},"omim":[{"mim_id":"608574","title":"EMSY TRANSCRIPTIONAL REPRESSOR, BRCA2 INTERACTING; EMSY","url":"https://www.omim.org/entry/608574"},{"mim_id":"606871","title":"JUNCTIONAL ADHESION MOLECULE 3; JAM3","url":"https://www.omim.org/entry/606871"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Centrosome","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EMSY"},"hgnc":{"alias_symbol":[],"prev_symbol":["C11orf30"]},"alphafold":{"accession":"Q7Z589","domains":[{"cath_id":"1.10.1240.40","chopping":"11-102","consensus_level":"medium","plddt":93.156,"start":11,"end":102}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z589","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z589-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z589-F1-predicted_aligned_error_v6.png","plddt_mean":42.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EMSY","jax_strain_url":"https://www.jax.org/strain/search?query=EMSY"},"sequence":{"accession":"Q7Z589","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7Z589.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7Z589/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z589"}},"corpus_meta":[{"pmid":"14651845","id":"PMC_14651845","title":"EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer.","date":"2003","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/14651845","citation_count":343,"is_preprint":false},{"pmid":"34963055","id":"PMC_34963055","title":"EMSY inhibits homologous recombination repair and the interferon response, promoting lung cancer immune evasion.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/34963055","citation_count":93,"is_preprint":false},{"pmid":"16236351","id":"PMC_16236351","title":"Amplification of EMSY, a novel oncogene on 11q13, in high grade ovarian surface epithelial carcinomas.","date":"2005","source":"Gynecologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/16236351","citation_count":71,"is_preprint":false},{"pmid":"17940002","id":"PMC_17940002","title":"The basic helix loop helix domain of maize R links transcriptional regulation and histone modifications by recruitment of an EMSY-related factor.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17940002","citation_count":70,"is_preprint":false},{"pmid":"22315412","id":"PMC_22315412","title":"The protein kinase Akt1 regulates the interferon response through phosphorylation of the transcriptional repressor EMSY.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22315412","citation_count":64,"is_preprint":false},{"pmid":"29030101","id":"PMC_29030101","title":"Genome-wide association study and meta-analysis in multiple populations identifies new loci for peanut allergy and establishes C11orf30/EMSY as a genetic risk factor for food allergy.","date":"2017","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29030101","citation_count":64,"is_preprint":false},{"pmid":"15355907","id":"PMC_15355907","title":"Amplification of the BRCA2 pathway gene EMSY in sporadic breast cancer is related to negative outcome.","date":"2004","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/15355907","citation_count":60,"is_preprint":false},{"pmid":"24582497","id":"PMC_24582497","title":"The breast cancer oncogene EMSY represses transcription of antimetastatic microRNA miR-31.","date":"2014","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/24582497","citation_count":49,"is_preprint":false},{"pmid":"16615912","id":"PMC_16615912","title":"Crystal structure of the HP1-EMSY complex reveals an unusual mode of HP1 binding.","date":"2006","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/16615912","citation_count":41,"is_preprint":false},{"pmid":"21409565","id":"PMC_21409565","title":"EMSY overexpression disrupts the BRCA2/RAD51 pathway in the DNA-damage response: implications for chromosomal instability/recombination syndromes as checkpoint diseases.","date":"2011","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/21409565","citation_count":38,"is_preprint":false},{"pmid":"26841866","id":"PMC_26841866","title":"Recruitment of the Mammalian Histone-modifying EMSY Complex to Target Genes Is Regulated by ZNF131.","date":"2016","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26841866","citation_count":35,"is_preprint":false},{"pmid":"31154673","id":"PMC_31154673","title":"High EMSY expression defines a BRCA-like subgroup of high-grade serous ovarian carcinoma with prolonged survival and hypersensitivity to platinum.","date":"2019","source":"Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31154673","citation_count":33,"is_preprint":false},{"pmid":"16145051","id":"PMC_16145051","title":"Genomic instability of human mammary epithelial cells overexpressing a