{"gene":"SMC2","run_date":"2026-06-10T07:46:35","timeline":{"discoveries":[{"year":1995,"finding":"Smc2p (yeast SMC2 ortholog) is a nuclear 135-kDa protein essential for chromosome segregation and condensation; temperature-sensitive smc2-6 mutation causes chromosome segregation defects and partial chromosome decondensation in mitosis. Smc2p forms complexes in vivo with both Smc1p and itself, indicating capacity for multimeric assembly.","method":"Temperature-sensitive mutant analysis, in vivo co-immunoprecipitation, nuclear fractionation","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with defined chromosomal phenotype plus reciprocal co-IP, foundational study replicated by subsequent work","pmids":["7698648"],"is_preprint":false},{"year":2000,"finding":"Human hCAP-E (SMC2) forms a stable heterodimeric complex with hCAP-C (SMC4) in human cells; this hCAP-C–hCAP-E complex co-immunoprecipitates CNAP1 (a XCAP-D2 homolog), constituting the human condensin complex. Condensin association with chromosomes is mitosis-specific, with the majority sequestered in the cytoplasm during interphase, though a subpopulation remains on interphase chromosomes; during late G2/early prophase condensin foci colocalize with phosphorylated histone H3 on partially condensed chromosomes.","method":"Co-immunoprecipitation of endogenous proteins from HeLa extracts, subcellular fractionation, immunofluorescence microscopy","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP of endogenous complex, cell-cycle fractionation, and localization with functional correlation, replicated context","pmids":["10958694"],"is_preprint":false},{"year":2003,"finding":"Yeast Smc2p and Smc4p form a stable heterodimer that self-associates into heterotetramers. Neither subunit alone hydrolyzes ATP, but equimolar mixing reconstitutes ATPase activity; ATPase is unaffected by DNA. The Smc2/4 complex binds both linear and circular DNA independent of adenylate nucleotide and, at high molar ratios, promotes chiral knotting of circular DNA trapped by topoisomerase II but not supercoiling by topoisomerase I. Two DNA-bound states exist: one salt-sensitive and one salt-resistant.","method":"In vitro reconstitution of purified proteins, sedimentation equilibrium, ATPase assay, DNA-binding and DNA-topology assays, competition-displacement experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified proteins, multiple orthogonal biochemical assays in one study","pmids":["12719426"],"is_preprint":false},{"year":2005,"finding":"Yeast Smc2/4 promotes (+) chiral knotting of DNA and constrains the DNA duplex to retrace its own path, sequestering both (+) and (-) loops (approximately one per kb) without altering net writhe or twist. An ATPase-dead Smc2/4 mutant retains chiral knotting activity, demonstrating ATP hydrolysis is not required for chiral DNA compaction. At high stoichiometries Smc2/4 saturates DNA and prevents relaxation by topoisomerase I and nick closure by DNA ligase. Electron microscopy reveals two protein-DNA species: long flexible filaments and uniform rings ('doughnuts').","method":"In vitro ATPase mutant analysis, topoisomerase-trapping assay, linking-number measurement, electron microscopy of protein-DNA complexes","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ATPase site mutagenesis plus multiple orthogonal in vitro topology and EM assays in one study","pmids":["16100111"],"is_preprint":false},{"year":2015,"finding":"Cross-linking/mass spectrometry combined with molecular modelling of chicken SMC2/SMC4 reveals that the two anti-parallel coiled-coil segments can lie closely apposed along their lengths in isolated condensin and in situ in mitotic chromosomes. Cross-linking data further suggest that histones H2A and H4 interact with the condensin complex, implicating roles for these histones in condensin–chromatin interactions.","method":"Amino acid-selective chemical cross-linking coupled to mass spectrometry, homology-based molecular modelling","journal":"Open biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cross-linking MS with structural modelling, single lab but two complementary methods","pmids":["25716199"],"is_preprint":false},{"year":2016,"finding":"Smc2-Smc4 coiled-coil dimers from yeast condensin are highly flexible polymers with a persistence length of ~4 nm and can adopt multiple architectures that interconvert dynamically; SMC head domains engage not only with each other but also with the hinge domain at the opposite end of the ~45-nm coiled coil.","method":"High-speed atomic force microscopy (AFM) in liquid","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct structural imaging of native proteins with dynamic observation, single