{"gene":"ESCO1","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2020,"finding":"ESCO1 acetylates cohesinSTAG1 complexes, and together with CTCF protects a subset of cohesinSTAG1 from removal by WAPL, enabling formation of long and presumably long-lived chromatin loops. ESCO1 contributes to boundary formation in chromatin looping.","method":"Cell-based assays in mammalian G1-phase cells measuring cohesin chromatin residence time, CTCF and ESCO1 depletion experiments, chromatin fractionation, and loop boundary analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (residence time measurement, depletion of ESCO1 and CTCF, boundary formation analysis) establishing pathway position; independently consistent with other cohesin acetylation studies","pmids":["32065581"],"is_preprint":false},{"year":2017,"finding":"ESCO1 is responsible for the majority of SMC3 acetylation in vertebrate cells, but its acetyltransferase activity is largely dispensable for mitotic sister chromatid cohesion; instead, ESCO1-dependent SMC3 modification primarily regulates non-cohesive cohesin activities (DNA repair, transcriptional control, chromosome loop formation/stabilization). Cohesion establishment is critically dependent on ESCO2, mediated by sequences in ESCO2's N-terminus.","method":"ESCO1 and ESCO2 gene inactivation in vertebrate cells, sister chromatid cohesion assays, SMC3 acetylation measurements, domain-swap rescue experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO/KD with defined phenotypic readouts and domain-swap rescue; findings replicated across multiple complementary approaches in the same study and consistent with other publications","pmids":["28847955"],"is_preprint":false},{"year":2015,"finding":"ESCO1 requires the cohesin regulatory subunit Pds5 (bound to Rad21) for SMC3 acetylation and sororin stabilization on chromatin. Pds5 interacts exclusively with ESCO1 (not ESCO2) via a unique and conserved N-terminal domain of ESCO1, and this interaction is essential for SMC3 acetylation and sister chromatid cohesion. ESCO1 localizes to cohesin sites on chromosomes throughout interphase in a Pds5-interaction-dependent manner and can acetylate SMC3 independently of DNA replication.","method":"Co-immunoprecipitation, Pds5 depletion experiments, chromosome localization assays (ChIP/immunofluorescence), domain mapping with ESCO1 mutants, cell-cycle-staged SMC3 acetylation assays","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction mapping, domain-dependency experiments, and multiple functional readouts (acetylation, cohesion, localization) in a single focused study","pmids":["26051894"],"is_preprint":false},{"year":2015,"finding":"ESCO1 is recruited by cohesin to over 11,000 chromatin sites genome-wide throughout the cell cycle via two short N-terminal motifs (A-box and B-box) unique to ESCO1 orthologs. Deletion of either motif causes derepression of ESCO1-proximal genes and functionally uncouples cohesion from SMC3 acetylation. Distinct ESCO1 mutations can separate its roles in cohesion establishment versus gene silencing.","method":"ChIP-seq for ESCO1 and cohesin genome-wide, cell-cycle-staged chromatin recruitment, motif-deletion mutant analysis, gene expression assays (derepression), and sister chromatid cohesion assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq combined with domain-deletion functional rescue experiments, multiple orthogonal readouts (chromatin binding, gene expression, cohesion)","pmids":["26305936"],"is_preprint":false},{"year":2016,"finding":"X-ray crystal structure of the ESCO1 zinc finger–acetyltransferase domain reveals structural homology to the Gcn5 HAT but with unique additional features including a zinc finger and an ~40-residue loop region involved in protein stability and SMC3 substrate binding. Structure-based mutagenesis identified key residues for substrate binding and catalysis, and rationalized disease-associated mutation effects.","method":"X-ray crystallography, structure-based mutagenesis, biochemical acetyltransferase assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure combined with mutagenesis and biochemical characterization in one study; single lab but multiple orthogonal methods","pmids":["27803161"],"is_preprint":false},{"year":2016,"finding":"Crystal structure of the ESCO1 acetyltransferase domain in complex with acetyl-CoA shows the active site lacks a canonical catalytic base. Mutation of surface glutamate E789 (near automodification target K803) strongly reduces ESCO1 autoacetylation. In vivo evidence (budding yeast Smc3 D114 mutant) indicates ESCO1 uses substrate-assisted catalysis for cohesion establishment. SAXS reveals ESCO1 is a dimer in solution.","method":"X-ray crystallography, SAXS, site-directed mutagenesis, in vivo yeast Smc3 acetylation assays","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with acetyl-CoA, SAXS for solution state, mutagenesis, and in vivo validation of substrate-assisted catalysis mechanism; single lab, multiple orthogonal