{"gene":"EMSY","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2003,"finding":"EMSY directly binds BRCA2 within the region encoded by exon 3, silences the activation potential of BRCA2 exon 3, associates with chromatin regulators HP1beta and BS69, and localizes to sites of DNA repair following DNA damage.","method":"Protein-protein interaction (binding assay), transactivation reporter assay, co-immunoprecipitation, immunofluorescence localization after DNA damage","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 — foundational paper with multiple orthogonal methods (binding, functional silencing assay, co-IP, localization), highly cited","pmids":["14651845"],"is_preprint":false},{"year":2005,"finding":"The N-terminal ENT domain of EMSY forms a homodimer via anti-parallel packing of its N-terminal alpha-helix, and the HP1beta-binding motif adjacent to the ENT domain is necessary and sufficient for EMSY to bind the chromoshadow domain (CSD) of HP1beta; biophysical and NMR analyses show the main complex is one EMSY dimer sandwiched between two HP1-CSD dimers.","method":"Crystal structure of EMSY residues 1–108 at 2.0 Å, NMR, biophysical binding assays, mutagenesis","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 — crystal structure combined with NMR and biophysical validation, confirmed by independent structural study (PMID:16615912)","pmids":["15947784"],"is_preprint":false},{"year":2006,"finding":"Crystal structure of the HP1beta chromo shadow domain in complex with the N-terminal domain of EMSY reveals that EMSY is bound by two HP1 CSD homodimers and the binding sequences differ from the consensus HP1 binding motif PXVXL, expanding understanding of HP1 binding specificity.","method":"X-ray crystallography at 1.8 Å resolution","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structure with functional implications, consistent with EMBO Reports structure","pmids":["16615912"],"is_preprint":false},{"year":2005,"finding":"Crystal structure of the ENT domain of human EMSY reveals a unique arrangement of five alpha-helices forming a helical bundle that shares structural homology with homeodomain DNA-binding domains; the ENT domain forms a homodimer via hydrophobic residues with a dissociation constant in the low micromolar range.","method":"X-ray crystallography","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure, consistent with EMBO Reports biophysical data","pmids":["15978617"],"is_preprint":false},{"year":2012,"finding":"Akt1 (but not Akt2) directly phosphorylates EMSY at Ser209, relieving EMSY-mediated repression of interferon-stimulated genes (ISGs); EMSY binds to the promoters of ISGs and functions as a direct transcriptional repressor in a BRCA2-dependent manner.","method":"In vitro kinase assay, chromatin immunoprecipitation (ChIP), siRNA knockdown, overexpression with reporter assays, viral infection model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro kinase assay identifying phospho-site, ChIP demonstrating promoter binding, multiple orthogonal methods","pmids":["22315412"],"is_preprint":false},{"year":2014,"finding":"EMSY is recruited to the miR-31 promoter by the DNA-binding factor ETS-1 and represses miR-31 transcription by delivering the H3K4me3 demethylase KDM5B/JARID1b/PLU-1, causing oncogenic transformation and metastatic features.","method":"ChIP, co-immunoprecipitation, luciferase reporter assay, in vitro transformation assay, in vivo tumor/metastasis model, miR-31 re-expression rescue","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including ChIP, co-IP, functional rescue, in vivo validation","pmids":["24582497"],"is_preprint":false},{"year":2016,"finding":"EMSY forms a complex with the H3K4me3 demethylase KDM5A and SIN3B; the transcription factor ZNF131 recruits EMSY to active, H3K4me3-marked promoters; EMSY positively correlates with transcriptional activity of target genes and stimulates cell proliferation.","method":"Quantitative interaction proteomics (mass spectrometry), ChIP-sequencing, EMSY knockout with rescue experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — quantitative proteomics, ChIP-seq, and genetic KO/rescue provide multiple orthogonal lines of evidence","pmids":["26841866"],"is_preprint":false},{"year":2011,"finding":"EMSY overexpression represses BRCA2/RAD51-mediated homologous recombination repair and DNA-damage replication/checkpoint independently of transcriptional interference, acting at least partly by overriding RPA and PALB2, which bind to the same BRCA2 N-terminal region as EMSY.","method":"Direct-repeat GFP (DR-GFP) recombination/repair assay, epistasis analysis with PALB2/RPA","journal":"Molecular genetics and genomics : MGG","confidence":"Medium","confidence_rationale":"Tier 2 — functional recombination assay with mechanistic epistasis analysis, single lab","pmids":["21409565"],"is_preprint":false},{"year":2017,"finding":"Protein kinase A (PKA) directly phosphorylates EMSY at threonine 207 (T207); this phospho-site is required for EMSY-driven suppression of DNA damage repair, and the suppression occurs via a BRCA2-independent mechanism.","method":"In vitro kinase assay, DR-GFP assay, RAD51 foci formation assay, immunoprecipitation, site-directed