truncated form of EMSY.","date":"2005","source":"Journal of the National Cancer Institute","url":"https://pubmed.ncbi.nlm.nih.gov/16145051","citation_count":33,"is_preprint":false},{"pmid":"19636701","id":"PMC_19636701","title":"Co-amplification of CCND1 and EMSY is associated with an adverse outcome in ER-positive tamoxifen-treated breast cancers.","date":"2009","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/19636701","citation_count":31,"is_preprint":false},{"pmid":"21735447","id":"PMC_21735447","title":"Functional characterization of EMSY gene amplification in human cancers.","date":"2011","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/21735447","citation_count":30,"is_preprint":false},{"pmid":"18393977","id":"PMC_18393977","title":"Genetic alterations of CCND1 and EMSY in breast cancers.","date":"2008","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/18393977","citation_count":30,"is_preprint":false},{"pmid":"15947784","id":"PMC_15947784","title":"Binding of EMSY to HP1beta: implications for recruitment of HP1beta and BS69.","date":"2005","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/15947784","citation_count":27,"is_preprint":false},{"pmid":"31158401","id":"PMC_31158401","title":"EMSY expression affects multiple components of the skin barrier with relevance to atopic dermatitis.","date":"2019","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31158401","citation_count":25,"is_preprint":false},{"pmid":"25546184","id":"PMC_25546184","title":"The locus C11orf30 increases susceptibility to poly-sensitization.","date":"2014","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/25546184","citation_count":23,"is_preprint":false},{"pmid":"38290515","id":"PMC_38290515","title":"Targeting EMSY-mediated methionine metabolism is a potential therapeutic strategy for triple-negative breast cancer.","date":"2024","source":"Cell reports. Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38290515","citation_count":20,"is_preprint":false},{"pmid":"15978617","id":"PMC_15978617","title":"Crystal structure of the ENT domain of human EMSY.","date":"2005","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15978617","citation_count":19,"is_preprint":false},{"pmid":"18787609","id":"PMC_18787609","title":"Amplification of EMSY gene in a subset of sporadic pancreatic adenocarcinomas.","date":"2008","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/18787609","citation_count":18,"is_preprint":false},{"pmid":"24641409","id":"PMC_24641409","title":"Expression of EMSY, a novel BRCA2-link protein, is associated with lymph node metastasis and increased tumor size in breast carcinomas.","date":"2014","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/24641409","citation_count":16,"is_preprint":false},{"pmid":"16029503","id":"PMC_16029503","title":"Common variation in EMSY and risk of breast and ovarian cancer: a case-control study using HapMap tagging SNPs.","date":"2005","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/16029503","citation_count":14,"is_preprint":false},{"pmid":"28824300","id":"PMC_28824300","title":"The EMSY Gene Collaborates with CCND1 in Non-Small Cell Lung Carcinogenesis.","date":"2017","source":"International journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/28824300","citation_count":13,"is_preprint":false},{"pmid":"14651841","id":"PMC_14651841","title":"The BRCA2-EMSY connection: implications for breast and ovarian tumorigenesis.","date":"2003","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/14651841","citation_count":13,"is_preprint":false},{"pmid":"23117821","id":"PMC_23117821","title":"Akt1, EMSY, BRCA2 and type I IFN signaling: a novel arm of the IFN response.","date":"2012","source":"Transcription","url":"https://pubmed.ncbi.nlm.nih.gov/23117821","citation_count":13,"is_preprint":false},{"pmid":"28099152","id":"PMC_28099152","title":"The EMSY threonine 207 phospho-site is required for EMSYdriven suppression of DNA damage repair.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28099152","citation_count":12,"is_preprint":false},{"pmid":"25927669","id":"PMC_25927669","title":"A novel mechanism of regulation of the anti-metastatic miR-31 by EMSY in breast cancer.","date":"2014","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/25927669","citation_count":12,"is_preprint":false},{"pmid":"24609898","id":"PMC_24609898","title":"The function of EMSY in cancer development.","date":"2014","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and 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migration of ovarian cancer cells.","date":"2014","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25510665","citation_count":6,"is_preprint":false},{"pmid":"27628328","id":"PMC_27628328","title":"EMSY