methods","pmids":["27112597"],"is_preprint":false},{"year":2018,"finding":"In mouse oocyte meiosis, ESCO1 localizes to both nucleus and cytoplasm, binds α-tubulin, and is required for α-tubulin acetylation to maintain microtubule stability and proper spindle assembly. Enzymatically dead ESCO1-G768D cannot restore α-tubulin acetylation or rescue spindle defects, and purified wild-type (but not mutant) ESCO1 acetylates an α-tubulin peptide in vitro.","method":"siRNA depletion in mouse oocytes, co-immunoprecipitation (ESCO1–α-tubulin), overexpression rescue with wild-type vs. catalytic mutant ESCO1, nocodazole resistance assay, in vitro acetyltransferase assay with purified ESCO1 and α-tubulin peptide","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro acetyltransferase assay with purified protein and peptide substrate, combined with Co-IP, loss-of-function and rescue experiments including catalytic mutant control; single lab but multiple orthogonal methods","pmids":["29361031"],"is_preprint":false},{"year":2019,"finding":"In porcine oocytes, ESCO1 localizes to the spindle apparatus (distinct from ESCO2, which is on chromosomes), binds α-tubulin, and is required for α-tubulin acetylation to maintain microtubule dynamics. Depletion of ESCO1 causes meiotic arrest with defective spindle/chromosome structure and reduced polar body extrusion.","method":"siRNA depletion in porcine oocytes, immunofluorescence localization, co-immunoprecipitation (ESCO1–α-tubulin), acetylated α-tubulin quantification","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and localization experiments with KD phenotype; single lab, consistent with mouse oocyte findings from same group but independent species validation","pmids":["31387516"],"is_preprint":false},{"year":2017,"finding":"In chicken DT40 cells, both ESCO1 and ESCO2 promote sister chromatid cohesion, but ESCO2 is additionally and specifically required for proliferation and centromere integrity. ESCO1 overexpression can fully suppress ESCO2-loss proliferation and centromere phenotypes but only partially rescues chromosome-arm cohesion defects. Combined inactivation of ESCO1 and ESCO2 causes lethality due to compromised mitotic chromosome segregation, and this lethality is not rescued by wapl deletion or acetyl-mimicking smc3-QQ mutations, indicating cohesion establishment is linked to interphase chromatin architecture.","method":"Conditional DT40 cell knockouts of ESCO1, ESCO2, WAPL, and SMC3 acetylation mutants; epistasis analysis; mitotic chromosome analysis; proliferation assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — multi-gene epistasis analysis in defined genetic backgrounds with multiple phenotypic readouts; replicated across several mutant combinations","pmids":["29196537"],"is_preprint":false},{"year":2020,"finding":"In Warsaw Breakage Syndrome (WABS) cells lacking DDX11, residual sister chromatid cohesion (SCC) depends predominantly on ESCO2, not ESCO1. Reciprocally, Roberts Syndrome cells (lacking ESCO2) depend on DDX11 for residual SCC. Synthetic lethality between DDX11 and ESCO2 (but not ESCO1 and DDX11) is rescued by WAPL knockdown, placing ESCO1 and ESCO2 on different but related cohesin fractions.","method":"SCC assays in patient-derived cells, siRNA knockdowns, synthetic lethality analysis, mitotic delay quantification, WAPL rescue experiments, cDNA rescue with human/mouse constructs and DDX11 DNA-binding mutant","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via genetic rescue and synthetic lethality in defined cell lines; single lab with multiple functional readouts","pmids":["31935221"],"is_preprint":false},{"year":2023,"finding":"The intrinsically disordered N-terminal tail of ESCO1 binds DNA with high affinity through electrostatic (charge-dependent) interactions. Neutralization of positive residues in the N-tail reduces DNA binding in vitro and reduces ESCO1 chromatin association in cells. Strikingly, disrupting DNA binding does not affect total SMC3 acetylation or sister chromatid cohesion, demonstrating that ESCO1 catalytic activity can occur independently of direct DNA binding.","method":"In vitro DNA-binding assays with purified ESCO1 N-tail, charge-neutralization mutagenesis, chromatin fractionation in cells, SMC3 acetylation assays, sister chromatid cohesion assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding assay plus mutagenesis plus cell-based chromatin association and functional assays; preprint, single lab, not yet peer-reviewed","pmids":["38106185"],"is_preprint":true}],"current_model":"ESCO1 is an acetyltransferase that acetylates the cohesin subunit SMC3 via substrate-assisted catalysis (established by crystal structure and mutagenesis), requiring interaction with the cohesin regulatory subunit Pds5 through a unique N-terminal domain; it is recruited to >11,000 cohesin-bound chromatin sites via A-box/B-box motifs throughout the cell cycle, where it stabilizes a subset of cohesinSTAG1 against WAPL-mediated removal (together with CTCF) to enable long chromatin loop formation and boundary establishment, while also silencing proximal genes; although responsible for most SMC3 acetylation, ESCO1 is largely dispensable for mitotic cohesion (which depends on ESCO2) and instead primarily regulates non-cohesive cohesin functions including chromatin architecture; additionally, ESCO1 directly acetylates α-tubulin via its catalytic activity to regulate spindle assembly in oocyte meiosis."