{"gene":"SMC1A","run_date":"2026-06-10T07:46:35","timeline":{"discoveries":[{"year":1995,"finding":"The human SB1.8/DXS423E gene (SMC1A) encodes a protein of 1233 amino acids homologous to yeast SMC1, containing an N-terminal NTP binding site, a central coiled-coil region, and a C-terminal helix-loop-helix domain — structural features shared with force-generating proteins myosin and kinesin — establishing it as a conserved chromosome segregation protein.","method":"Sequence analysis, structural comparison, chromosomal mapping","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — sequence/structural characterization with domain mapping, single study, no functional mutagenesis","pmids":["7757074"],"is_preprint":false},{"year":1995,"finding":"The human DXS423E/SMC1A gene escapes X chromosome inactivation, as demonstrated by expression in somatic cell hybrids retaining the inactive human X chromosome; this defines a new region in proximal Xp11.21 not subject to X inactivation.","method":"Somatic cell hybrid expression analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional localization via somatic cell hybrid assay, single lab, single method","pmids":["7757075"],"is_preprint":false},{"year":1995,"finding":"In contrast to the human gene, the mouse Sb1.8 (SMC1A ortholog) is subject to X inactivation, establishing species-specific difference in X-inactivation escape for this locus.","method":"Restriction enzyme analysis and sequence analysis of mRNA from mice with Searle's translocation; cell line analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct experimental demonstration in mouse model, single lab, two orthogonal methods","pmids":["7757076"],"is_preprint":false},{"year":2008,"finding":"CdLS-associated mutated SMC1A and SMC3 hinge domains bind DNA with higher affinity than wild-type proteins; CdLS cell lines with these mutations display genomic instability and sensitivity to ionizing radiation and interstrand crosslinking agents, indicating that CdLS mutations affect the dynamic association between SMC1A and DNA.","method":"In vitro DNA binding affinity assay of mutant hinge domains, genotoxic sensitivity assays on patient cell lines","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical reconstitution of DNA binding with mutant proteins plus multiple orthogonal functional assays, single lab","pmids":["18996922"],"is_preprint":false},{"year":2009,"finding":"SMC1A-related CdLS is not caused by altered levels of SMC1A transcript; both wild-type and mutant alleles are expressed, and females express ~2× more SMC1A mRNA than males. Transcriptional profiling shows distinct gene expression signatures in SMC1A mutant versus NIPBL mutant CdLS, consistent with a dominant-negative effect of mutant SMC1A protein in females.","method":"Quantitative gene expression analysis, transcriptional profiling of 23 selected genes, allelic expression analysis","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple expression methods, single lab, mechanism inferred from expression data with no direct protein functional assay","pmids":["19701948"],"is_preprint":false},{"year":2011,"finding":"SMC1A mutations at codon 496 (p.Arg496His) impair the cellular response to genotoxic treatments, establishing that this residue is required for normal DNA damage response function of SMC1A.","method":"Genotoxic sensitivity assays on patient-derived cell lines carrying specific SMC1A mutation","journal":"American journal of medical genetics. Part A","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, single mutation, functional genotoxic assay without reconstitution","pmids":["22140011"],"is_preprint":false},{"year":2016,"finding":"miR-638 directly targets SMC1A mRNA (validated by luciferase reporter assay) and suppresses SMC1A protein expression during terminal differentiation, thereby reducing DNA damage repair capacity and γH2AX recruitment to DNA break sites.","method":"Luciferase reporter assay, Western blot, γH2AX recruitment assay","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase validation of miRNA-mRNA interaction plus functional DNA repair readout, single lab","pmids":["27405111"],"is_preprint":false},{"year":2018,"finding":"Phosphorylated SMC1A (at S957 and S966) promotes hepatocellular carcinoma cell proliferation and migration; phosphomimetic mutants S957D/S966D rescue proliferation and migration defects caused by SMC1A knockdown, establishing that phosphorylation of these residues is functionally important for SMC1A oncogenic activity.","method":"SMC1A knockdown, phosphomimetic mutant re-expression, proliferation and migration assays, in vivo xenograft","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rescue experiment with phosphomimetic mutants, multiple functional assays, single lab","pmids":["29988990"],"is_preprint":false},{"year":2021,"finding":"SIRT2 physically interacts with SMC1A (identified by mass spectrometry) and deacetylates it; deacetylation of SMC1A then promotes its phosphorylation to properly drive mitosis. Inhibition of SIRT2 or sustained SMC1A-K579 acetylation causes abnormal chromosome segregation and mitotic catastrophe, establishing a deacetylation-phosphorylation regulatory axis for SMC1A in mitosis.","method":"Mass spectrometry, Co-IP, deacetylation assays, site-specific acetylation mutants, chromosome segregation assays, cell viability assays","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mass spectrometry identification of interaction, biochemical deacetylation assay, mutagenesis of acetylation site (K579), multiple orthogonal functional readouts, single lab","pmids":["33627431"],"is_preprint":false},{"year":2021,"finding":"KIAA1429 binds the 3' UTR motif of SMC1A mRNA directly and enhances SMC1A mRNA stability in an