mutagenesis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 1–2 — in vitro kinase assay identifying PKA as writer plus functional assays, single lab","pmids":["28099152"],"is_preprint":false},{"year":2021,"finding":"KEAP1 targets EMSY for ubiquitin-mediated proteasomal degradation; loss of KEAP1 in NSCLC stabilizes EMSY, causing HRR defects (BRCAness phenotype) and suppression of the type I interferon/STING response, leading to cancer immune evasion.","method":"Genetic knockout/knockdown, ubiquitination assays, RAD51 foci/HR repair assays, PARP inhibitor sensitivity assays, STING agonist treatment, in vivo tumor models","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including ubiquitination assay, HR repair assays, in vivo models, published in Cell","pmids":["34963055"],"is_preprint":false},{"year":2024,"finding":"EMSY competitively binds to the Jmjc domain of KDM5B, inhibiting its demethylase enzyme activity, thereby reshaping methionine metabolism and promoting cancer stem cell self-renewal and tumorigenesis in an H3K4 methylation-dependent manner.","method":"Multiomics integration, co-immunoprecipitation, KDM5B enzyme activity assay, H3K4 methylation analysis, metabolomics, ALDH+ cell enrichment assay","journal":"Cell reports. Medicine","confidence":"Medium","confidence_rationale":"Tier 2 — enzymatic activity assay plus co-IP and functional readouts, single lab","pmids":["38290515"],"is_preprint":false},{"year":2014,"finding":"EMSY interacts with beta-catenin and activates beta-catenin/TCF signaling to promote ovarian cancer cell growth and migration.","method":"Co-immunoprecipitation, overexpression and siRNA knockdown with growth/migration assays, in vivo xenograft model","journal":"Tumour biology","confidence":"Medium","confidence_rationale":"Tier 3 — single co-IP plus functional assays, single lab","pmids":["25510665"],"is_preprint":false},{"year":2025,"finding":"EMSY interacts with beta-catenin to promote transcriptional activation of LDHA, enhancing glycolysis (lactate production) in ovarian cancer cells.","method":"Co-immunoprecipitation, siRNA knockdown, lactate and LDHA expression assays, glycolysis inhibition rescue","journal":"European journal of medical research","confidence":"Low","confidence_rationale":"Tier 3 — single co-IP with functional assays, single lab, no independent replication","pmids":["41023769"],"is_preprint":false},{"year":2010,"finding":"Loss-of-function of EMSY in Xenopus tropicalis via morpholino knockdown impairs gastrulation movements, disrupts dorsal structures, downregulates regional markers (Xbra, Chd, Gsc, Shh, Sox3, Sox17), upregulates p53, and induces apoptosis, establishing an essential developmental role for EMSY.","method":"Morpholino antisense knockdown in Xenopus tropicalis embryos, in situ hybridization for regional markers, p53/Bax expression analysis, TUNEL assay","journal":"New biotechnology","confidence":"Medium","confidence_rationale":"Tier 2 — clean loss-of-function with defined phenotypic readouts in a vertebrate model organism, multiple marker analyses","pmids":["21056705"],"is_preprint":false},{"year":2019,"finding":"siRNA knockdown of EMSY in organotypic skin culture enhances barrier function with increased expression of filaggrin, filaggrin-2, and long-chain ceramides; conversely, EMSY overexpression in keratinocytes reduces markers of barrier formation, establishing EMSY as a transcriptional regulator of skin barrier genes.","method":"siRNA knockdown in organotypic skin culture, mass spectrometric proteomics, quantitative lipid analysis, electron microscopy, overexpression experiments","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 — bidirectional genetic manipulation with proteomic and lipid readouts, multiple orthogonal methods","pmids":["31158401"],"is_preprint":false},{"year":2005,"finding":"Overexpression of a truncated EMSY containing its BRCA2-interacting domain in human mammary epithelial cells induces genomic instability (structural chromosomal abnormalities) that increases progressively with passage and is exacerbated by mitomycin C treatment, mimicking the chromosomal instability associated with BRCA2 loss.","method":"Lentiviral transduction of truncated EMSY, metaphase chromosome analysis, mitomycin C clastogen assay","journal":"Journal of the National Cancer Institute","confidence":"Medium","confidence_rationale":"Tier 2 — defined cellular phenotype via loss-of-function mimic with quantitative chromosomal readout","pmids":["16145051"],"is_preprint":false}],"current_model":"EMSY is a nuclear chromatin regulatory protein that binds BRCA2 (via its exon 3-encoded domain) and HP1beta/BS69 through its ENT domain and adjacent motif, forming a complex with KDM5A/SIN3B to regulate H3K4 methylation at gene promoters; it functions as a transcriptional repressor of interferon-stimulated genes and miR-31 (the latter by recruiting KDM5B via ETS-1), and is subject to post-translational regulation by Akt1-mediated phosphorylation at Ser209 (relieving ISG repression) and PKA-mediated phosphorylation at Thr207 (required for DNA damage repair suppression), while its protein stability is controlled by KEAP1-mediated ubiquitin-proteasomal degradation; overexpression or amplification of EMSY impairs homologous recombination repair by disrupting the BRCA2/RAD51/PALB2 axis, producing a BRCAness phenotype and suppressing innate immune signaling."