},"narrative":{"mechanistic_narrative":"ESCO1 is an acetyltransferase that controls cohesin function and chromatin architecture by acetylating the cohesin subunit SMC3, accounting for the majority of SMC3 acetylation in vertebrate cells [PMID:28847955]. Its catalytic module is structurally homologous to the Gcn5 HAT but carries unique features including a zinc finger and an SMC3-binding loop, and it employs substrate-assisted catalysis through an active site that lacks a canonical catalytic base [PMID:27803161, PMID:27112597]. ESCO1 acts throughout interphase rather than being coupled to DNA replication: a unique conserved N-terminal domain mediates its exclusive interaction with the cohesin regulatory subunit Pds5, which is required for SMC3 acetylation and chromatin localization [PMID:26051894], while A-box and B-box motifs recruit it to over 11,000 cohesin-bound chromatin sites where it also silences proximal genes [PMID:26305936]. Functionally, ESCO1 (together with CTCF) protects a subset of cohesin-STAG1 from WAPL-mediated removal to enable formation of long chromatin loops and boundaries [PMID:32065581]. In contrast to ESCO2, which is critically required for mitotic sister chromatid cohesion, centromere integrity, and proliferation, ESCO1's acetyltransferase activity is largely dispensable for cohesion and instead governs non-cohesive cohesin activities including chromatin loop formation and transcriptional control [PMID:28847955, PMID:29196537]. Beyond cohesin, ESCO1 directly acetylates α-tubulin in oocyte meiosis to maintain microtubule stability and proper spindle assembly [PMID:29361031].","teleology":[{"year":2015,"claim":"Established how ESCO1 is targeted to chromatin and what its essential cofactor is, distinguishing it mechanistically from ESCO2.","evidence":"Co-IP, Pds5 depletion, domain mapping and cell-cycle-staged acetylation assays in mammalian cells; ChIP-seq with motif-deletion mutants","pmids":["26051894","26305936"],"confidence":"High","gaps":["How A-box/B-box motifs read cohesin-bound sites mechanistically is undefined","Relationship between Pds5 binding and motif-based recruitment not resolved"]},{"year":2016,"claim":"Defined the catalytic mechanism and structural architecture of ESCO1, showing it uses substrate-assisted catalysis without a canonical catalytic base.","evidence":"X-ray crystallography of the ZnF–acetyltransferase domain alone and with acetyl-CoA, SAXS, structure-based mutagenesis, and in vivo yeast Smc3 mutant validation","pmids":["27803161","27112597"],"confidence":"High","gaps":["No structure of ESCO1 bound to the SMC3 substrate","Functional significance of the solution dimer in cells unclear"]},{"year":2017,"claim":"Resolved the division of labor between the two ESCO paralogs, showing ESCO1 does most SMC3 acetylation but is dispensable for cohesion while ESCO2 is essential.","evidence":"ESCO1/ESCO2 gene inactivation, cohesion and acetylation assays, and domain-swap rescue in vertebrate cells; DT40 multi-gene epistasis","pmids":["28847955","29196537"],"confidence":"High","gaps":["Molecular basis for ESCO2-specific cohesion function not fully mapped","How ESCO1-dependent acetylation selectively affects non-cohesive cohesin is unclear"]},{"year":2018,"claim":"Extended ESCO1 substrate range beyond cohesin by showing it directly acetylates α-tubulin to regulate meiotic spindle assembly.","evidence":"siRNA depletion in mouse oocytes, Co-IP, rescue with catalytic-mutant ESCO1, nocodazole assay, and in vitro acetylation of an α-tubulin peptide with purified protein","pmids":["29361031"],"confidence":"High","gaps":["Whether tubulin acetylation occurs in somatic cells unknown","Acetylated lysine site on α-tubulin not defined"]},{"year":2019,"claim":"Confirmed the spindle-associated tubulin-acetylation role of ESCO1 in a second species and reinforced its spatial separation from ESCO2.","evidence":"siRNA depletion, immunofluorescence localization, Co-IP and acetylated α-tubulin quantification in porcine oocytes","pmids":["31387516"],"confidence":"Medium","gaps":["Same lab lineage as mouse study; independent validation limited","Direct catalytic test in porcine system not performed"]},{"year":2020,"claim":"Placed ESCO1 in the chromatin-loop pathway, showing it stabilizes a CTCF-associated cohesin-STAG1 pool against WAPL to enable long loops, and distinguished its cohesin fraction from ESCO2/DDX11.","evidence":"Cohesin residence-time measurement, ESCO1/CTCF depletion and boundary analysis; synthetic-lethality and WAPL-rescue assays in patient-derived cells","pmids":["32065581","31935221"],"confidence":"Medium","gaps":["Mechanism