m6A-independent manner; SMC1A in turn binds the SNAIL promoter region and promotes SNAIL transcription, thereby driving EMT in breast cancer. This defines a KIAA1429/SMC1A/SNAIL axis.","method":"RNA binding protein pulldown, mRNA stability assay, chromatin binding (promoter), knockdown/overexpression functional assays, in vivo metastasis model","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA-protein binding and promoter binding demonstrated, multiple methods, single lab","pmids":["34976433"],"is_preprint":false},{"year":2023,"finding":"CdLS-associated SMC1A mutations introduced into the budding yeast SMC1A ortholog caused measurable defects in sister chromatid cohesion, mitotic progression, and DNA damage sensitivity, establishing that cohesion function is directly impaired by CdLS mutations.","method":"Yeast genetic system with CdLS mutation knock-in, sister chromatid cohesion assays, mitotic progression assays, DNA damage sensitivity assays","journal":"Genetics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution in yeast model system with multiple orthogonal functional readouts, specific CdLS mutations tested, single lab","pmids":["37650609"],"is_preprint":false},{"year":2024,"finding":"The SMC1A and SMC3 ATPase domains undergo specific but concerted structural rearrangements during the cohesin ATPase cycle: the SMC1A proximal coiled coil is conformationally stable, while SMC3's is intrinsically flexible; ATP-dependent SMC1A/SMC3 heterodimer engagement (engaged state) favors SMC3 flexibility, which is counteracted by NIPBL and DNA binding (clamped state); opening of the SMC3/RAD21 interface (open-engaged state) stiffens SMC3 and constricts the DNA-binding chamber. Interface plasticity between SMC1A and SMC3 ATPase domains enables these rearrangements while keeping the ATP gate shut.","method":"Structural characterization (cryo-EM/crystallography implied by 'characterize distinct steps'), biochemical ATPase assays, domain-specific conformational analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structural and biochemical characterization of multiple ATPase cycle states with functional validation of domain roles, single lab but multiple orthogonal approaches","pmids":["39240714"],"is_preprint":false},{"year":2025,"finding":"SMC1A physically interacts with the chromatin organizer SATB1; SATB1 deletion results in aberrant SMC1A binding and reduced chromatin contacts at co-occupied sites, establishing that SATB1 facilitates chromatin looping through direct interaction with the cohesin complex (including SMC1A) during T cell development.","method":"Co-immunoprecipitation, ChIP-seq, chromatin interaction analysis (Hi-C or similar), Satb1 knockout","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — reciprocal Co-IP with functional genomic readout, preprint only, single lab","pmids":[],"is_preprint":true},{"year":2025,"finding":"In SLE monocytes, SMC1A redistributes to active enhancers of immune/inflammatory genes and induces their transcription; SMC1A shows female-biased expression in SLE monocytes. Increased SMC1A binding at enhancers of cytokine genes (e.g., IL6) is associated with enhanced cytokine secretion, establishing SMC1A as a chromatin regulatory factor that amplifies inflammatory gene expression.","method":"ChIP-seq (SMC1A binding), chromatin accessibility and activity profiling (ATAC-seq, H3K27ac), transcriptome analysis, cytokine secretion assay","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — SMC1A ChIP-seq integrated with chromatin activity and transcriptomic data plus functional cytokine readout, single lab, multiple orthogonal methods","pmids":["41285778"],"is_preprint":false},{"year":2026,"finding":"SMC1A facilitates enhancer-promoter interactions at the Nestin locus to activate Nestin transcription in HCC; Nestin overexpression rescues malignant phenotypes after SMC1A depletion. Upstream, IGF2BP1 binds m6A-modified regions in the SMC1A 3'-UTR and stabilizes SMC1A mRNA, maintaining the SMC1A-Nestin axis.","method":"ChIP/chromatin conformation assay (enhancer-promoter interaction), SMC1A knockdown with Nestin rescue, RNA-protein binding assay (IGF2BP1-SMC1A mRNA), m6A site mapping, xenograft model","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods including chromatin interaction, rescue experiment, and m6A-RBP binding, single lab","pmids":["42170732"],"is_preprint":false}],"current_model":"SMC1A encodes a core ATPase subunit of the cohesin ring complex that undergoes specific ATP-dependent conformational rearrangements (with SMC3) to mediate DNA binding and sister chromatid cohesion; it escapes X-inactivation in humans, is phosphorylated by ATM/ATR at S957/S966 to drive proper mitosis, is deacetylated at K579 by SIRT2 to promote that phosphorylation and prevent mitotic catastrophe, and also functions as a chromatin architectural factor at enhancers to regulate inflammatory and oncogenic transcriptional programs — with CdLS-causing mutations specifically increasing DNA-binding affinity of the hinge domain and impairing cohesin dynamics and DNA damage responses."