lab","pmids":["26904946"],"is_preprint":false},{"year":2010,"finding":"The human SMC2 hinge domain dimerizes with SMC4 through hinge–hinge interaction; the hinge domain with short coiled coils was crystallized and diffraction data to 2.4 Å were obtained, enabling SAD phasing for structural determination.","method":"Protein crystallization, X-ray crystallography (SAD phasing), preliminary structural analysis","journal":"Acta crystallographica Section F","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystallographic data reported as preliminary with no full structure deposited; single lab, single method","pmids":["20823528"],"is_preprint":false},{"year":2012,"finding":"SMC2 transcription is directly activated by WNT signaling through binding of the β-catenin·TCF4 transcription factor to the SMC2 promoter; the precise promoter region required for β-catenin-mediated activation was identified. SMC2 siRNA knockdown significantly reduced tumor cell proliferation in vivo in nude mice.","method":"Chromatin immunoprecipitation, promoter deletion/reporter assays, siRNA knockdown with in vivo xenograft model","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding shown by ChIP and reporter assay, in vivo functional validation, single lab","pmids":["23095742"],"is_preprint":false},{"year":2017,"finding":"A region of Nesprin-2 predicted as an SMC domain (aa 1436–1766) physically interacts with SMC2 and SMC4 (core condensin subunits) throughout the cell cycle, with particularly strong interaction during S phase; Nesprin-2 knockdown does not affect condensin distribution but causes significantly higher numbers of chromatin bridges in anaphase.","method":"Co-immunoprecipitation/pulldown, cell-cycle fractionation, siRNA knockdown with chromosome bridge quantification","journal":"International journal of cell biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP, knockdown phenotype without direct mechanistic pathway placement of SMC2","pmids":["29445399"],"is_preprint":false},{"year":2021,"finding":"MCPH1 inhibits condensin II during interphase by binding (via a short linear motif) to the NCAPG2 subunit of condensin II; fusion of SMC2 with NCAPH2 (kleisin) abrogates MCPH1-mediated inhibition of condensin II's chromatin association, paralleling the mechanism by which WAPL regulates cohesin via its kleisin interface.","method":"Mouse embryonic stem cell Mcph1 deletion, SMC2–NCAPH2 fusion protein construction, Hi-C chromosome conformation analysis, epistasis with CDK1 inhibition","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with defined fusion-protein rescue, multiple orthogonal methods (Hi-C, cell biology, pharmacological), mechanistic parallel validated","pmids":["34850681"],"is_preprint":false},{"year":2021,"finding":"SMC2 knockdown in MYCN-amplified neuroblastoma cells induces DNA damage and synergistic lethality/apoptosis; SMC2 transcription is regulated by MYCN and SMC2 cooperates with MYCN to transcriptionally regulate DNA damage response genes, revealing an interphase role for SMC2 beyond chromosome condensation.","method":"siRNA knockdown, apoptosis assays, transcriptional reporter analysis, co-regulation analysis in MYCN-amplified vs. non-amplified cells","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined apoptotic/DNA-damage phenotype and transcriptional co-regulation data, single lab","pmids":["24553121"],"is_preprint":false},{"year":2023,"finding":"Oocyte-specific conditional knockout of SMC2 in mice causes female infertility; oocyte meiotic maturation and ovulation occur normally but chromosome condensation is defective, DNA damage accumulates, pronuclei are abnormally organized, micronuclei appear in fertilized eggs, and embryo development arrests at the one-cell stage, demonstrating that maternal SMC2 is essential for embryonic development via chromosome condensation.","method":"Conditional knockout mouse model (oocyte-specific Cre), chromosome condensation assay, immunofluorescence for DNA damage markers","journal":"Journal of cellular physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean conditional KO with specific, well-defined chromosome condensation and developmental arrest phenotype","pmids":["37642322"],"is_preprint":false},{"year":2025,"finding":"AURKA phosphorylates SMC2 at T574 when pre-rRNA transcription (Pol I) is inhibited during mitosis; this phosphorylation disrupts the SMC2/SMC4 interaction and their binding to chromosomal DNA, causing chromosome segregation defects. A phosphorylation-deficient SMC2 T574A mutant rescues mitotic catastrophe caused by Pol I inhibition. Pre-rRNAs normally protect SMC2 from AURKA-mediated phosphorylation.","method":"Quantitative proteomics/mass spectrometry, co-immunoprecipitation, in vitro kinase