copy number variation in male breast cancers characterized for BRCA1 and BRCA2 mutations.","date":"2016","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/27628328","citation_count":5,"is_preprint":false},{"pmid":"15318925","id":"PMC_15318925","title":"EMSY links breast cancer gene 2 to the 'Royal Family'.","date":"2004","source":"Breast cancer research : BCR","url":"https://pubmed.ncbi.nlm.nih.gov/15318925","citation_count":5,"is_preprint":false},{"pmid":"31812328","id":"PMC_31812328","title":"Genetic variants of the C11orf30-LRRC32 region are associated with childhood asthma in the Chinese population.","date":"2019","source":"Allergologia et immunopathologia","url":"https://pubmed.ncbi.nlm.nih.gov/31812328","citation_count":4,"is_preprint":false},{"pmid":"33213402","id":"PMC_33213402","title":"Polymorphisms in the airway epithelium related genes CDHR3 and EMSY are associated with asthma susceptibility.","date":"2020","source":"BMC pulmonary medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33213402","citation_count":4,"is_preprint":false},{"pmid":"21056705","id":"PMC_21056705","title":"Loss of Xenopus tropicalis EMSY causes impairment of gastrulation and upregulation of p53.","date":"2010","source":"New biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/21056705","citation_count":1,"is_preprint":false},{"pmid":"41023769","id":"PMC_41023769","title":"EMSY enhances glycolysis in ovarian cancer cells.","date":"2025","source":"European journal of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/41023769","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.12.18.629025","title":"Chromatin accessibility classification of TAD boundaries discloses new architectural proteins","date":"2024-12-20","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.18.629025","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":20316,"output_tokens":3802,"usd":0.058989,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11501,"output_tokens":4300,"usd":0.082503,"stage2_stop_reason":"end_turn"},"total_usd":0.141492,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"EMSY binds directly to BRCA2 within a region encoded by exon 3, silences the transcriptional activation potential of BRCA2 exon 3, associates with chromatin regulators HP1beta and BS69, and localizes to sites of DNA repair following DNA damage.\",\n      \"method\": \"Co-immunoprecipitation, transcriptional reporter assays, protein interaction studies, and localization to DNA damage sites\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assays, functional transcriptional silencing demonstrated, replicated across multiple subsequent studies\",\n      \"pmids\": [\"14651845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Crystal structure of the HP1beta chromo shadow domain (CSD) in complex with the N-terminal domain of EMSY at 1.8 Å resolution reveals that EMSY is bound by two HP1 CSD homodimers, and the binding sequences differ from the consensus HP1 binding motif PXVXL.\",\n      \"method\": \"X-ray crystallography at 1.8 Å resolution\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure with functional validation of an unusual binding mode\",\n      \"pmids\": [\"16615912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Crystal structure of the ENT domain of EMSY at 2.0 Å resolution reveals a unique five-alpha-helix helical bundle. The ENT domain forms a homodimer via anti-parallel packing of the N-terminal alpha-helix, stabilized by hydrophobic residues, with a dissociation constant in the low micromolar range.\",\n      \"method\": \"X-ray crystallography at 2.0 Å resolution; biophysical characterization of dimerization\",\n      \"journal\": \"Journal of Molecular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus biophysical binding measurements in a focused structural study\",\n      \"pmids\": [\"15978617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The HP1beta-binding motif adjacent to the ENT domain is necessary and sufficient for EMSY binding to the chromoshadow domain of HP1beta. Biophysical and NMR analyses show the main complex consists of one EMSY dimer sandwiched between two HP1-CSD dimers.\",\n      \"method\": \"Crystal structure at 2.0 Å, NMR, biophysical binding assays, mutagenesis of the binding motif\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure, NMR, and mutagenesis combined in a single study establish the binding determinants\",\n      \"pmids\": [\"15947784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Akt1 (but not Akt2) phosphorylates EMSY at Ser209, relieving EMSY-mediated repression of interferon-stimulated genes (ISGs). EMSY binds directly to ISG promoters and represses them in a BRCA2-dependent manner; the Akt1/EMSY/ISG pathway is activated by viral infection and IFN and inhibits HSV-1 and VSV replication.