by which acetylation confers WAPL resistance on specific loops not defined","How ESCO1 vs ESCO2 cohesin pools are partitioned molecularly is unresolved"]},{"year":2023,"claim":"Tested whether ESCO1's intrinsic DNA binding drives its catalytic function, finding it contributes to chromatin association but is dispensable for SMC3 acetylation and cohesion.","evidence":"In vitro DNA-binding assays with purified N-tail, charge-neutralization mutagenesis, chromatin fractionation, acetylation and cohesion assays (preprint)","pmids":["38106185"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Functional role of the N-tail DNA binding (if not for catalysis) undefined"]},{"year":null,"claim":"How ESCO1 selectively directs SMC3 acetylation toward non-cohesive, architectural cohesin functions while ESCO2 supports cohesion remains mechanistically unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of ESCO1 engaging chromatin-bound cohesin","Determinants of cohesin-pool selectivity unknown","Physiological scope of tubulin acetylation beyond oocytes unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1,4,5,6]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,6]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[10]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[2,3]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,6]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[6,7]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,8]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3]}],"complexes":["cohesin"],"partners":["SMC3","PDS5","RAD21","CTCF","TUBA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5FWF5","full_name":"N-acetyltransferase ESCO1","aliases":["CTF7 homolog 1","Establishment factor-like protein 1","EFO1","EFO1p","hEFO1","Establishment of cohesion 1 homolog 1","ECO1 homolog 1","ESO1 homolog 1"],"length_aa":840,"mass_kda":95.0,"function":"Acetyltransferase required for the establishment of sister chromatid cohesion (PubMed:15958495, PubMed:18614053). Couples the processes of cohesion and DNA replication to ensure that only sister chromatids become paired together. In contrast to the structural cohesins, the deposition and establishment factors are required only during S phase. Acts by mediating the acetylation of cohesin component SMC3 (PubMed:18614053)","subcellular_location":"Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q5FWF5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ESCO1","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CALM1","stoichiometry":0.2},{"gene":"CALM2","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ESCO1","total_profiled":1310},"omim":[{"mim_id":"613203","title":"DNA REPLICATION AND SISTER CHROMATID COHESION 1; DSCC1","url":"https://www.omim.org/entry/613203"},{"mim_id":"613202","title":"CHROMOSOME TRANSMISSION FIDELITY FACTOR 8; CHTF8","url":"https://www.omim.org/entry/613202"},{"mim_id":"613201","title":"CHROMOSOME TRANSMISSION FIDELITY FACTOR 18; CHTF18","url":"https://www.omim.org/entry/613201"},{"mim_id":"613200","title":"PDS5 COHESIN-ASSOCIATED FACTOR A; PDS5A","url":"https://www.omim.org/entry/613200"},{"mim_id":"610754","title":"WAPL COHESIN RELEASE FACTOR; WAPL","url":"https://www.omim.org/entry/610754"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ESCO1"},"hgnc":{"alias_symbol":["ESO1","EFO1","KIAA1911"],"prev_symbol":[]},"alphafold":{"accession":"Q5FWF5","domains":[{"cath_id":"-","chopping":"615-648","consensus_level":"medium","plddt":91.1818,"start":615,"end":648},{"cath_id":"3.40.630.30","chopping":"653-835","consensus_level":"high","plddt":88.647,"start":653,"end":835}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5FWF5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5FWF5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5FWF5-F1-predicted_aligned_error_v6.png","plddt_mean":52.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ESCO1","jax_strain_url":"https://www.jax.org/strain/search?query=ESCO1"},"sequence":{"accession":"Q5FWF5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5FWF5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5FWF5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5FWF5"}},"corpus_meta":[{"pmid":"32065581","id":"PMC_32065581","title":"ESCO1 and CTCF enable formation of long chromatin loops by protecting cohesinSTAG1 from WAPL.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/32065581","citation_count":134,"is_preprint":false},{"pmid":"28847955","id":"PMC_28847955","title":"Esco1 and Esco2 regulate distinct cohesin functions during cell cycle progression.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28847955","citation_count":82,"is_preprint":false},{"pmid":"26051894","id":"PMC_26051894","title":"Esco1 Acetylates Cohesin via a Mechanism Different from That of Esco2.","date":"2015","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/26051894","citation_count":78,"is_preprint":false},{"pmid":"26305936","id":"PMC_26305936","title":"Cohesin recruits the Esco1 acetyltransferase genome wide to repress transcription and promote cohesion in somatic cells.