},"narrative":{"mechanistic_narrative":"SMC1A encodes a conserved ATPase subunit of the cohesin ring that mediates sister chromatid cohesion and chromosome segregation; it pairs an N-terminal NTP-binding site, a central coiled-coil, and a C-terminal helix-loop-helix domain in an architecture shared with force-generating motor proteins [PMID:7757074]. Within cohesin, the SMC1A and SMC3 ATPase domains undergo concerted, ATP-dependent conformational rearrangements: SMC1A's proximal coiled coil is conformationally stable while SMC3's is intrinsically flexible, and engagement of the heterodimer, NIPBL/DNA-driven clamping, and opening of the SMC3/RAD21 interface remodel the DNA-binding chamber through interface plasticity that keeps the ATP gate shut [PMID:39240714]. SMC1A activity is tuned by post-translational regulation in mitosis: SIRT2 binds and deacetylates SMC1A at K579, which in turn licenses its phosphorylation to drive proper chromosome segregation and prevent mitotic catastrophe [PMID:33627431]. Beyond cohesion, SMC1A acts as a chromatin architectural factor that facilitates enhancer–promoter looping, partnering with the chromatin organizer SATB1 to establish chromatin contacts and redistributing to active enhancers of inflammatory cytokine genes to amplify their transcription [PMID:41285778]. Cornelia de Lange syndrome–associated SMC1A mutations increase the DNA-binding affinity of the hinge domain and produce genomic instability with sensitivity to genotoxic agents [PMID:18996922], and engineering these mutations into the orthologous gene directly impairs sister chromatid cohesion, mitotic progression, and DNA damage tolerance [PMID:37650609]. In humans, the SMC1A locus escapes X chromosome inactivation, unlike its mouse ortholog [PMID:7757075, PMID:7757076].","teleology":[{"year":1995,"claim":"Established SMC1A's identity as a conserved chromosome segregation protein by defining its motor-like domain architecture, before any direct functional assay existed.","evidence":"Sequence analysis, structural comparison, and chromosomal mapping of the human SB1.8/DXS423E gene","pmids":["7757074"],"confidence":"Medium","gaps":["Domain assignment was inferred from homology, not biochemistry","No demonstration of cohesin assembly or ATPase activity"]},{"year":1995,"claim":"Resolved the X-inactivation status of the locus, showing the human gene escapes inactivation whereas the mouse ortholog does not, defining a species-specific dosage difference.","evidence":"Somatic cell hybrid expression analysis in human; restriction/sequence analysis in mice with Searle's translocation","pmids":["7757075","7757076"],"confidence":"Medium","gaps":["Functional consequence of escape for SMC1A dosage in cohesin not addressed","Mechanism of escape unknown"]},{"year":2008,"claim":"Showed that CdLS-causing hinge mutations alter SMC1A-DNA interaction biochemically, linking the disease to dysregulated cohesin-DNA dynamics rather than loss of expression.","evidence":"In vitro DNA binding affinity assays of mutant hinge domains plus genotoxic sensitivity assays on patient cell lines","pmids":["18996922"],"confidence":"High","gaps":["Higher DNA affinity not connected to a defined step of the ATPase cycle","Cohesion defect not directly measured in this study"]},{"year":2009,"claim":"Distinguished SMC1A-CdLS from NIPBL-CdLS at the expression level, supporting a dominant-negative mode of action for mutant SMC1A protein.","evidence":"Quantitative and allelic expression analysis with transcriptional profiling of CdLS patient samples","pmids":["19701948"],"confidence":"Medium","gaps":["Dominant-negative mechanism inferred from expression, not protein assay","Functional readout limited to transcript signatures"]},{"year":2011,"claim":"Identified a specific residue (R496) required for the SMC1A DNA damage response, extending the genotype-function map beyond the hinge.","evidence":"Genotoxic sensitivity assays on patient-derived cells carrying p.Arg496His","pmids":["22140011"],"confidence":"Medium","gaps":["Single mutation, no reconstitution","Molecular role of R496 in cohesin undefined"]},{"year":2016,"claim":"Placed SMC1A under post-transcriptional control, with miR-638 suppressing SMC1A to limit DNA damage repair capacity during differentiation.","evidence":"Luciferase reporter validation of miR-638 targeting, Western blot, and γH2AX recruitment assay","pmids":["27405111"],"confidence":"Medium","gaps":["Physiological contexts of miR-638 regulation beyond differentiation unclear","Direct cohesin consequence not measured"]},{"year":2018,"claim":"Demonstrated that phosphorylation at S957/S966 is functionally required for SMC1A's pro-proliferative, pro-migratory activity in cancer cells.","evidence":"SMC1A knockdown with phosphomimetic S957D/S966D rescue, proliferation/migration assays, and xenograft","pmids":["29988990"],"confidence":"Medium","gaps":["Upstream kinase not identified in this study","Mechanistic link from phosphorylation to motility not resolved"]},{"year":2021,"claim":"Defined a deacetylation-phosphorylation regulatory axis, showing SIRT2 deacetylation of SMC1A K579 licenses its phosphorylation to ensure faithful mitosis.","evidence":"Mass spectrometry, Co-IP, deacetylation assays, K579 acetylation mutants, and chromosome segregation/viability assays","pmids":["33627431"],"confidence":"High","gaps":["Coupling between K579 deacetylation and the specific phospho-sites not structurally defined","Whether this axis operates outside mitosis unknown"]},{"year":2021,"claim":"Established SMC1A as a sequence-specific chromatin regulator of transcription, binding the SNAIL promoter downstream of KIAA1429-mediated mRNA stabilization to drive EMT.","evidence":"RNA-protein pulldown, mRNA stability assay, promoter chromatin binding, and in vivo metastasis model in breast cancer","pmids":["34976433"],"confidence":"Medium","gaps":["Whether SNAIL activation requires intact cohesin or a non-cohesin SMC1A role unclear","Direct vs cohesin-mediated promoter occupancy not separated"]},{"year":2023,"claim":"Provided causal genetic proof that CdLS mutations directly impair cohesion function, mitotic progression, and DNA damage tolerance via knock-in to the orthologous gene.","evidence":"Budding yeast knock-in of CdLS mutations with sister chromatid cohesion, mitotic, and DNA damage sensitivity assays","pmids":["37650609"],"confidence":"High","gaps":["Yeast system may not capture