\",\n      \"method\": \"In vitro kinase assay, ChIP showing EMSY binding to ISG promoters, overexpression/knockdown with ISG expression readouts, site-specific phosphorylation mapping\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay identifying phospho-site, ChIP, gain/loss-of-function, and antiviral functional readout in a single focused study\",\n      \"pmids\": [\"22315412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"EMSY is recruited to the miR-31 promoter by the DNA-binding transcription factor ETS-1, where it represses miR-31 transcription by delivering the H3K4me3 demethylase KDM5B/JARID1b/PLU-1, leading to loss of the antimetastatic miRNA and promoting cell migration, invasion, and colony formation.\",\n      \"method\": \"ChIP showing EMSY and KDM5B at the miR-31 promoter, co-immunoprecipitation of EMSY with ETS-1 and KDM5B, reporter assays, in vitro transformation and in vivo tumor/metastasis assays with EMSY overexpression\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal ChIP, Co-IP of complex components, functional in vitro and in vivo readouts, multiple orthogonal methods\",\n      \"pmids\": [\"24582497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"EMSY forms a complex with the H3K4me3 demethylase KDM5A and SIN3B (Sin3/HDAC). The transcription factor ZNF131 is a substoichiometric interactor that recruits EMSY to active, H3K4me3-marked promoters. In most cases EMSY positively correlates with transcriptional activity of its target genes and stimulates cell proliferation.\",\n      \"method\": \"Quantitative interaction proteomics, ChIP-sequencing, EMSY knockout cell line with rescue experiments\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative MS interactomics, ChIP-seq, and genetic KO with rescue in a single focused study\",\n      \"pmids\": [\"26841866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"EMSY overexpression represses BRCA2/RAD51-dependent homologous recombination repair independently of transcriptional repression. Because EMSY, RPA and PALB2 all bind the same BRCA2 region, EMSY overexpression likely overrides RPA and PALB2 at DNA-damage sites, crippling the BRCA2/RAD51 complex.\",\n      \"method\": \"Direct-repeat GFP recombination/repair assay, overexpression of EMSY with quantification of recombination frequency\",\n      \"journal\": \"Molecular Genetics and Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — defined cellular HR assay with clear phenotype, single lab, single method\",\n      \"pmids\": [\"21409565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"EMSY overexpression impairs homologous recombination repair. Protein kinase A (PKA) directly phosphorylates EMSY at threonine 207 (T207), and this phospho-site is required for EMSY-driven suppression of DNA damage repair in a BRCA2-independent manner.\",\n      \"method\": \"DR-GFP and RAD51 foci formation assays, in vitro kinase assay with PKA, immunoprecipitation experiments\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Weak — in vitro kinase assay identifying phospho-site plus functional DR-GFP assay, single lab\",\n      \"pmids\": [\"28099152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KEAP1 targets EMSY for ubiquitin-mediated degradation; loss of KEAP1 in NSCLC stabilizes EMSY protein, producing homologous recombination repair defects (BRCAness phenotype) and sensitivity to PARP inhibitors. EMSY accumulation also suppresses the type I interferon response and impairs innate immune signaling, fostering cancer immune evasion.\",\n      \"method\": \"Genetic loss-of-function of KEAP1, ubiquitin-mediated degradation assays, HRR assays, PARP inhibitor sensitivity assays, interferon response gene expression, STING agonist rescue experiments\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (protein stability, HRR assay, immune signaling), published in Cell with genetic and pharmacological validation\",\n      \"pmids\": [\"34963055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Overexpression of a truncated EMSY (including its BRCA2-interacting domain) in human telomerase-immortalized breast epithelial cells induces structural chromosomal abnormalities and increases chromosome breaks after mitomycin C treatment, mimicking the chromosomal instability associated with BRCA2 loss.