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/26305936","citation_count":35,"is_preprint":false},{"pmid":"29361031","id":"PMC_29361031","title":"The cohesion establishment factor Esco1 acetylates α-tubulin to ensure proper spindle assembly in oocyte meiosis.","date":"2018","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/29361031","citation_count":35,"is_preprint":false},{"pmid":"29196537","id":"PMC_29196537","title":"ESCO1/2's roles in chromosome structure and interphase chromatin organization.","date":"2017","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/29196537","citation_count":34,"is_preprint":false},{"pmid":"23755103","id":"PMC_23755103","title":"Sequencing of candidate chromosome instability genes in endometrial cancers reveals somatic mutations in ESCO1, CHTF18, and MRE11A.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23755103","citation_count":27,"is_preprint":false},{"pmid":"31935221","id":"PMC_31935221","title":"Non-redundant roles in sister chromatid cohesion of the DNA helicase DDX11 and the SMC3 acetyl transferases ESCO1 and ESCO2.","date":"2020","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/31935221","citation_count":16,"is_preprint":false},{"pmid":"26547586","id":"PMC_26547586","title":"Increased expression of ESCO1 is correlated with poor patient survival and its role in human bladder cancer.","date":"2015","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26547586","citation_count":13,"is_preprint":false},{"pmid":"27803161","id":"PMC_27803161","title":"Molecular Basis for Cohesin Acetylation by Establishment of Sister Chromatid Cohesion N-Acetyltransferase ESCO1.","date":"2016","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27803161","citation_count":13,"is_preprint":false},{"pmid":"27112597","id":"PMC_27112597","title":"Sister Chromatid Cohesion Establishment Factor ESCO1 Operates by Substrate-Assisted Catalysis.","date":"2016","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/27112597","citation_count":10,"is_preprint":false},{"pmid":"31387516","id":"PMC_31387516","title":"Distinct roles of cohesin acetyltransferases Esco1 and Esco2 in porcine oocyte meiosis I.","date":"2019","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/31387516","citation_count":3,"is_preprint":false},{"pmid":"38106185","id":"PMC_38106185","title":"The intrinsically disordered tail of ESCO1 binds DNA in a charge-dependent manner.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38106185","citation_count":0,"is_preprint":false},{"pmid":"39956919","id":"PMC_39956919","title":"ESCO1 as a novel predictive biomarker and potential therapeutic target in renal cell carcinoma.","date":"2025","source":"Tumori","url":"https://pubmed.ncbi.nlm.nih.gov/39956919","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8618,"output_tokens":3448,"usd":0.038787,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11104,"output_tokens":2942,"usd":0.064535,"stage2_stop_reason":"end_turn"},"total_usd":0.103322,"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\": 2020,\n      \"finding\": \"ESCO1 acetylates cohesinSTAG1 complexes, and together with CTCF protects a subset of cohesinSTAG1 from removal by WAPL, enabling formation of long and presumably long-lived chromatin loops. ESCO1 contributes to boundary formation in chromatin looping.\",\n      \"method\": \"Cell-based assays in mammalian G1-phase cells measuring cohesin chromatin residence time, CTCF and ESCO1 depletion experiments, chromatin fractionation, and loop boundary analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (residence time measurement, depletion of ESCO1 and CTCF, boundary formation analysis) establishing pathway position; independently consistent with other cohesin acetylation studies\",\n      \"pmids\": [\"32065581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ESCO1 is responsible for the majority of SMC3 acetylation in vertebrate cells, but its acetyltransferase activity is largely dispensable for mitotic sister chromatid cohesion; instead, ESCO1-dependent SMC3 modification primarily regulates non-cohesive cohesin activities (DNA repair, transcriptional control, chromosome loop formation/stabilization). Cohesion establishment is critically dependent on ESCO2, mediated by sequences in ESCO2's N-terminus.\",\n      \"method\": \"ESCO1 and ESCO2 gene inactivation in vertebrate cells, sister chromatid cohesion assays, SMC3 acetylation measurements, domain-swap rescue experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO/KD with defined phenotypic readouts and domain-swap rescue; findings replicated across multiple complementary approaches in the same study and consistent with other publications\",\n      \"pmids\": [\"28847955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ESCO1 requires the cohesin regulatory subunit Pds5 (bound to Rad21) for SMC3 acetylation and sororin stabilization on chromatin. Pds5 interacts exclusively with ESCO1 (not ESCO2) via a unique and conserved N-terminal domain of ESCO1, and this interaction is essential for SMC3 acetylation and sister chromatid cohesion. ESCO1 localizes to cohesin sites on chromosomes throughout interphase in a Pds5-interaction-dependent manner and can acetylate SMC3 independently of DNA replication.