human-specific regulation","Quantitative link between altered DNA affinity and cohesion loss not fully resolved"]},{"year":2024,"claim":"Resolved the conformational logic of the cohesin ATPase cycle, defining SMC1A's stable coiled coil and the engaged/clamped/open-engaged transitions that remodel the DNA-binding chamber.","evidence":"Structural characterization of distinct ATPase states with biochemical ATPase assays and domain-specific conformational analysis","pmids":["39240714"],"confidence":"High","gaps":["How CdLS hinge mutations perturb these defined states not directly tested","In-cell relevance of each state not validated"]},{"year":2025,"claim":"Connected SMC1A to chromatin looping and to inflammatory gene activation, via SATB1 partnership and enhancer redistribution in immune cells.","evidence":"Co-IP/ChIP-seq/Hi-C with Satb1 knockout (preprint); SMC1A ChIP-seq with ATAC-seq/H3K27ac, transcriptomics, and cytokine secretion in SLE monocytes","pmids":["41285778"],"confidence":"Medium","gaps":["SATB1 interaction reported only in preprint","Whether enhancer redistribution requires the full cohesin ring not established"]},{"year":2026,"claim":"Showed SMC1A facilitates enhancer-promoter contacts to activate Nestin in HCC, with IGF2BP1-mediated m6A stabilization sustaining SMC1A levels.","evidence":"Chromatin conformation assays, SMC1A knockdown with Nestin rescue, IGF2BP1-SMC1A mRNA binding, m6A mapping, and xenografts","pmids":["42170732"],"confidence":"Medium","gaps":["Selectivity of SMC1A for the Nestin locus not mechanistically explained","Relationship between this looping role and canonical cohesin function unclear"]},{"year":null,"claim":"How SMC1A's post-translational modifications and partner-directed enhancer targeting are integrated with the structurally defined ATPase cycle to switch the same protein between cohesion, DNA repair, and transcriptional architecture remains unresolved.","evidence":"No single study in the corpus unifies the regulatory, structural, and chromatin-looping roles","pmids":[],"confidence":"Low","gaps":["No structural mapping of CdLS, acetylation, or phospho-sites onto defined ATPase states","Cohesin-dependent vs independent transcriptional roles not separated","Tissue-specific control of SMC1A targeting undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[11]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[3,11]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,11]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[9,13,14]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[3,11]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[13,14]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[8,10]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[3,5,6]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[12,13,14]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[9,13,14]}],"complexes":["cohesin"],"partners":["SMC3","NIPBL","RAD21","SIRT2","SATB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14683","full_name":"Structural maintenance of chromosomes protein 1A","aliases":["Sb1.8"],"length_aa":1233,"mass_kda":143.2,"function":"Involved in chromosome cohesion during cell cycle and in DNA repair. Central component of cohesin complex. The cohesin complex is required for the cohesion of sister chromatids after DNA replication. The cohesin complex apparently forms a large proteinaceous ring within which sister chromatids can be trapped. At anaphase, the complex is cleaved and dissociates from chromatin, allowing sister chromatids to segregate. The cohesin complex may also play a role in spindle pole assembly during mitosis. Involved in DNA repair via its interaction with BRCA1 and its related phosphorylation by ATM, or via its phosphorylation by ATR. Works as a downstream effector both in the ATM/NBS1 branch and in the ATR/MSH2 branch of S-phase checkpoint","subcellular_location":"Nucleus; Chromosome; Chromosome, centromere, kinetochore","url":"https://www.uniprot.org/uniprotkb/Q14683/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SMC1A","classification":"Common Essential","n_dependent_lines":1191,"n_total_lines":1208,"dependency_fraction":0.9859271523178808},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000072501","cell_line_id":"CID001034","localizations":[{"compartment":"chromatin","grade":3},{"compartment":"nucleoplasm","grade":3},{"compartment":"nuclear_punctae","grade":1}],"interactors":[{"gene":"RAD21","stoichiometry":10.0},{"gene":"SUB1","stoichiometry":10.0},{"gene":"PDS5B","stoichiometry":10.0},{"gene":"SMC3","stoichiometry":10.0},{"gene":"STAG2","stoichiometry":10.0},{"gene":"WAPL","stoichiometry":10.0},{"gene":"ARGLU1","stoichiometry":4.0},{"gene":"PDS5A","stoichiometry":4.0},{"gene":"WAPAL","stoichiometry":4.0},{"gene":"EMC9","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001034","total_profiled":1310},"omim":[{"mim_id":"621570","title":"CORNELIA DE LANGE SYNDROME 7; CDLS7","url":"https://www.omim.org/entry/621570"},{"mim_id":"620568","title":"CORNELIA DE LANGE SYNDROME 6; CDLS6","url":"https://www.omim.org/entry/620568"},{"mim_id":"619533","title":"RAD21 COHESIN COMPLEX COMPONENT-LIKE 1; RAD21L1","url":"https://www.omim.org/entry/619533"},{"mim_id":"617680","title":"SSU72 HOMOLOG, RNA POLYMERASE II CTD PHOSPHATASE; SSU72","url":"https://www.omim.org/entry/617680"},{"mim_id":"617155","title":"SUPPRESSION OF TUMORIGENICITY 18; ST18","url":"https://www.omim.org/entry/617155"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SMC1A"},"hgnc":{"alias_symbol":["DXS423E","KIAA0178","SB1.8","Smcb"],"prev_symbol":["SMC1L1"]},"alphafold":{"accession":"Q14683","domains":[{"cath_id":"3.40.50.300","chopping":"1-133_1150-1233","consensus_level":"medium","plddt":86.5121,"start":1,"end":1233},{"cath_id":"1.10.287.1700","chopping":"256-357_800-892","consensus_level":"medium","plddt":83.1149,"start":256,"end":892},{"cath_id":"3.30.70.1620","chopping":"521-548_569-674","consensus_level":"medium","plddt":84.4881,"start":521,"end":674}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14683","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14683-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14683-F1-predicted_aligned_error_v6.png","plddt_mean":82.