\",\n      \"method\": \"Lentiviral overexpression, metaphase chromosome analysis, mitomycin C challenge\",\n      \"journal\": \"Journal of the National Cancer Institute\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — defined cellular phenotype (chromosomal instability) with a specific reagent, single lab\",\n      \"pmids\": [\"16145051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"EMSY interacts with beta-catenin and activates beta-catenin/TCF signaling in ovarian cancer cells, promoting cell growth and migration; knockdown of EMSY inhibits growth, migration, and tumorigenesis in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation of EMSY with beta-catenin, TCF reporter assays, siRNA knockdown, xenograft tumor assays\",\n      \"journal\": \"Tumour Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — Co-IP and reporter assay with in vivo validation, single lab\",\n      \"pmids\": [\"25510665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EMSY interacts with beta-catenin and promotes LDHA transcriptional activation, enhancing glycolysis (lactate production) in ovarian cancer cells; knockdown of EMSY inhibits beta-catenin-driven LDHA transcription.\",\n      \"method\": \"Co-immunoprecipitation of EMSY with beta-catenin, LDHA knockdown rescue, lactate production assays, glycolysis inhibition experiments\",\n      \"journal\": \"European Journal of Medical Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — Co-IP plus functional metabolic assay and knockdown rescue, single lab\",\n      \"pmids\": [\"41023769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EMSY competitively binds to the Jmjc domain of KDM5B, inhibiting its enzyme activity, thereby reshaping methionine metabolism and promoting cancer stem cell self-renewal and tumorigenesis in an H3K4 methylation-dependent manner in triple-negative breast cancer.\",\n      \"method\": \"Multiomics integration, co-immunoprecipitation of EMSY with KDM5B Jmjc domain, H3K4 methylation assays, methionine deprivation and PARP inhibitor functional assays\",\n      \"journal\": \"Cell Reports Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — Co-IP and methylation assays with functional readouts, single lab\",\n      \"pmids\": [\"38290515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Loss-of-function of EMSY in Xenopus tropicalis via antisense morpholino oligonucleotides impairs gastrulation movements, disrupts dorsal structures, downregulates regional markers (Xbra, Chd, Gsc, Shh, Sox3, Sox17), and upregulates p53 expression and Bax/apoptosis, demonstrating an essential developmental role.\",\n      \"method\": \"Antisense morpholino knockdown in Xenopus embryos, in situ hybridization for regional markers, p53/Bax expression analysis\",\n      \"journal\": \"New Biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — morpholino loss-of-function with multiple molecular marker readouts, single lab, ortholog study\",\n      \"pmids\": [\"21056705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"siRNA knockdown of EMSY in skin organotypic culture enhances barrier function, increasing expression of filaggrin, filaggrin-2, and long-chain ceramides; conversely, EMSY overexpression in keratinocytes reduces markers of barrier formation, demonstrating that EMSY transcriptionally represses genes required for skin barrier assembly.\",\n      \"method\": \"siRNA knockdown in organotypic skin culture, mass spectrometry proteomics, lipid analysis, electron microscopy, immunohistochemistry\",\n      \"journal\": \"The Journal of Allergy and Clinical Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (proteomics, lipid analysis, EM) in a single focused study with both KD and OE\",\n      \"pmids\": [\"31158401\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EMSY is a nuclear protein that binds BRCA2 exon 3 to silence its transcriptional activation potential and impair homologous recombination repair (causing BRCAness), associates with HP1beta (via a structurally defined non-canonical motif), and assembles into a KDM5A/SIN3B repressor complex recruited to active promoters by ZNF131; it is phosphorylated by Akt1 at Ser209 and by PKA at Thr207 to modulate its repressive functions, suppresses the type I interferon response, promotes beta-catenin/TCF signaling and glycolysis, and is subject to KEAP1-mediated ubiquitin degradation whose loss stabilizes EMSY and drives immune evasion in cancer.