\",\n      \"method\": \"Co-immunoprecipitation, Pds5 depletion experiments, chromosome localization assays (ChIP/immunofluorescence), domain mapping with ESCO1 mutants, cell-cycle-staged SMC3 acetylation assays\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction mapping, domain-dependency experiments, and multiple functional readouts (acetylation, cohesion, localization) in a single focused study\",\n      \"pmids\": [\"26051894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ESCO1 is recruited by cohesin to over 11,000 chromatin sites genome-wide throughout the cell cycle via two short N-terminal motifs (A-box and B-box) unique to ESCO1 orthologs. Deletion of either motif causes derepression of ESCO1-proximal genes and functionally uncouples cohesion from SMC3 acetylation. Distinct ESCO1 mutations can separate its roles in cohesion establishment versus gene silencing.\",\n      \"method\": \"ChIP-seq for ESCO1 and cohesin genome-wide, cell-cycle-staged chromatin recruitment, motif-deletion mutant analysis, gene expression assays (derepression), and sister chromatid cohesion assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq combined with domain-deletion functional rescue experiments, multiple orthogonal readouts (chromatin binding, gene expression, cohesion)\",\n      \"pmids\": [\"26305936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"X-ray crystal structure of the ESCO1 zinc finger–acetyltransferase domain reveals structural homology to the Gcn5 HAT but with unique additional features including a zinc finger and an ~40-residue loop region involved in protein stability and SMC3 substrate binding. Structure-based mutagenesis identified key residues for substrate binding and catalysis, and rationalized disease-associated mutation effects.\",\n      \"method\": \"X-ray crystallography, structure-based mutagenesis, biochemical acetyltransferase assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure combined with mutagenesis and biochemical characterization in one study; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"27803161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structure of the ESCO1 acetyltransferase domain in complex with acetyl-CoA shows the active site lacks a canonical catalytic base. Mutation of surface glutamate E789 (near automodification target K803) strongly reduces ESCO1 autoacetylation. In vivo evidence (budding yeast Smc3 D114 mutant) indicates ESCO1 uses substrate-assisted catalysis for cohesion establishment. SAXS reveals ESCO1 is a dimer in solution.\",\n      \"method\": \"X-ray crystallography, SAXS, site-directed mutagenesis, in vivo yeast Smc3 acetylation assays\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with acetyl-CoA, SAXS for solution state, mutagenesis, and in vivo validation of substrate-assisted catalysis mechanism; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"27112597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In mouse oocyte meiosis, ESCO1 localizes to both nucleus and cytoplasm, binds α-tubulin, and is required for α-tubulin acetylation to maintain microtubule stability and proper spindle assembly. Enzymatically dead ESCO1-G768D cannot restore α-tubulin acetylation or rescue spindle defects, and purified wild-type (but not mutant) ESCO1 acetylates an α-tubulin peptide in vitro.\",\n      \"method\": \"siRNA depletion in mouse oocytes, co-immunoprecipitation (ESCO1–α-tubulin), overexpression rescue with wild-type vs. catalytic mutant ESCO1, nocodazole resistance assay, in vitro acetyltransferase assay with purified ESCO1 and α-tubulin peptide\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro acetyltransferase assay with purified protein and peptide substrate, combined with Co-IP, loss-of-function and rescue experiments including catalytic mutant control; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"29361031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In porcine oocytes, ESCO1 localizes to the spindle apparatus (distinct from ESCO2, which is on chromosomes), binds α-tubulin, and is required for α-tubulin acetylation to maintain microtubule dynamics. Depletion of ESCO1 causes meiotic arrest with defective spindle/chromosome structure and reduced polar body extrusion.