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SMC1A","jax_strain_url":"https://www.jax.org/strain/search?query=SMC1A"},"sequence":{"accession":"Q14683","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14683.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14683/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14683"}},"corpus_meta":[{"pmid":"17273969","id":"PMC_17273969","title":"Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of cornelia de Lange syndrome with predominant mental retardation.","date":"2007","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17273969","citation_count":416,"is_preprint":false},{"pmid":"16604071","id":"PMC_16604071","title":"X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations.","date":"2006","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16604071","citation_count":361,"is_preprint":false},{"pmid":"18996922","id":"PMC_18996922","title":"Cornelia de Lange syndrome mutations in SMC1A or SMC3 affect binding to DNA.","date":"2008","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18996922","citation_count":93,"is_preprint":false},{"pmid":"28548707","id":"PMC_28548707","title":"Phenotypes and genotypes in individuals with SMC1A variants.","date":"2017","source":"American journal of medical genetics. 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amino acids homologous to yeast SMC1, containing an N-terminal NTP binding site, a central coiled-coil region, and a C-terminal helix-loop-helix domain — structural features shared with force-generating proteins myosin and kinesin — establishing it as a conserved chromosome segregation protein.\",\n      \"method\": \"Sequence analysis, structural comparison, chromosomal mapping\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — sequence/structural characterization with domain mapping, single study, no functional mutagenesis\",\n      \"pmids\": [\"7757074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The human DXS423E/SMC1A gene escapes X chromosome inactivation, as demonstrated by expression in somatic cell hybrids retaining the inactive human X chromosome; this defines a new region in proximal Xp11.21 not subject to X inactivation.\",\n      \"method\": \"Somatic cell hybrid expression analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional localization via somatic cell hybrid assay, single lab, single method\",\n      \"pmids\": [\"7757075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"In contrast to the human gene, the mouse Sb1.8 (SMC1A ortholog) is subject to X inactivation, establishing species-specific difference in X-inactivation escape for this locus.\",\n      \"method\": \"Restriction enzyme analysis and sequence analysis of mRNA from mice with Searle's translocation; cell line analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct experimental demonstration in mouse model, single lab, two orthogonal methods\",\n      \"pmids\": [\"7757076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CdLS-associated mutated SMC1A and SMC3 hinge domains bind DNA with higher affinity than wild-type proteins; CdLS cell lines with these mutations display genomic instability and sensitivity to ionizing radiation and interstrand crosslinking agents, indicating that CdLS mutations affect the dynamic association between SMC1A and DNA.\",\n      \"method\": \"In vitro DNA binding affinity assay of mutant hinge domains, genotoxic sensitivity assays on patient cell lines\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution of DNA binding with mutant proteins plus multiple orthogonal functional assays, single lab\",\n      \"pmids\": [\"18996922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SMC1A-related CdLS is not caused by altered levels of SMC1A transcript; both wild-type and mutant alleles are expressed, and females express ~2× more SMC1A mRNA than males. Transcriptional profiling shows distinct gene expression signatures in SMC1A mutant versus NIPBL mutant CdLS, consistent with a dominant-negative effect of mutant SMC1A protein in females.\",\n      \"method\": \"Quantitative gene expression analysis, transcriptional profiling of 23 selected genes, allelic expression analysis\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple expression methods, single lab, mechanism inferred from expression data with no direct protein functional assay\",\n      \"pmids\": [\"19701948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SMC1A mutations at codon 496 (p.Arg496His) impair the cellular response to genotoxic treatments, establishing that this residue is required for normal DNA damage response function of SMC1A.\",\n      \"method\": \"Genotoxic sensitivity assays on patient-derived cell lines carrying specific SMC1A mutation\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, single mutation, functional genotoxic assay without reconstitution\",\n      \"pmids\": [\"22140011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-638 directly targets SMC1A mRNA (validated by luciferase reporter assay) and suppresses SMC1A protein expression during terminal differentiation, thereby reducing DNA damage repair capacity and γH2AX recruitment to DNA break sites.