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EMSY is a nuclear chromatin-associated protein that couples transcriptional repression to the control of genome stability, functioning as a central effector of the \\\"BRCAness\\\" phenotype [#0, #9]. It binds directly to the BRCA2 region encoded by exon 3, silencing the transcriptional activation potential of that domain, and localizes to sites of DNA damage [#0]; through this interaction EMSY overexpression cripples BRCA2/RAD51-dependent homologous recombination repair independently of transcription, plausibly by displacing RPA and PALB2 from a shared BRCA2 surface, and produces chromosomal instability resembling BRCA2 loss [#7, #10]. EMSY engages the chromatin machinery through an N-terminal ENT domain that homodimerizes and an adjacent non-canonical motif that binds two HP1beta chromoshadow-domain dimers, assembling a defined EMSY-HP1beta architecture [#1, #2, #3]. It nucleates H3K4me3-demethylase repressor complexes — recruiting KDM5B via ETS-1 to silence the antimetastatic miR-31 [#5], and assembling with KDM5A and SIN3B and being targeted to active, H3K4me3-marked promoters by ZNF131 [#6] — and competitively inhibits KDM5B catalytic activity to reshape methionine metabolism and stem-cell self-renewal [#13]. EMSY-mediated repression is gated by phosphorylation: Akt1 phosphorylates Ser209 to relieve repression of interferon-stimulated genes and enable an antiviral response, while PKA phosphorylates Thr207 to drive suppression of DNA repair [#4, #8]. EMSY protein levels are restrained by KEAP1-directed ubiquitin-mediated degradation; KEAP1 loss stabilizes EMSY, generating HR-repair defects, PARP-inhibitor sensitivity, and suppression of the type I interferon response that fosters cancer immune evasion [#9]. EMSY additionally interacts with beta-catenin to activate TCF signaling and LDHA-driven glycolysis [#11, #12], and is required for normal vertebrate development and for restraint of the skin barrier program [#14, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established EMSY as a BRCA2-binding nuclear protein, framing how a non-mutated BRCA2 pathway could be inactivated and linking EMSY to both transcription and DNA repair.\",\n      \"evidence\": \"Co-IP, transcriptional reporter assays, and localization to DNA damage sites\",\n      \"pmids\": [\"14651845\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the structural basis of any interaction\", \"Did not establish whether repression and repair functions are separable\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolved the architecture of EMSY's N-terminal module, showing the ENT domain forms a low-micromolar homodimer and that an adjacent motif binds HP1beta, defining how EMSY docks onto chromatin machinery.\",\n      \"evidence\": \"X-ray crystallography (2.0 Å), NMR, biophysical and mutagenesis analyses of ENT dimerization and HP1beta-CSD binding\",\n      \"pmids\": [\"15978617\", \"15947784\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect the structural module to a transcriptional or repair output in cells\", \"Functional consequence of dimerization untested in vivo\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed that a BRCA2-interacting EMSY fragment is sufficient to induce chromosomal instability, providing the first phenotypic link between EMSY overexpression and a BRCA2-loss-like state.\",\n      \"evidence\": \"Lentiviral overexpression of truncated EMSY, metaphase analysis, mitomycin C challenge in breast epithelial cells\",\n      \"pmids\": [\"16145051\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Used a truncated construct, not full-length protein\", \"Single lab; mechanism of instability not resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Determined the high-resolution structure of the EMSY-HP1beta CSD complex, revealing a 2:2 binding mode that diverges from the canonical PXVXL motif.\",\n      \"evidence\": \"X-ray crystallography at 1.8 Å\",\n      \"pmids\": [\"16615912\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular consequence of the non-canonical mode not tested\", \"Stoichiometry with full repressor complexes unaddressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Separated EMSY's repair function from its transcriptional function, showing overexpression suppresses BRCA2/RAD51 HR repair, likely by competing with RPA and PALB2 at a shared BRCA2 surface.\",\n      \"evidence\": \"DR-GFP recombination assay with EMSY overexpression\",\n      \"pmids\": [\"21409565\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Competition with RPA/PALB2 inferred, not directly demonstrated\", \"Single method, single lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified Akt1-specific phosphorylation of EMSY at Ser209 as a switch that relieves repression of interferon-stimulated genes, embedding EMSY in antiviral signaling.