\",\n      \"method\": \"siRNA depletion in porcine oocytes, immunofluorescence localization, co-immunoprecipitation (ESCO1–α-tubulin), acetylated α-tubulin quantification\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and localization experiments with KD phenotype; single lab, consistent with mouse oocyte findings from same group but independent species validation\",\n      \"pmids\": [\"31387516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In chicken DT40 cells, both ESCO1 and ESCO2 promote sister chromatid cohesion, but ESCO2 is additionally and specifically required for proliferation and centromere integrity. ESCO1 overexpression can fully suppress ESCO2-loss proliferation and centromere phenotypes but only partially rescues chromosome-arm cohesion defects. Combined inactivation of ESCO1 and ESCO2 causes lethality due to compromised mitotic chromosome segregation, and this lethality is not rescued by wapl deletion or acetyl-mimicking smc3-QQ mutations, indicating cohesion establishment is linked to interphase chromatin architecture.\",\n      \"method\": \"Conditional DT40 cell knockouts of ESCO1, ESCO2, WAPL, and SMC3 acetylation mutants; epistasis analysis; mitotic chromosome analysis; proliferation assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multi-gene epistasis analysis in defined genetic backgrounds with multiple phenotypic readouts; replicated across several mutant combinations\",\n      \"pmids\": [\"29196537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In Warsaw Breakage Syndrome (WABS) cells lacking DDX11, residual sister chromatid cohesion (SCC) depends predominantly on ESCO2, not ESCO1. Reciprocally, Roberts Syndrome cells (lacking ESCO2) depend on DDX11 for residual SCC. Synthetic lethality between DDX11 and ESCO2 (but not ESCO1 and DDX11) is rescued by WAPL knockdown, placing ESCO1 and ESCO2 on different but related cohesin fractions.\",\n      \"method\": \"SCC assays in patient-derived cells, siRNA knockdowns, synthetic lethality analysis, mitotic delay quantification, WAPL rescue experiments, cDNA rescue with human/mouse constructs and DDX11 DNA-binding mutant\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via genetic rescue and synthetic lethality in defined cell lines; single lab with multiple functional readouts\",\n      \"pmids\": [\"31935221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The intrinsically disordered N-terminal tail of ESCO1 binds DNA with high affinity through electrostatic (charge-dependent) interactions. Neutralization of positive residues in the N-tail reduces DNA binding in vitro and reduces ESCO1 chromatin association in cells. Strikingly, disrupting DNA binding does not affect total SMC3 acetylation or sister chromatid cohesion, demonstrating that ESCO1 catalytic activity can occur independently of direct DNA binding.\",\n      \"method\": \"In vitro DNA-binding assays with purified ESCO1 N-tail, charge-neutralization mutagenesis, chromatin fractionation in cells, SMC3 acetylation assays, sister chromatid cohesion assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding assay plus mutagenesis plus cell-based chromatin association and functional assays; preprint, single lab, not yet peer-reviewed\",\n      \"pmids\": [\"38106185\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ESCO1 is an acetyltransferase that acetylates the cohesin subunit SMC3 via substrate-assisted catalysis (established by crystal structure and mutagenesis), requiring interaction with the cohesin regulatory subunit Pds5 through a unique N-terminal domain; it is recruited to >11,000 cohesin-bound chromatin sites via A-box/B-box motifs throughout the cell cycle, where it stabilizes a subset of cohesinSTAG1 against WAPL-mediated removal (together with CTCF) to enable long chromatin loop formation and boundary establishment, while also silencing proximal genes; although responsible for most SMC3 acetylation, ESCO1 is largely dispensable for mitotic cohesion (which depends on ESCO2) and instead primarily regulates non-cohesive cohesin functions including chromatin architecture; additionally, ESCO1 directly acetylates α-tubulin via its catalytic activity to regulate spindle assembly in oocyte meiosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ESCO1 is an acetyltransferase that controls cohesin function and chromatin architecture by acetylating the cohesin subunit SMC3, accounting for the majority of SMC3 acetylation in vertebrate cells [#1]. Its catalytic module is structurally homologous to the Gcn5 HAT but carries unique features including a zinc finger and an SMC3-binding loop, and it employs substrate-assisted catalysis through an active site that lacks a canonical catalytic base [#4, #5]. ESCO1 acts throughout interphase rather than being coupled to DNA replication: a unique conserved N-terminal domain mediates its exclusive interaction with the cohesin regulatory subunit Pds5, which is required for SMC3 acetylation and chromatin localization [#2], while A-box and B-box motifs recruit it to over 11,000 cohesin-bound chromatin sites where it also silences proximal genes [#3]. Functionally, ESCO1 (together with CTCF) protects a subset of cohesin-STAG1 from WAPL-mediated removal to enable formation of long chromatin loops and boundaries [#0]. In contrast to ESCO2, which is critically required for mitotic sister chromatid cohesion, centromere integrity, and proliferation, ESCO1's acetyltransferase activity is largely dispensable for cohesion and instead governs non-cohesive cohesin activities including chromatin loop formation and transcriptional control [#1, #8]. Beyond cohesin, ESCO1 directly acetylates \\u03b1-tubulin in oocyte meiosis to maintain microtubule stability and proper spindle assembly [#6].