\",\n      \"method\": \"Luciferase reporter assay, Western blot, γH2AX recruitment assay\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase validation of miRNA-mRNA interaction plus functional DNA repair readout, single lab\",\n      \"pmids\": [\"27405111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Phosphorylated SMC1A (at S957 and S966) promotes hepatocellular carcinoma cell proliferation and migration; phosphomimetic mutants S957D/S966D rescue proliferation and migration defects caused by SMC1A knockdown, establishing that phosphorylation of these residues is functionally important for SMC1A oncogenic activity.\",\n      \"method\": \"SMC1A knockdown, phosphomimetic mutant re-expression, proliferation and migration assays, in vivo xenograft\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rescue experiment with phosphomimetic mutants, multiple functional assays, single lab\",\n      \"pmids\": [\"29988990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SIRT2 physically interacts with SMC1A (identified by mass spectrometry) and deacetylates it; deacetylation of SMC1A then promotes its phosphorylation to properly drive mitosis. Inhibition of SIRT2 or sustained SMC1A-K579 acetylation causes abnormal chromosome segregation and mitotic catastrophe, establishing a deacetylation-phosphorylation regulatory axis for SMC1A in mitosis.\",\n      \"method\": \"Mass spectrometry, Co-IP, deacetylation assays, site-specific acetylation mutants, chromosome segregation assays, cell viability assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mass spectrometry identification of interaction, biochemical deacetylation assay, mutagenesis of acetylation site (K579), multiple orthogonal functional readouts, single lab\",\n      \"pmids\": [\"33627431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KIAA1429 binds the 3' UTR motif of SMC1A mRNA directly and enhances SMC1A mRNA stability in an m6A-independent manner; SMC1A in turn binds the SNAIL promoter region and promotes SNAIL transcription, thereby driving EMT in breast cancer. This defines a KIAA1429/SMC1A/SNAIL axis.\",\n      \"method\": \"RNA binding protein pulldown, mRNA stability assay, chromatin binding (promoter), knockdown/overexpression functional assays, in vivo metastasis model\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA-protein binding and promoter binding demonstrated, multiple methods, single lab\",\n      \"pmids\": [\"34976433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CdLS-associated SMC1A mutations introduced into the budding yeast SMC1A ortholog caused measurable defects in sister chromatid cohesion, mitotic progression, and DNA damage sensitivity, establishing that cohesion function is directly impaired by CdLS mutations.\",\n      \"method\": \"Yeast genetic system with CdLS mutation knock-in, sister chromatid cohesion assays, mitotic progression assays, DNA damage sensitivity assays\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution in yeast model system with multiple orthogonal functional readouts, specific CdLS mutations tested, single lab\",\n      \"pmids\": [\"37650609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The SMC1A and SMC3 ATPase domains undergo specific but concerted structural rearrangements during the cohesin ATPase cycle: the SMC1A proximal coiled coil is conformationally stable, while SMC3's is intrinsically flexible; ATP-dependent SMC1A/SMC3 heterodimer engagement (engaged state) favors SMC3 flexibility, which is counteracted by NIPBL and DNA binding (clamped state); opening of the SMC3/RAD21 interface (open-engaged state) stiffens SMC3 and constricts the DNA-binding chamber. Interface plasticity between SMC1A and SMC3 ATPase domains enables these rearrangements while keeping the ATP gate shut.\",\n      \"method\": \"Structural characterization (cryo-EM/crystallography implied by 'characterize distinct steps'), biochemical ATPase assays, domain-specific conformational analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural and biochemical characterization of multiple ATPase cycle states with functional validation of domain roles, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"39240714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SMC1A physically interacts with the chromatin organizer SATB1; SATB1 deletion results in aberrant SMC1A binding and reduced chromatin contacts at co-occupied sites, establishing that SATB1 facilitates chromatin looping through direct interaction with the cohesin complex (including SMC1A) during T cell development.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, chromatin interaction analysis (Hi-C or similar), Satb1 knockout\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — reciprocal Co-IP with functional genomic readout, preprint only, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In SLE monocytes, SMC1A redistributes to active enhancers of immune/inflammatory genes and induces their transcription; SMC1A shows female-biased expression in SLE monocytes. Increased SMC1A binding at enhancers of cytokine genes (e.g., IL6) is associated with enhanced cytokine secretion, establishing SMC1A as a chromatin regulatory factor that amplifies inflammatory gene expression.\",\n      \"method\": \"ChIP-seq (SMC1A binding), chromatin accessibility and activity profiling (ATAC-seq, H3K27ac), transcriptome analysis, cytokine secretion assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — SMC1A ChIP-seq integrated with chromatin activity and transcriptomic data plus functional cytokine readout, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41285778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SMC1A facilitates enhancer-promoter interactions at the Nestin locus to activate Nestin transcription in HCC; Nestin overexpression rescues malignant phenotypes after SMC1A depletion. Upstream, IGF2BP1 binds m6A-modified regions in the SMC1A 3'-UTR and stabilizes SMC1A mRNA, maintaining the SMC1A-Nestin axis.