},"narrative":{"teleology":[{"year":2003,"claim":"The discovery of EMSY as a direct BRCA2-binding partner that silences the BRCA2 exon 3 activation domain and localizes to DNA damage sites established it as a candidate link between chromatin regulation and homologous recombination repair.","evidence":"Protein-protein binding assays, transactivation reporter, co-IP with HP1beta/BS69, immunofluorescence after DNA damage in human cells","pmids":["14651845"],"confidence":"High","gaps":["Mechanism by which EMSY silences BRCA2 transcriptional activity was not defined","Whether EMSY directly impairs HR repair was untested","Nature of EMSY chromatin targeting unknown"]},{"year":2005,"claim":"Structural determination of the ENT domain and its HP1beta complex revealed that EMSY homodimerizes through its helical bundle and engages HP1 chromoshadow domains via a non-canonical motif, providing a molecular framework for its chromatin association.","evidence":"Crystal structures at 2.0 Å (ENT domain) and 1.8 Å (HP1beta–EMSY complex), NMR, biophysical binding assays","pmids":["15947784","15978617","16615912"],"confidence":"High","gaps":["Whether HP1beta interaction is required for EMSY's repressive or DNA repair functions was not tested","Full-length EMSY structure remains undetermined"]},{"year":2005,"claim":"Overexpression of the BRCA2-interacting fragment of EMSY was shown to induce progressive chromosomal instability in mammary epithelial cells, providing the first functional evidence that EMSY excess phenocopies BRCA2 loss.","evidence":"Lentiviral transduction of truncated EMSY in human mammary epithelial cells, metaphase chromosome analysis with and without mitomycin C","pmids":["16145051"],"confidence":"Medium","gaps":["Used truncated rather than full-length EMSY","Direct measurement of HR pathway was not performed","In vivo relevance of overexpression levels not established"]},{"year":2011,"claim":"Functional HR repair assays demonstrated that EMSY overexpression directly represses BRCA2/RAD51-mediated homologous recombination by competing with PALB2 and RPA for the BRCA2 N-terminus, distinguishing its repair-suppressive role from transcriptional effects.","evidence":"DR-GFP recombination assay, epistasis analysis with PALB2 and RPA in human cells","pmids":["21409565"],"confidence":"Medium","gaps":["Single laboratory study","Endogenous EMSY stoichiometry effects not examined","Structural basis of EMSY–PALB2 competition unknown"]},{"year":2012,"claim":"Identification of Akt1-mediated phosphorylation of EMSY at Ser209 and demonstration of EMSY as a direct transcriptional repressor at ISG promoters established a signaling axis linking PI3K/Akt to innate immune gene regulation via EMSY.","evidence":"In vitro kinase assay, ChIP at ISG promoters, siRNA knockdown, overexpression reporters, viral infection model","pmids":["22315412"],"confidence":"High","gaps":["Whether Ser209 phosphorylation alters EMSY–BRCA2 interaction was not addressed","Phosphatase reversing the modification unknown","In vivo immune consequences not tested"]},{"year":2014,"claim":"EMSY was shown to repress miR-31 transcription by being recruited to its promoter via ETS-1 and delivering the H3K4me3 demethylase KDM5B, revealing a gene-specific mechanism linking EMSY to epigenetic silencing and metastatic transformation.","evidence":"ChIP, co-IP, luciferase reporter, in vitro transformation assay, in vivo tumor/metastasis models with miR-31 rescue","pmids":["24582497"],"confidence":"High","gaps":["How many other loci use the ETS-1/EMSY/KDM5B axis was unknown","Whether KDM5B recruitment is the sole effector of miR-31 repression not tested"]},{"year":2016,"claim":"Quantitative proteomics and ChIP-seq revealed that EMSY forms a stable complex with KDM5A/SIN3B at H3K4me3-marked active promoters, recruited by ZNF131, broadening its role from a gene-specific repressor to a genome-wide chromatin regulator.","evidence":"Quantitative interaction proteomics (mass spectrometry), ChIP-seq, EMSY knockout and rescue in human cells","pmids":["26841866"],"confidence":"High","gaps":["Whether KDM5A and KDM5B operate at overlapping or distinct EMSY target loci was not resolved","Whether SIN3B is required for EMSY's repressive activity was not demonstrated"]},{"year":2017,"claim":"Discovery that PKA phosphorylates EMSY at Thr207 and that this modification is required for EMSY-driven DNA damage repair suppression through a BRCA2-independent mechanism identified a second kinase input and an alternative pathway for EMSY's repair-inhibitory function.","evidence":"In vitro kinase assay, DR-GFP assay, RAD51 foci assay, site-directed mutagenesis","pmids":["28099152"],"confidence":"Medium","gaps":["BRCA2-independent mechanism downstream of pThr207 not identified","Single laboratory","Relationship between Akt1 (Ser209) and PKA (Thr207) phosphorylation events not examined"]},{"year":2021,"claim":"Identification of KEAP1 as the E3 ligase adaptor targeting EMSY for proteasomal degradation unified the BRCAness and innate immune evasion phenotypes: KEAP1 loss stabilizes EMSY, which