assay, phospho-specific antibody generation, SMC2 T574A site-directed mutagenesis with rescue experiment","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with mutagenesis, phospho-specific antibody validation, and functional rescue, single lab but multiple orthogonal methods","pmids":["41203590"],"is_preprint":false},{"year":2025,"finding":"Solution AFM imaging of yeast condensin shows that head engagement upon ATP binding is coupled to hinge opening in the Smc2/Smc4 heterodimer; after ADP release, the N-terminal region of the kleisin subunit Brn1 re-associates with the Smc2 head, linking ATPase cycle steps to defined conformational states.","method":"Solution atomic force microscopy (AFM) with varying nucleotides (AMP-PNP, ATPγS, ADP, ATP), coarse-grained molecular dynamics simulation","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct structural imaging with nucleotide variation, single lab preprint, no mutagenesis validation","pmids":["bio_10.1101_2024.12.16.628603"],"is_preprint":true}],"current_model":"SMC2 (hCAP-E) is the core ATPase subunit of the condensin complex that heterodimerizes with SMC4 through their hinge domains to form a flexible V-shaped scaffold; the Smc2/4 dimer possesses a reconstituted ATPase activity (neither subunit alone is active), uses ATP binding—but not hydrolysis—to drive chiral DNA compaction by constraining DNA to retrace its path, and is regulated during interphase by MCPH1 (which blocks condensin II's SMC2–kleisin interface) and by AURKA-mediated phosphorylation at T574 (which disrupts SMC2/SMC4 interaction and chromosome binding when pre-rRNA levels fall); SMC2 is also transcriptionally activated by the WNT/β-catenin–TCF4 pathway and is essential for mitotic chromosome condensation, segregation, and embryonic development."},"narrative":{"mechanistic_narrative":"SMC2 is the core ATPase subunit of the condensin complex and is essential for mitotic and meiotic chromosome condensation and faithful segregation [PMID:7698648, PMID:37642322]. It forms a stable heterodimer with SMC4 through hinge–hinge interaction, generating a flexible, dynamically interconverting V-shaped coiled-coil scaffold that recruits non-SMC subunits such as CNAP1/CAP-D2 to constitute condensin [PMID:10958694, PMID:20823528, PMID:26904946]. ATPase activity is an emergent property of the dimer—neither SMC2 nor SMC4 alone hydrolyzes ATP, and reconstitution requires equimolar mixing [PMID:12719426]. The complex binds DNA and compacts it by constraining the duplex to retrace its own path and sequestering chiral loops; this chiral DNA compaction depends on ATP binding but not on ATP hydrolysis, as an ATPase-dead mutant retains the activity, while the nucleotide cycle drives coupled head-engagement and hinge-opening conformational transitions [PMID:12719426, PMID:16100111, PMID:bio_10.1101_2024.12.16.628603]. Condensin loading is cell-cycle regulated: the bulk of the complex is sequestered in the cytoplasm during interphase and associates with chromosomes at mitosis [PMID:10958694]. During interphase, MCPH1 restrains condensin II by blocking the SMC2–kleisin (NCAPH2) interface, a control bypassed by an SMC2–NCAPH2 fusion [PMID:34850681], and during mitosis AURKA phosphorylates SMC2 at T574 to disrupt the SMC2/SMC4 interaction and chromosomal binding when pre-rRNA levels fall, with a T574A mutant rescuing the resulting segregation catastrophe [PMID:41203590]. Beyond condensation, SMC2 has interphase functions in the DNA damage response, cooperating transcriptionally with MYCN, and its own expression is directly activated by WNT/β-catenin·TCF4 signaling [PMID:24553121, PMID:23095742].","teleology":[{"year":1995,"claim":"Established SMC2 as a nuclear protein genetically required for chromosome condensation and segregation, defining its core cellular role before any molecular mechanism was known.","evidence":"Temperature-sensitive mutant analysis and in vivo co-IP in yeast","pmids":["7698648"],"confidence":"High","gaps":["Did not identify the obligate partner subunit or biochemical activity","Multimeric assembly inferred from co-IP, not reconstituted"]},{"year":2000,"claim":"Identified the human SMC2(hCAP-E)–SMC4(hCAP-C) heterodimer and its association with CNAP1 as the condensin complex, and showed chromosome association is mitosis-specific with interphase cytoplasmic sequestration.","evidence":"Reciprocal co-IP of endogenous proteins, subcellular fractionation, and immunofluorescence in HeLa cells","pmids":["10958694"],"confidence":"High","gaps":["Did not define how condensin is loaded or activated at mitosis","Mechanism of cytoplasmic sequestration unresolved"]},{"year":2003,"claim":"Demonstrated that ATPase activity is emergent from the SMC2/SMC4 dimer and