\",\n      \"method\": \"ChIP/chromatin conformation assay (enhancer-promoter interaction), SMC1A knockdown with Nestin rescue, RNA-protein binding assay (IGF2BP1-SMC1A mRNA), m6A site mapping, xenograft model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods including chromatin interaction, rescue experiment, and m6A-RBP binding, single lab\",\n      \"pmids\": [\"42170732\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SMC1A encodes a core ATPase subunit of the cohesin ring complex that undergoes specific ATP-dependent conformational rearrangements (with SMC3) to mediate DNA binding and sister chromatid cohesion; it escapes X-inactivation in humans, is phosphorylated by ATM/ATR at S957/S966 to drive proper mitosis, is deacetylated at K579 by SIRT2 to promote that phosphorylation and prevent mitotic catastrophe, and also functions as a chromatin architectural factor at enhancers to regulate inflammatory and oncogenic transcriptional programs — with CdLS-causing mutations specifically increasing DNA-binding affinity of the hinge domain and impairing cohesin dynamics and DNA damage responses.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SMC1A encodes a conserved ATPase subunit of the cohesin ring that mediates sister chromatid cohesion and chromosome segregation; it pairs an N-terminal NTP-binding site, a central coiled-coil, and a C-terminal helix-loop-helix domain in an architecture shared with force-generating motor proteins [#0]. Within cohesin, the SMC1A and SMC3 ATPase domains undergo concerted, ATP-dependent conformational rearrangements: SMC1A's proximal coiled coil is conformationally stable while SMC3's is intrinsically flexible, and engagement of the heterodimer, NIPBL/DNA-driven clamping, and opening of the SMC3/RAD21 interface remodel the DNA-binding chamber through interface plasticity that keeps the ATP gate shut [#11]. SMC1A activity is tuned by post-translational regulation in mitosis: SIRT2 binds and deacetylates SMC1A at K579, which in turn licenses its phosphorylation to drive proper chromosome segregation and prevent mitotic catastrophe [#8]. Beyond cohesion, SMC1A acts as a chromatin architectural factor that facilitates enhancer–promoter looping, partnering with the chromatin organizer SATB1 to establish chromatin contacts [#12] and redistributing to active enhancers of inflammatory cytokine genes to amplify their transcription [#13]. Cornelia de Lange syndrome–associated SMC1A mutations increase the DNA-binding affinity of the hinge domain and produce genomic instability with sensitivity to genotoxic agents [#3], and engineering these mutations into the orthologous gene directly impairs sister chromatid cohesion, mitotic progression, and DNA damage tolerance [#10]. In humans, the SMC1A locus escapes X chromosome inactivation, unlike its mouse ortholog [#1, #2].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established SMC1A's identity as a conserved chromosome segregation protein by defining its motor-like domain architecture, before any direct functional assay existed.\",\n      \"evidence\": \"Sequence analysis, structural comparison, and chromosomal mapping of the human SB1.8/DXS423E gene\",\n      \"pmids\": [\"7757074\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Domain assignment was inferred from homology, not biochemistry\", \"No demonstration of cohesin assembly or ATPase activity\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Resolved the X-inactivation status of the locus, showing the human gene escapes inactivation whereas the mouse ortholog does not, defining a species-specific dosage difference.\",\n      \"evidence\": \"Somatic cell hybrid expression analysis in human; restriction/sequence analysis in mice with Searle's translocation\",\n      \"pmids\": [\"7757075\", \"7757076\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of escape for SMC1A dosage in cohesin not addressed\", \"Mechanism of escape unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed that CdLS-causing hinge mutations alter SMC1A-DNA interaction biochemically, linking the disease to dysregulated cohesin-DNA dynamics rather than loss of expression.\",\n      \"evidence\": \"In vitro DNA binding affinity assays of mutant hinge domains plus genotoxic sensitivity assays on patient cell lines\",\n      \"pmids\": [\"18996922\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Higher DNA affinity not connected to a defined step of the ATPase cycle\", \"Cohesion defect not directly measured in this study\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Distinguished SMC1A-CdLS from NIPBL-CdLS at the expression level, supporting a dominant-negative mode of action for mutant SMC1A protein.\",\n      \"evidence\": \"Quantitative and allelic expression analysis with transcriptional profiling of CdLS patient samples\",\n      \"pmids\": [\"19701948\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Dominant-negative mechanism inferred from expression, not protein assay\", \"Functional readout limited to transcript signatures\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified a specific residue (R496) required for the SMC1A DNA damage response, extending the genotype-function map beyond the hinge.\",\n      \"evidence\": \"Genotoxic sensitivity assays on patient-derived cells carrying p.Arg496His\",\n      \"pmids\": [\"22140011\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single mutation, no reconstitution\", \"Molecular role of R496 in cohesin undefined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed SMC1A under post-transcriptional control, with miR-638 suppressing SMC1A to limit DNA damage repair capacity during differentiation.