impairs HR repair and suppresses STING signaling, explaining PARP inhibitor sensitivity in KEAP1-mutant NSCLC.","evidence":"Ubiquitination assays, HR repair assays, PARP inhibitor sensitivity, STING agonist treatment, in vivo tumor models in NSCLC","pmids":["34963055"],"confidence":"High","gaps":["Degron motif on EMSY for KEAP1 recognition not mapped","Whether other E3 ligases also regulate EMSY is unknown","Applicability beyond NSCLC not established"]},{"year":2024,"claim":"EMSY was found to competitively bind the JmjC catalytic domain of KDM5B and directly inhibit its demethylase activity, linking EMSY to H3K4me3 preservation at metabolic loci and cancer stem cell self-renewal.","evidence":"Co-IP, KDM5B enzyme activity assay, H3K4 methylation and metabolomics analysis, ALDH+ cell enrichment","pmids":["38290515"],"confidence":"Medium","gaps":["Whether EMSY inhibition of KDM5B enzymatic activity operates at the same loci as EMSY-mediated KDM5B recruitment (miR-31) is unresolved","Single laboratory","Structural basis of JmjC domain inhibition by EMSY unknown"]},{"year":null,"claim":"Major unresolved questions include the full-length structure of EMSY, how its multiple phosphorylation events and KEAP1-mediated degradation are coordinated in vivo, and whether the opposing modes of KDM5B regulation (recruitment vs. enzymatic inhibition) are context-dependent.","evidence":"","pmids":[],"confidence":"High","gaps":["No full-length EMSY structure","Integrated model of Akt1/PKA phosphorylation and KEAP1 degradation regulation absent","Context rules for KDM5B recruitment vs. inhibition undefined","Genome-wide target repertoire under physiological EMSY levels not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[4,5,6,14]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,9,10]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[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-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[5,6,10]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0,7,8,9]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,5,6,14]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,9]}],"complexes":["EMSY–KDM5A–SIN3B","EMSY–HP1beta"],"partners":["BRCA2","CBX1","KDM5A","KDM5B","SIN3B","ZNF131","ETS1","KEAP1"],"other_free_text":[]},"mechanistic_narrative":"EMSY is a nuclear chromatin regulatory protein that functions as a transcriptional repressor and modulator of homologous recombination repair by bridging interactions between chromatin-modifying complexes and gene-specific promoters. Through its N-terminal ENT domain, EMSY homodimerizes and binds HP1beta via a non-canonical chromoshadow domain interaction, while forming complexes with KDM5A/SIN3B at H3K4me3-marked promoters and recruiting KDM5B to specific loci such as the miR-31 promoter via ETS-1, thereby reshaping H3K4 methylation and gene expression [PMID:15947784, PMID:26841866, PMID:24582497, PMID:38290515]. EMSY directly binds the BRCA2 exon 3-encoded region, silencing its transactivation potential, and when overexpressed or stabilized—as occurs upon loss of KEAP1-mediated ubiquitin-proteasomal degradation—impairs BRCA2/RAD51/PALB2-dependent homologous recombination repair, producing a BRCAness phenotype and suppressing STING-mediated innate immune signaling [PMID:14651845, PMID:21409565, PMID:34963055]. EMSY is post-translationally regulated by Akt1 phosphorylation at Ser209, which relieves its repression of interferon-stimulated genes, and by PKA phosphorylation at Thr207, which is required for its suppression of DNA damage repair through a BRCA2-independent mechanism [PMID:22315412, PMID:28099152]."},"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":342,"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":87,"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":63,"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":"21830950","id":"PMC_21830950","title":"EMSY-like genes are required for full RPP7-mediated race-specific immunity and basal defense in Arabidopsis.","date":"2011","source":"Molecular plant-microbe interactions : MPMI","url":"https://pubmed.ncbi.nlm.nih.gov/21830950","citation_count":32,"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":"29875242","id":"PMC_29875242","title":"Arabidopsis Histone Reader EMSY-LIKE 1 Binds H3K36 and Suppresses Geminivirus Infection.","date":"2018","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/29875242","citation_count":23,"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 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Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38290515","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":"31203898","id":"PMC_31203898","title":"Arabidopsis EMSY-like (EML) histone readers are necessary for post-fertilization seed development, but prevent fertilization-independent seed formation.","date":"2019","source":"Plant science : an international journal of experimental plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/31203898","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 Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24609898","citation_count":10,"is_preprint":false},{"pmid":"20349280","id":"PMC_20349280","title":"Expression