that the complex binds DNA and promotes chiral knotting, providing the first biochemical activity for the scaffold.","evidence":"In vitro reconstitution of purified yeast proteins with ATPase, DNA-binding, and topology assays","pmids":["12719426"],"confidence":"High","gaps":["Did not separate ATP binding from hydrolysis in the compaction mechanism","Physiological relevance of high molar ratios untested"]},{"year":2005,"claim":"Resolved the mechanism of DNA compaction—constraining DNA to retrace its path and sequester loops—and showed ATP hydrolysis is dispensable for chiral compaction.","evidence":"ATPase-dead mutagenesis, topoisomerase-trapping, linking-number measurement, and EM of protein-DNA species in vitro","pmids":["16100111"],"confidence":"High","gaps":["Role of ATP hydrolysis in the cell remained undefined","Did not connect filament/ring species to in vivo condensin states"]},{"year":2010,"claim":"Provided structural basis for SMC2–SMC4 dimerization by crystallizing the hinge–hinge interface.","evidence":"Crystallization and SAD-phased X-ray diffraction of the human SMC2 hinge domain","pmids":["20823528"],"confidence":"Medium","gaps":["Reported as preliminary with no full refined structure","Single domain only; full-length architecture not resolved"]},{"year":2016,"claim":"Characterized the SMC2/SMC4 coiled coils as highly flexible, dynamically interconverting polymers in which heads can engage the distal hinge, refining the mechanical model of condensin.","evidence":"High-speed AFM in liquid (2016) and cross-linking MS with molecular modelling of chicken condensin (2015)","pmids":["26904946","25716199"],"confidence":"Medium","gaps":["Functional consequence of head-hinge engagement not tested by mutagenesis","Histone H2A/H4 contacts inferred from cross-links only"]},{"year":2012,"claim":"Placed SMC2 downstream of an oncogenic transcriptional input by showing WNT/β-catenin·TCF4 directly activates the SMC2 promoter and that SMC2 supports tumor proliferation.","evidence":"ChIP, promoter reporter/deletion assays, and siRNA knockdown in a xenograft model","pmids":["23095742"],"confidence":"Medium","gaps":["Did not link transcriptional regulation to a specific condensin output","Single tumor context"]},{"year":2021,"claim":"Revealed interphase regulation of SMC2-containing condensin II by MCPH1 acting through the SMC2–kleisin interface, establishing a cohesin-like control logic.","evidence":"Mouse ESC Mcph1 deletion, SMC2–NCAPH2 fusion rescue, Hi-C, and CDK1-inhibition epistasis","pmids":["34850681"],"confidence":"High","gaps":["Structural basis of MCPH1 blockade of the SMC2 interface not resolved","Does not address condensin I regulation"]},{"year":2021,"claim":"Uncovered a non-condensation, interphase role for SMC2 in the DNA damage response through cooperation with MYCN.","evidence":"siRNA knockdown, apoptosis assays, and transcriptional co-regulation analysis in MYCN-amplified neuroblastoma cells","pmids":["24553121"],"confidence":"Medium","gaps":["Direct DNA-binding role versus transcriptional cofactor role not separated","No mechanism for SMC2–MYCN physical cooperation"]},{"year":2023,"claim":"Confirmed maternal SMC2 is essential in vivo for chromosome condensation in oocytes and for embryonic development past the one-cell stage.","evidence":"Oocyte-specific conditional knockout mouse with condensation and DNA-damage assays","pmids":["37642322"],"confidence":"High","gaps":["Did not dissect which condensin complex or partner mediates the meiotic role","Developmental arrest mechanism downstream of condensation defect unclear"]},{"year":2025,"claim":"Connected SMC2 activity to nucleolar/rRNA status via AURKA phosphorylation of T574 that disrupts SMC2/SMC4 binding to DNA, with pre-rRNA acting as a protective signal.","evidence":"Proteomics, in vitro kinase assay, phospho-specific antibody, and SMC2 T574A rescue of Pol I-inhibition-induced mitotic catastrophe","pmids":["41203590"],"confidence":"High","gaps":["Mechanism by which pre-rRNA shields T574 not defined","Single lab; physiological frequency of this regulation unclear"]},{"year":2025,"claim":"Coupled discrete steps of the ATPase cycle to defined conformational states, showing head engagement upon ATP binding drives hinge opening and that kleisin re-associates with the SMC2 head after ADP release.","evidence":"Solution AFM with nucleotide variation and coarse-grained MD simulation of yeast condensin (preprint)","pmids":["bio_10.1101_2024.12.16.628603"],"confidence":"Medium","gaps":["No mutagenesis validation of the proposed cycle","Preprint, not peer-reviewed"]},{"year":null,"claim":"How the ATP-binding-driven conformational cycle is mechanically converted into the loop sequestration and chiral