\",\n      \"evidence\": \"Luciferase reporter validation of miR-638 targeting, Western blot, and γH2AX recruitment assay\",\n      \"pmids\": [\"27405111\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological contexts of miR-638 regulation beyond differentiation unclear\", \"Direct cohesin consequence not measured\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated that phosphorylation at S957/S966 is functionally required for SMC1A's pro-proliferative, pro-migratory activity in cancer cells.\",\n      \"evidence\": \"SMC1A knockdown with phosphomimetic S957D/S966D rescue, proliferation/migration assays, and xenograft\",\n      \"pmids\": [\"29988990\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream kinase not identified in this study\", \"Mechanistic link from phosphorylation to motility not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a deacetylation-phosphorylation regulatory axis, showing SIRT2 deacetylation of SMC1A K579 licenses its phosphorylation to ensure faithful mitosis.\",\n      \"evidence\": \"Mass spectrometry, Co-IP, deacetylation assays, K579 acetylation mutants, and chromosome segregation/viability assays\",\n      \"pmids\": [\"33627431\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coupling between K579 deacetylation and the specific phospho-sites not structurally defined\", \"Whether this axis operates outside mitosis unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established SMC1A as a sequence-specific chromatin regulator of transcription, binding the SNAIL promoter downstream of KIAA1429-mediated mRNA stabilization to drive EMT.\",\n      \"evidence\": \"RNA-protein pulldown, mRNA stability assay, promoter chromatin binding, and in vivo metastasis model in breast cancer\",\n      \"pmids\": [\"34976433\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SNAIL activation requires intact cohesin or a non-cohesin SMC1A role unclear\", \"Direct vs cohesin-mediated promoter occupancy not separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided causal genetic proof that CdLS mutations directly impair cohesion function, mitotic progression, and DNA damage tolerance via knock-in to the orthologous gene.\",\n      \"evidence\": \"Budding yeast knock-in of CdLS mutations with sister chromatid cohesion, mitotic, and DNA damage sensitivity assays\",\n      \"pmids\": [\"37650609\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Yeast system may not capture human-specific regulation\", \"Quantitative link between altered DNA affinity and cohesion loss not fully resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved the conformational logic of the cohesin ATPase cycle, defining SMC1A's stable coiled coil and the engaged/clamped/open-engaged transitions that remodel the DNA-binding chamber.\",\n      \"evidence\": \"Structural characterization of distinct ATPase states with biochemical ATPase assays and domain-specific conformational analysis\",\n      \"pmids\": [\"39240714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CdLS hinge mutations perturb these defined states not directly tested\", \"In-cell relevance of each state not validated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected SMC1A to chromatin looping and to inflammatory gene activation, via SATB1 partnership and enhancer redistribution in immune cells.\",\n      \"evidence\": \"Co-IP/ChIP-seq/Hi-C with Satb1 knockout (preprint); SMC1A ChIP-seq with ATAC-seq/H3K27ac, transcriptomics, and cytokine secretion in SLE monocytes\",\n      \"pmids\": [\"41285778\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SATB1 interaction reported only in preprint\", \"Whether enhancer redistribution requires the full cohesin ring not established\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed SMC1A facilitates enhancer-promoter contacts to activate Nestin in HCC, with IGF2BP1-mediated m6A stabilization sustaining SMC1A levels.\",\n      \"evidence\": \"Chromatin conformation assays, SMC1A knockdown with Nestin rescue, IGF2BP1-SMC1A mRNA binding, m6A mapping, and xenografts\",\n      \"pmids\": [\"42170732\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Selectivity of SMC1A for the Nestin locus not mechanistically explained\", \"Relationship between this looping role and canonical cohesin function unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SMC1A's post-translational modifications and partner-directed enhancer targeting are integrated with the structurally defined ATPase cycle to switch the same protein between cohesion, DNA repair, and transcriptional architecture remains unresolved.\",\n      \"evidence\": \"No single study in the corpus unifies the regulatory, structural, and chromatin-looping roles\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural mapping of CdLS, acetylation, or phospho-sites onto defined ATPase states\", \"Cohesin-dependent vs independent transcriptional roles not separated\", \"Tissue-specific control of SMC1A targeting undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3, 11]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 11]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [9, 13, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [3, 11]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [13, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [8, 10]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [3, 5, 6]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [12, 13, 14]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [9, 13, 14]}\n    ],\n    \"complexes\": [\"cohesin\"],\n    \"partners\": [\"SMC3\", \"NIPBL\", \"RAD21\", \"SIRT2\", \"SATB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}