of EMSY gene in sporadic ovarian cancer.","date":"2010","source":"Molecular biology 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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},{"pmid":null,"id":"bio_10.1101_2024.07.25.605061","title":"Co-recognition of histone acetylation and H3K4 trimethylation by GTE4-EML complex in Arabidopsis","date":"2024-07-25","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.25.605061","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21724,"output_tokens":3625,"usd":0.059774},"stage2":{"model":"claude-opus-4-6","input_tokens":7061,"output_tokens":3088,"usd":0.168758},"total_usd":0.228532,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"EMSY directly binds BRCA2 within the region encoded by exon 3, silences the 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\": \"Protein-protein interaction (binding assay), transactivation reporter assay, co-immunoprecipitation, immunofluorescence localization after DNA damage\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — foundational paper with multiple orthogonal methods (binding, functional silencing assay, co-IP, localization), highly cited\",\n      \"pmids\": [\"14651845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The N-terminal ENT domain of EMSY forms a homodimer via anti-parallel packing of its N-terminal alpha-helix, and the HP1beta-binding motif adjacent to the ENT domain is necessary and sufficient for EMSY to bind the chromoshadow domain (CSD) of HP1beta; biophysical and NMR analyses show the main complex is one EMSY dimer sandwiched between two HP1-CSD dimers.\",\n      \"method\": \"Crystal structure of EMSY residues 1–108 at 2.0 Å, NMR, biophysical binding assays, mutagenesis\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure combined with NMR and biophysical validation, confirmed by independent structural study (PMID:16615912)\",\n      \"pmids\": [\"15947784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Crystal structure of the HP1beta chromo shadow domain in complex with the N-terminal domain of EMSY reveals that EMSY is bound by two HP1 CSD homodimers and the binding sequences differ from the consensus HP1 binding motif PXVXL, expanding understanding of HP1 binding specificity.\",\n      \"method\": \"X-ray crystallography at 1.8 Å resolution\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure with functional implications, consistent with EMBO Reports structure\",\n      \"pmids\": [\"16615912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Crystal structure of the ENT domain of human EMSY reveals a unique arrangement of five alpha-helices forming a helical bundle that shares structural homology with homeodomain DNA-binding domains; the ENT domain forms a homodimer via hydrophobic residues with a dissociation constant in the low micromolar range.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure, consistent with EMBO Reports biophysical data\",\n      \"pmids\": [\"15978617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Akt1 (but not Akt2) directly phosphorylates EMSY at Ser209, relieving EMSY-mediated repression of interferon-stimulated genes (ISGs); EMSY binds to the promoters of ISGs and functions as a direct transcriptional repressor in a BRCA2-dependent manner.\",\n      \"method\": \"In vitro kinase assay, chromatin immunoprecipitation (ChIP), siRNA knockdown, overexpression with reporter assays, viral infection model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro kinase assay identifying phospho-site, ChIP demonstrating promoter binding, multiple orthogonal methods\",\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 factor ETS-1 and represses miR-31 transcription by delivering the H3K4me3 demethylase KDM5B/JARID1b/PLU-1, causing oncogenic transformation and metastatic features.\",\n      \"method\": \"ChIP, co-immunoprecipitation, luciferase reporter assay, in vitro transformation assay, in vivo tumor/metastasis model, miR-31 re-expression rescue\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including ChIP, co-IP, functional rescue, in vivo validation\",\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; the transcription factor ZNF131 recruits EMSY to active, H3K4me3-marked promoters; EMSY positively correlates with transcriptional activity of target genes and stimulates cell proliferation.\",\n      \"method\": \"Quantitative interaction proteomics (mass spectrometry), ChIP-sequencing, EMSY knockout with rescue experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — quantitative proteomics, ChIP-seq, and genetic KO/rescue provide multiple orthogonal lines of evidence\",\n      \"pmids\": [\"26841866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"EMSY overexpression represses BRCA2/RAD51-mediated homologous recombination repair and DNA-damage replication/checkpoint independently of transcriptional interference, acting at least partly by overriding RPA and PALB2, which bind to the same BRCA2 N-terminal region as EMSY.