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established how ESCO1 is targeted to chromatin and what its essential cofactor is, distinguishing it mechanistically from ESCO2.\",\n      \"evidence\": \"Co-IP, Pds5 depletion, domain mapping and cell-cycle-staged acetylation assays in mammalian cells; ChIP-seq with motif-deletion mutants\",\n      \"pmids\": [\"26051894\", \"26305936\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How A-box/B-box motifs read cohesin-bound sites mechanistically is undefined\", \"Relationship between Pds5 binding and motif-based recruitment not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the catalytic mechanism and structural architecture of ESCO1, showing it uses substrate-assisted catalysis without a canonical catalytic base.\",\n      \"evidence\": \"X-ray crystallography of the ZnF\\u2013acetyltransferase domain alone and with acetyl-CoA, SAXS, structure-based mutagenesis, and in vivo yeast Smc3 mutant validation\",\n      \"pmids\": [\"27803161\", \"27112597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of ESCO1 bound to the SMC3 substrate\", \"Functional significance of the solution dimer in cells unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved the division of labor between the two ESCO paralogs, showing ESCO1 does most SMC3 acetylation but is dispensable for cohesion while ESCO2 is essential.\",\n      \"evidence\": \"ESCO1/ESCO2 gene inactivation, cohesion and acetylation assays, and domain-swap rescue in vertebrate cells; DT40 multi-gene epistasis\",\n      \"pmids\": [\"28847955\", \"29196537\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for ESCO2-specific cohesion function not fully mapped\", \"How ESCO1-dependent acetylation selectively affects non-cohesive cohesin is unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended ESCO1 substrate range beyond cohesin by showing it directly acetylates \\u03b1-tubulin to regulate meiotic spindle assembly.\",\n      \"evidence\": \"siRNA depletion in mouse oocytes, Co-IP, rescue with catalytic-mutant ESCO1, nocodazole assay, and in vitro acetylation of an \\u03b1-tubulin peptide with purified protein\",\n      \"pmids\": [\"29361031\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether tubulin acetylation occurs in somatic cells unknown\", \"Acetylated lysine site on \\u03b1-tubulin not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Confirmed the spindle-associated tubulin-acetylation role of ESCO1 in a second species and reinforced its spatial separation from ESCO2.\",\n      \"evidence\": \"siRNA depletion, immunofluorescence localization, Co-IP and acetylated \\u03b1-tubulin quantification in porcine oocytes\",\n      \"pmids\": [\"31387516\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Same lab lineage as mouse study; independent validation limited\", \"Direct catalytic test in porcine system not performed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed ESCO1 in the chromatin-loop pathway, showing it stabilizes a CTCF-associated cohesin-STAG1 pool against WAPL to enable long loops, and distinguished its cohesin fraction from ESCO2/DDX11.\",\n      \"evidence\": \"Cohesin residence-time measurement, ESCO1/CTCF depletion and boundary analysis; synthetic-lethality and WAPL-rescue assays in patient-derived cells\",\n      \"pmids\": [\"32065581\", \"31935221\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which acetylation confers WAPL resistance on specific loops not defined\", \"How ESCO1 vs ESCO2 cohesin pools are partitioned molecularly is unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Tested whether ESCO1's intrinsic DNA binding drives its catalytic function, finding it contributes to chromatin association but is dispensable for SMC3 acetylation and cohesion.\",\n      \"evidence\": \"In vitro DNA-binding assays with purified N-tail, charge-neutralization mutagenesis, chromatin fractionation, acetylation and cohesion assays (preprint)\",\n      \"pmids\": [\"38106185\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Functional role of the N-tail DNA binding (if not for catalysis) undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ESCO1 selectively directs SMC3 acetylation toward non-cohesive, architectural cohesin functions while ESCO2 supports cohesion remains mechanistically unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of ESCO1 engaging chromatin-bound cohesin\", \"Determinants of cohesin-pool selectivity unknown\", \"Physiological scope of tubulin acetylation beyond oocytes unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1, 4, 5, 6]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\"cohesin\"],\n    \"partners\": [\"SMC3\", \"PDS5\", \"RAD21\", \"CTCF\", \"TUBA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}