compaction observed biochemically, and how interphase regulatory inputs (MCPH1, AURKA, transcription) are integrated on the same SMC2 scaffold, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model linking nucleotide state to DNA-loop geometry","Cross-talk between mitotic and interphase regulatory mechanisms uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[2,3,13]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[2,3]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,5]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,1,11]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[9]}],"complexes":["condensin","condensin II"],"partners":["SMC4","NCAPH2","MCPH1","AURKA","CNAP1","MYCN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95347","full_name":"Structural maintenance of chromosomes protein 2","aliases":["Chromosome-associated protein E","hCAP-E","XCAP-E homolog"],"length_aa":1197,"mass_kda":135.7,"function":"Central component of the condensin complex, a complex required for conversion of interphase chromatin into mitotic-like condense chromosomes. The condensin complex probably introduces positive supercoils into relaxed DNA in the presence of type I topoisomerases and converts nicked DNA into positive knotted forms in the presence of type II topoisomerases","subcellular_location":"Nucleus; Cytoplasm; Chromosome","url":"https://www.uniprot.org/uniprotkb/O95347/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SMC2","classification":"Common Essential","n_dependent_lines":1206,"n_total_lines":1208,"dependency_fraction":0.9983443708609272},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NCAPH","stoichiometry":10.0},{"gene":"ACTG1","stoichiometry":0.2},{"gene":"ATG4B","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"DNM2","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SMC2","total_profiled":1310},"omim":[{"mim_id":"615638","title":"NON-SMC CONDENSIN I COMPLEX SUBUNIT D2; NCAPD2","url":"https://www.omim.org/entry/615638"},{"mim_id":"615222","title":"SMITH-MCCORT DYSPLASIA 2; SMC2","url":"https://www.omim.org/entry/615222"},{"mim_id":"611230","title":"NON-SMC CONDENSIN II COMPLEX SUBUNIT H2; NCAPH2","url":"https://www.omim.org/entry/611230"},{"mim_id":"609276","title":"NON-SMC CONDENSIN II COMPLEX SUBUNIT D3; NCAPD3","url":"https://www.omim.org/entry/609276"},{"mim_id":"608532","title":"NON-SMC CONDENSIN II COMPLEX SUBUNIT G2; NCAPG2","url":"https://www.omim.org/entry/608532"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":24.0}],"url":"https://www.proteinatlas.org/search/SMC2"},"hgnc":{"alias_symbol":["hCAP-E","CAP-E"],"prev_symbol":["SMC2L1"]},"alphafold":{"accession":"O95347","domains":[{"cath_id":"3.40.50.300","chopping":"1-143_1107-1197","consensus_level":"medium","plddt":80.6414,"start":1,"end":1197},{"cath_id":"-","chopping":"196-250_923-981","consensus_level":"medium","plddt":78.4536,"start":196,"end":981},{"cath_id":"3.30.70.1620","chopping":"488-675","consensus_level":"medium","plddt":87.7163,"start":488,"end":675}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95347","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95347-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95347-F1-predicted_aligned_error_v6.png","plddt_mean":83.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SMC2","jax_strain_url":"https://www.jax.org/strain/search?query=SMC2"},"sequence":{"accession":"O95347","fasta_url":"https://rest.uniprot.org/uniprotkb/O95347.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95347/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95347"}},"corpus_meta":[{"pmid":"7698648","id":"PMC_7698648","title":"SMC2, 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transduced with micro-dystrophin CS1 cDNA by lentiviral vector into mdx mice.","date":"2007","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/17726457","citation_count":68,"is_preprint":false},{"pmid":"24667746","id":"PMC_24667746","title":"Bovine exome sequence analysis and targeted SNP genotyping of recessive fertility defects BH1, HH2, and HH3 reveal a putative causative mutation in SMC2 for HH3.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24667746","citation_count":58,"is_preprint":false},{"pmid":"12719426","id":"PMC_12719426","title":"Biochemical analysis of the yeast condensin Smc2/4 complex: an ATPase that promotes knotting of circular DNA.