\",\n      \"method\": \"Direct-repeat GFP (DR-GFP) recombination/repair assay, epistasis analysis with PALB2/RPA\",\n      \"journal\": \"Molecular genetics and genomics : MGG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional recombination assay with mechanistic epistasis analysis, single lab\",\n      \"pmids\": [\"21409565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Protein kinase A (PKA) directly phosphorylates EMSY at threonine 207 (T207); this phospho-site is required for EMSY-driven suppression of DNA damage repair, and the suppression occurs via a BRCA2-independent mechanism.\",\n      \"method\": \"In vitro kinase assay, DR-GFP assay, RAD51 foci formation assay, immunoprecipitation, site-directed mutagenesis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro kinase assay identifying PKA as writer plus functional assays, single lab\",\n      \"pmids\": [\"28099152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KEAP1 targets EMSY for ubiquitin-mediated proteasomal degradation; loss of KEAP1 in NSCLC stabilizes EMSY, causing HRR defects (BRCAness phenotype) and suppression of the type I interferon/STING response, leading to cancer immune evasion.\",\n      \"method\": \"Genetic knockout/knockdown, ubiquitination assays, RAD51 foci/HR repair assays, PARP inhibitor sensitivity assays, STING agonist treatment, in vivo tumor models\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including ubiquitination assay, HR repair assays, in vivo models, published in Cell\",\n      \"pmids\": [\"34963055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EMSY competitively binds to the Jmjc domain of KDM5B, inhibiting its demethylase enzyme activity, thereby reshaping methionine metabolism and promoting cancer stem cell self-renewal and tumorigenesis in an H3K4 methylation-dependent manner.\",\n      \"method\": \"Multiomics integration, co-immunoprecipitation, KDM5B enzyme activity assay, H3K4 methylation analysis, metabolomics, ALDH+ cell enrichment assay\",\n      \"journal\": \"Cell reports. Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — enzymatic activity assay plus co-IP and functional readouts, single lab\",\n      \"pmids\": [\"38290515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"EMSY interacts with beta-catenin and activates beta-catenin/TCF signaling to promote ovarian cancer cell growth and migration.\",\n      \"method\": \"Co-immunoprecipitation, overexpression and siRNA knockdown with growth/migration assays, in vivo xenograft model\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single co-IP plus functional assays, single lab\",\n      \"pmids\": [\"25510665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EMSY interacts with beta-catenin to promote transcriptional activation of LDHA, enhancing glycolysis (lactate production) in ovarian cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, lactate and LDHA expression assays, glycolysis inhibition rescue\",\n      \"journal\": \"European journal of medical research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single co-IP with functional assays, single lab, no independent replication\",\n      \"pmids\": [\"41023769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Loss-of-function of EMSY in Xenopus tropicalis via morpholino knockdown impairs gastrulation movements, disrupts dorsal structures, downregulates regional markers (Xbra, Chd, Gsc, Shh, Sox3, Sox17), upregulates p53, and induces apoptosis, establishing an essential developmental role for EMSY.\",\n      \"method\": \"Morpholino antisense knockdown in Xenopus tropicalis embryos, in situ hybridization for regional markers, p53/Bax expression analysis, TUNEL assay\",\n      \"journal\": \"New biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function with defined phenotypic readouts in a vertebrate model organism, multiple marker analyses\",\n      \"pmids\": [\"21056705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"siRNA knockdown of EMSY in organotypic skin culture enhances barrier function with increased expression of filaggrin, filaggrin-2, and long-chain ceramides; conversely, EMSY overexpression in keratinocytes reduces markers of barrier formation, establishing EMSY as a transcriptional regulator of skin barrier genes.\",\n      \"method\": \"siRNA knockdown in organotypic skin culture, mass spectrometric proteomics, quantitative lipid analysis, electron microscopy, overexpression experiments\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional genetic manipulation with proteomic and lipid readouts, multiple orthogonal methods\",\n      \"pmids\": [\"31158401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Overexpression of a truncated EMSY containing its BRCA2-interacting domain in human mammary epithelial cells induces genomic instability (structural chromosomal abnormalities) that increases progressively with passage and is exacerbated by mitomycin C treatment, mimicking the chromosomal instability associated with BRCA2 loss.