\",\n      \"evidence\": \"In vitro kinase assay, ChIP at ISG promoters, gain/loss-of-function with antiviral readouts against HSV-1 and VSV\",\n      \"pmids\": [\"22315412\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of Ser209 phosphorylation not established\", \"How phosphorylation alters chromatin binding mechanistically unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined EMSY as a recruitable corepressor that delivers an H3K4me3 demethylase to specific promoters and links it to beta-catenin oncogenic signaling.\",\n      \"evidence\": \"ChIP and Co-IP placing EMSY/KDM5B at the miR-31 promoter via ETS-1; Co-IP with beta-catenin, TCF reporter, knockdown and xenograft assays\",\n      \"pmids\": [\"24582497\", \"25510665\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"beta-catenin interaction shown by Co-IP without structural mapping\", \"Generality of ETS-1/KDM5B recruitment beyond miR-31 untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mapped EMSY's native repressor complex (KDM5A/SIN3B) and its recruitment by ZNF131 to active promoters, refining EMSY as a chromatin regulator that frequently correlates with target gene activity.\",\n      \"evidence\": \"Quantitative interaction proteomics, ChIP-seq, and EMSY knockout with rescue\",\n      \"pmids\": [\"26841866\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation of positive correlation with repressor recruitment incomplete\", \"Substoichiometric ZNF131 role not structurally defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed PKA phosphorylates EMSY at Thr207 to drive BRCA2-independent suppression of DNA repair, adding a second kinase input controlling EMSY's genome-stability function.\",\n      \"evidence\": \"DR-GFP and RAD51 foci assays, in vitro PKA kinase assay, immunoprecipitation\",\n      \"pmids\": [\"28099152\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which T207 phosphorylation alters repair unclear\", \"Single lab; physiological PKA trigger not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified KEAP1 as the degron controlling EMSY abundance and showed that KEAP1 loss stabilizes EMSY to produce BRCAness, PARP-inhibitor sensitivity, and type I interferon suppression driving immune evasion.\",\n      \"evidence\": \"KEAP1 loss-of-function, ubiquitin-degradation assays, HRR and PARP-inhibitor sensitivity assays, interferon readouts, STING agonist rescue\",\n      \"pmids\": [\"34963055\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degron motif on EMSY not mapped\", \"Relationship between KEAP1-axis and kinase phospho-switches unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated that EMSY can act as a direct competitive inhibitor of KDM5B catalytic activity, linking its chromatin role to methionine metabolism and stem-cell self-renewal.\",\n      \"evidence\": \"Multiomics, Co-IP with KDM5B Jmjc domain, H3K4 methylation and methionine-deprivation functional assays\",\n      \"pmids\": [\"38290515\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation with EMSY-KDM5A/SIN3B complex recruitment unclear\", \"Single lab; structural basis of Jmjc competition not solved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended the EMSY/beta-catenin axis to metabolic reprogramming, showing EMSY promotes LDHA transcription and glycolysis in ovarian cancer.\",\n      \"evidence\": \"Co-IP with beta-catenin, LDHA knockdown rescue, lactate and glycolysis assays\",\n      \"pmids\": [\"41023769\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect promoter occupancy at LDHA not established\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple inputs converging on EMSY — KEAP1-mediated stability, Akt1/PKA phosphorylation, and partner choice between repressor complexes versus KDM5B inhibition — are integrated to select between DNA-repair suppression, interferon repression, and oncogenic transcription remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking phospho-switches to KEAP1 abundance control\", \"Context-dependence across tissues and tumor types not systematically dissected\", \"No structure of full-length EMSY in any functional complex\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 4, 5, 6, 15]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 13]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 4, 6]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 7, 9]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 5, 6]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 3, 5, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [11, 12]}\n    ],\n    \"complexes\": [\n      \"EMSY-KDM5A-SIN3B repressor complex\",\n      \"EMSY-HP1beta chromoshadow complex\"\n    ],\n    \"partners\": [\n      \"BRCA2\",\n      \"HP1beta\",\n      \"KDM5B\",\n      \"KDM5A\",\n      \"SIN3B\",\n      \"ZNF131\",\n      \"ETS-1\",\n      \"CTNNB1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}