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12719426","citation_count":56,"is_preprint":false},{"pmid":"23095742","id":"PMC_23095742","title":"Human SMC2 protein, a core subunit of 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crystallization and preliminary X-ray crystallographic analysis of a human condensin SMC2 hinge domain with short coiled coils.","date":"2010","source":"Acta crystallographica. Section F, Structural biology and crystallization communications","url":"https://pubmed.ncbi.nlm.nih.gov/20823528","citation_count":2,"is_preprint":false},{"pmid":"37642322","id":"PMC_37642322","title":"Maternal SMC2 is essential for embryonic development via participating chromosome condensation in mice.","date":"2023","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/37642322","citation_count":1,"is_preprint":false},{"pmid":"40134128","id":"PMC_40134128","title":"SMC2 and Condensin II Subunits Are Essential for the Development of Hematopoietic Stem and Progenitor Cells in Zebrafish.","date":"2025","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/40134128","citation_count":1,"is_preprint":false},{"pmid":"41203590","id":"PMC_41203590","title":"Pre-rRNAs control mitosis by maintaining chromosomal segregation through protecting SMC2 from AURKA-mediated phosphorylation.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/41203590","citation_count":0,"is_preprint":false},{"pmid":"40356391","id":"PMC_40356391","title":"Deciphering Plasmodium Condensin Core Subunits of Structural Maintenance of Chromosomes 2 (SMC2) as a Putative Drug Target for Antimalarial Drug.","date":"2025","source":"Recent advances in anti-infective drug discovery","url":"https://pubmed.ncbi.nlm.nih.gov/40356391","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.12.16.628603","title":"Solution AFM imaging and coarse-grained molecular modeling of yeast condensin structural variation coupled to the ATP hydrolysis cycle","date":"2025-01-03","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.16.628603","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.18.25340532","title":"Common and rare variant genetic contributions in African Americans with autism","date":"2025-11-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.18.25340532","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16267,"output_tokens":3663,"usd":0.051873,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11490,"output_tokens":3951,"usd":0.078113,"stage2_stop_reason":"end_turn"},"total_usd":0.129986,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"Smc2p (yeast SMC2 ortholog) is a nuclear 135-kDa protein essential for chromosome segregation and condensation; temperature-sensitive smc2-6 mutation causes chromosome segregation defects and partial chromosome decondensation in mitosis. Smc2p forms complexes in vivo with both Smc1p and itself, indicating capacity for multimeric assembly.\",\n      \"method\": \"Temperature-sensitive mutant analysis, in vivo co-immunoprecipitation, nuclear fractionation\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with defined chromosomal phenotype plus reciprocal co-IP, foundational study replicated by subsequent work\",\n      \"pmids\": [\"7698648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Human hCAP-E (SMC2) forms a stable heterodimeric complex with hCAP-C (SMC4) in human cells; this hCAP-C–hCAP-E complex co-immunoprecipitates CNAP1 (a XCAP-D2 homolog), constituting the human condensin complex. Condensin association with chromosomes is mitosis-specific, with the majority sequestered in the cytoplasm during interphase, though a subpopulation remains on interphase chromosomes; during late G2/early prophase condensin foci colocalize with phosphorylated histone H3 on partially condensed chromosomes.\",\n      \"method\": \"Co-immunoprecipitation of endogenous proteins from HeLa extracts, subcellular fractionation, immunofluorescence microscopy\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP of endogenous complex, cell-cycle fractionation, and localization with functional correlation, replicated context\",\n      \"pmids\": [\"10958694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Yeast Smc2p and Smc4p form a stable heterodimer that self-associates into heterotetramers. Neither subunit alone hydrolyzes ATP, but equimolar mixing reconstitutes ATPase activity; ATPase is unaffected by DNA. The Smc2/4 complex binds both linear and circular DNA independent of adenylate nucleotide and, at high molar ratios, promotes chiral knotting of circular DNA trapped by topoisomerase II but not supercoiling by topoisomerase I. Two DNA-bound states exist: one salt-sensitive and one salt-resistant.