\",\n      \"method\": \"Lentiviral transduction of truncated EMSY, metaphase chromosome analysis, mitomycin C clastogen assay\",\n      \"journal\": \"Journal of the National Cancer Institute\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined cellular phenotype via loss-of-function mimic with quantitative chromosomal readout\",\n      \"pmids\": [\"16145051\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EMSY is a nuclear chromatin regulatory protein that binds BRCA2 (via its exon 3-encoded domain) and HP1beta/BS69 through its ENT domain and adjacent motif, forming a complex with KDM5A/SIN3B to regulate H3K4 methylation at gene promoters; it functions as a transcriptional repressor of interferon-stimulated genes and miR-31 (the latter by recruiting KDM5B via ETS-1), and is subject to post-translational regulation by Akt1-mediated phosphorylation at Ser209 (relieving ISG repression) and PKA-mediated phosphorylation at Thr207 (required for DNA damage repair suppression), while its protein stability is controlled by KEAP1-mediated ubiquitin-proteasomal degradation; overexpression or amplification of EMSY impairs homologous recombination repair by disrupting the BRCA2/RAD51/PALB2 axis, producing a BRCAness phenotype and suppressing innate immune signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"EMSY is a nuclear chromatin regulatory protein that functions as a transcriptional repressor and modulator of homologous recombination repair by bridging interactions between chromatin-modifying complexes and gene-specific promoters. Through its N-terminal ENT domain, EMSY homodimerizes and binds HP1beta via a non-canonical chromoshadow domain interaction, while forming complexes with KDM5A/SIN3B at H3K4me3-marked promoters and recruiting KDM5B to specific loci such as the miR-31 promoter via ETS-1, thereby reshaping H3K4 methylation and gene expression [PMID:15947784, PMID:26841866, PMID:24582497, PMID:38290515]. EMSY directly binds the BRCA2 exon 3-encoded region, silencing its transactivation potential, and when overexpressed or stabilized—as occurs upon loss of KEAP1-mediated ubiquitin-proteasomal degradation—impairs BRCA2/RAD51/PALB2-dependent homologous recombination repair, producing a BRCAness phenotype and suppressing STING-mediated innate immune signaling [PMID:14651845, PMID:21409565, PMID:34963055]. EMSY is post-translationally regulated by Akt1 phosphorylation at Ser209, which relieves its repression of interferon-stimulated genes, and by PKA phosphorylation at Thr207, which is required for its suppression of DNA damage repair through a BRCA2-independent mechanism [PMID:22315412, PMID:28099152].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"The discovery of EMSY as a direct BRCA2-binding partner that silences the BRCA2 exon 3 activation domain and localizes to DNA damage sites established it as a candidate link between chromatin regulation and homologous recombination repair.\",\n      \"evidence\": \"Protein-protein binding assays, transactivation reporter, co-IP with HP1beta/BS69, immunofluorescence after DNA damage in human cells\",\n      \"pmids\": [\"14651845\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which EMSY silences BRCA2 transcriptional activity was not defined\", \"Whether EMSY directly impairs HR repair was untested\", \"Nature of EMSY chromatin targeting unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Structural determination of the ENT domain and its HP1beta complex revealed that EMSY homodimerizes through its helical bundle and engages HP1 chromoshadow domains via a non-canonical motif, providing a molecular framework for its chromatin association.\",\n      \"evidence\": \"Crystal structures at 2.0 Å (ENT domain) and 1.8 Å (HP1beta–EMSY complex), NMR, biophysical binding assays\",\n      \"pmids\": [\"15947784\", \"15978617\", \"16615912\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HP1beta interaction is required for EMSY's repressive or DNA repair functions was not tested\", \"Full-length EMSY structure remains undetermined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Overexpression of the BRCA2-interacting fragment of EMSY was shown to induce progressive chromosomal instability in mammary epithelial cells, providing the first functional evidence that EMSY excess phenocopies BRCA2 loss.\",\n      \"evidence\": \"Lentiviral transduction of truncated EMSY in human mammary epithelial cells, metaphase chromosome analysis with and without mitomycin C\",\n      \"pmids\": [\"16145051\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Used truncated rather than full-length EMSY\", \"Direct measurement of HR pathway was not performed\", \"In vivo relevance of overexpression levels not established\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Functional HR repair assays demonstrated that EMSY overexpression directly represses BRCA2/RAD51-mediated homologous recombination by competing with PALB2 and RPA for the BRCA2 N-terminus, distinguishing its repair-suppressive role from transcriptional effects.\",\n      \"evidence\": \"DR-GFP recombination assay, epistasis analysis with PALB2 and RPA in human cells\",\n      \"pmids\": [\"21409565\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single laboratory study\", \"Endogenous EMSY stoichiometry effects not examined\", \"Structural basis of EMSY–PALB2 competition unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of Akt1-mediated phosphorylation of EMSY at Ser209 and demonstration of EMSY as a direct transcriptional repressor at ISG promoters established a signaling axis linking PI3K/Akt to innate immune gene regulation via EMSY.