\",\n      \"method\": \"In vitro reconstitution of purified proteins, sedimentation equilibrium, ATPase assay, DNA-binding and DNA-topology assays, competition-displacement experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified proteins, multiple orthogonal biochemical assays in one study\",\n      \"pmids\": [\"12719426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Yeast Smc2/4 promotes (+) chiral knotting of DNA and constrains the DNA duplex to retrace its own path, sequestering both (+) and (-) loops (approximately one per kb) without altering net writhe or twist. An ATPase-dead Smc2/4 mutant retains chiral knotting activity, demonstrating ATP hydrolysis is not required for chiral DNA compaction. At high stoichiometries Smc2/4 saturates DNA and prevents relaxation by topoisomerase I and nick closure by DNA ligase. Electron microscopy reveals two protein-DNA species: long flexible filaments and uniform rings ('doughnuts').\",\n      \"method\": \"In vitro ATPase mutant analysis, topoisomerase-trapping assay, linking-number measurement, electron microscopy of protein-DNA complexes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ATPase site mutagenesis plus multiple orthogonal in vitro topology and EM assays in one study\",\n      \"pmids\": [\"16100111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Cross-linking/mass spectrometry combined with molecular modelling of chicken SMC2/SMC4 reveals that the two anti-parallel coiled-coil segments can lie closely apposed along their lengths in isolated condensin and in situ in mitotic chromosomes. Cross-linking data further suggest that histones H2A and H4 interact with the condensin complex, implicating roles for these histones in condensin–chromatin interactions.\",\n      \"method\": \"Amino acid-selective chemical cross-linking coupled to mass spectrometry, homology-based molecular modelling\",\n      \"journal\": \"Open biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cross-linking MS with structural modelling, single lab but two complementary methods\",\n      \"pmids\": [\"25716199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Smc2-Smc4 coiled-coil dimers from yeast condensin are highly flexible polymers with a persistence length of ~4 nm and can adopt multiple architectures that interconvert dynamically; SMC head domains engage not only with each other but also with the hinge domain at the opposite end of the ~45-nm coiled coil.\",\n      \"method\": \"High-speed atomic force microscopy (AFM) in liquid\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct structural imaging of native proteins with dynamic observation, single lab\",\n      \"pmids\": [\"26904946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The human SMC2 hinge domain dimerizes with SMC4 through hinge–hinge interaction; the hinge domain with short coiled coils was crystallized and diffraction data to 2.4 Å were obtained, enabling SAD phasing for structural determination.\",\n      \"method\": \"Protein crystallization, X-ray crystallography (SAD phasing), preliminary structural analysis\",\n      \"journal\": \"Acta crystallographica Section F\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystallographic data reported as preliminary with no full structure deposited; single lab, single method\",\n      \"pmids\": [\"20823528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SMC2 transcription is directly activated by WNT signaling through binding of the β-catenin·TCF4 transcription factor to the SMC2 promoter; the precise promoter region required for β-catenin-mediated activation was identified. SMC2 siRNA knockdown significantly reduced tumor cell proliferation in vivo in nude mice.\",\n      \"method\": \"Chromatin immunoprecipitation, promoter deletion/reporter assays, siRNA knockdown with in vivo xenograft model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding shown by ChIP and reporter assay, in vivo functional validation, single lab\",\n      \"pmids\": [\"23095742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A region of Nesprin-2 predicted as an SMC domain (aa 1436–1766) physically interacts with SMC2 and SMC4 (core condensin subunits) throughout the cell cycle, with particularly strong interaction during S phase; Nesprin-2 knockdown does not affect condensin distribution but causes significantly higher numbers of chromatin bridges in anaphase.\",\n      \"method\": \"Co-immunoprecipitation/pulldown, cell-cycle fractionation, siRNA knockdown with chromosome bridge quantification\",\n      \"journal\": \"International journal of cell biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP, knockdown phenotype without direct mechanistic pathway placement of SMC2\",\n      \"pmids\": [\"29445399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MCPH1 inhibits condensin II during interphase by binding (via a short linear motif) to the NCAPG2 subunit of condensin II; fusion of SMC2 with NCAPH2 (kleisin) abrogates MCPH1-mediated inhibition of condensin II's chromatin association, paralleling the mechanism by which WAPL regulates cohesin via its kleisin interface.