\",\n      \"evidence\": \"In vitro kinase assay, ChIP at ISG promoters, siRNA knockdown, overexpression reporters, viral infection model\",\n      \"pmids\": [\"22315412\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Ser209 phosphorylation alters EMSY–BRCA2 interaction was not addressed\", \"Phosphatase reversing the modification unknown\", \"In vivo immune consequences not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"EMSY was shown to repress miR-31 transcription by being recruited to its promoter via ETS-1 and delivering the H3K4me3 demethylase KDM5B, revealing a gene-specific mechanism linking EMSY to epigenetic silencing and metastatic transformation.\",\n      \"evidence\": \"ChIP, co-IP, luciferase reporter, in vitro transformation assay, in vivo tumor/metastasis models with miR-31 rescue\",\n      \"pmids\": [\"24582497\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How many other loci use the ETS-1/EMSY/KDM5B axis was unknown\", \"Whether KDM5B recruitment is the sole effector of miR-31 repression not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Quantitative proteomics and ChIP-seq revealed that EMSY forms a stable complex with KDM5A/SIN3B at H3K4me3-marked active promoters, recruited by ZNF131, broadening its role from a gene-specific repressor to a genome-wide chromatin regulator.\",\n      \"evidence\": \"Quantitative interaction proteomics (mass spectrometry), ChIP-seq, EMSY knockout and rescue in human cells\",\n      \"pmids\": [\"26841866\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether KDM5A and KDM5B operate at overlapping or distinct EMSY target loci was not resolved\", \"Whether SIN3B is required for EMSY's repressive activity was not demonstrated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Discovery that PKA phosphorylates EMSY at Thr207 and that this modification is required for EMSY-driven DNA damage repair suppression through a BRCA2-independent mechanism identified a second kinase input and an alternative pathway for EMSY's repair-inhibitory function.\",\n      \"evidence\": \"In vitro kinase assay, DR-GFP assay, RAD51 foci assay, site-directed mutagenesis\",\n      \"pmids\": [\"28099152\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"BRCA2-independent mechanism downstream of pThr207 not identified\", \"Single laboratory\", \"Relationship between Akt1 (Ser209) and PKA (Thr207) phosphorylation events not examined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of KEAP1 as the E3 ligase adaptor targeting EMSY for proteasomal degradation unified the BRCAness and innate immune evasion phenotypes: KEAP1 loss stabilizes EMSY, which impairs HR repair and suppresses STING signaling, explaining PARP inhibitor sensitivity in KEAP1-mutant NSCLC.\",\n      \"evidence\": \"Ubiquitination assays, HR repair assays, PARP inhibitor sensitivity, STING agonist treatment, in vivo tumor models in NSCLC\",\n      \"pmids\": [\"34963055\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degron motif on EMSY for KEAP1 recognition not mapped\", \"Whether other E3 ligases also regulate EMSY is unknown\", \"Applicability beyond NSCLC not established\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"EMSY was found to competitively bind the JmjC catalytic domain of KDM5B and directly inhibit its demethylase activity, linking EMSY to H3K4me3 preservation at metabolic loci and cancer stem cell self-renewal.\",\n      \"evidence\": \"Co-IP, KDM5B enzyme activity assay, H3K4 methylation and metabolomics analysis, ALDH+ cell enrichment\",\n      \"pmids\": [\"38290515\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether EMSY inhibition of KDM5B enzymatic activity operates at the same loci as EMSY-mediated KDM5B recruitment (miR-31) is unresolved\", \"Single laboratory\", \"Structural basis of JmjC domain inhibition by EMSY unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major unresolved questions include the full-length structure of EMSY, how its multiple phosphorylation events and KEAP1-mediated degradation are coordinated in vivo, and whether the opposing modes of KDM5B regulation (recruitment vs. enzymatic inhibition) are context-dependent.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full-length EMSY structure\", \"Integrated model of Akt1/PKA phosphorylation and KEAP1 degradation regulation absent\", \"Context rules for KDM5B recruitment vs. inhibition undefined\", \"Genome-wide target repertoire under physiological EMSY levels not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [4, 5, 6, 14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 9, 10]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [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\": \"GO:0042393\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [5, 6, 10]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 7, 8, 9]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 5, 6, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 9]}\n    ],\n    \"complexes\": [\n      \"EMSY–KDM5A–SIN3B\",\n      \"EMSY–HP1beta\"\n    ],\n    \"partners\": [\n      \"BRCA2\",\n      \"CBX1\",\n      \"KDM5A\",\n      \"KDM5B\",\n      \"SIN3B\",\n      \"ZNF131\",\n      \"ETS1\",\n      \"KEAP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}