\",\n      \"method\": \"Mouse embryonic stem cell Mcph1 deletion, SMC2–NCAPH2 fusion protein construction, Hi-C chromosome conformation analysis, epistasis with CDK1 inhibition\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with defined fusion-protein rescue, multiple orthogonal methods (Hi-C, cell biology, pharmacological), mechanistic parallel validated\",\n      \"pmids\": [\"34850681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SMC2 knockdown in MYCN-amplified neuroblastoma cells induces DNA damage and synergistic lethality/apoptosis; SMC2 transcription is regulated by MYCN and SMC2 cooperates with MYCN to transcriptionally regulate DNA damage response genes, revealing an interphase role for SMC2 beyond chromosome condensation.\",\n      \"method\": \"siRNA knockdown, apoptosis assays, transcriptional reporter analysis, co-regulation analysis in MYCN-amplified vs. non-amplified cells\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined apoptotic/DNA-damage phenotype and transcriptional co-regulation data, single lab\",\n      \"pmids\": [\"24553121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Oocyte-specific conditional knockout of SMC2 in mice causes female infertility; oocyte meiotic maturation and ovulation occur normally but chromosome condensation is defective, DNA damage accumulates, pronuclei are abnormally organized, micronuclei appear in fertilized eggs, and embryo development arrests at the one-cell stage, demonstrating that maternal SMC2 is essential for embryonic development via chromosome condensation.\",\n      \"method\": \"Conditional knockout mouse model (oocyte-specific Cre), chromosome condensation assay, immunofluorescence for DNA damage markers\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean conditional KO with specific, well-defined chromosome condensation and developmental arrest phenotype\",\n      \"pmids\": [\"37642322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AURKA phosphorylates SMC2 at T574 when pre-rRNA transcription (Pol I) is inhibited during mitosis; this phosphorylation disrupts the SMC2/SMC4 interaction and their binding to chromosomal DNA, causing chromosome segregation defects. A phosphorylation-deficient SMC2 T574A mutant rescues mitotic catastrophe caused by Pol I inhibition. Pre-rRNAs normally protect SMC2 from AURKA-mediated phosphorylation.\",\n      \"method\": \"Quantitative proteomics/mass spectrometry, co-immunoprecipitation, in vitro kinase assay, phospho-specific antibody generation, SMC2 T574A site-directed mutagenesis with rescue experiment\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with mutagenesis, phospho-specific antibody validation, and functional rescue, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"41203590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Solution AFM imaging of yeast condensin shows that head engagement upon ATP binding is coupled to hinge opening in the Smc2/Smc4 heterodimer; after ADP release, the N-terminal region of the kleisin subunit Brn1 re-associates with the Smc2 head, linking ATPase cycle steps to defined conformational states.\",\n      \"method\": \"Solution atomic force microscopy (AFM) with varying nucleotides (AMP-PNP, ATPγS, ADP, ATP), coarse-grained molecular dynamics simulation\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct structural imaging with nucleotide variation, single lab preprint, no mutagenesis validation\",\n      \"pmids\": [\"bio_10.1101_2024.12.16.628603\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SMC2 (hCAP-E) is the core ATPase subunit of the condensin complex that heterodimerizes with SMC4 through their hinge domains to form a flexible V-shaped scaffold; the Smc2/4 dimer possesses a reconstituted ATPase activity (neither subunit alone is active), uses ATP binding—but not hydrolysis—to drive chiral DNA compaction by constraining DNA to retrace its path, and is regulated during interphase by MCPH1 (which blocks condensin II's SMC2–kleisin interface) and by AURKA-mediated phosphorylation at T574 (which disrupts SMC2/SMC4 interaction and chromosome binding when pre-rRNA levels fall); SMC2 is also transcriptionally activated by the WNT/β-catenin–TCF4 pathway and is essential for mitotic chromosome condensation, segregation, and embryonic development.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SMC2 is the core ATPase subunit of the condensin complex and is essential for mitotic and meiotic chromosome condensation and faithful segregation [#0, #11]. It forms a stable heterodimer with SMC4 through hinge\\u2013hinge interaction, generating a flexible, dynamically interconverting V-shaped coiled-coil scaffold that recruits non-SMC subunits such as CNAP1/CAP-D2 to constitute condensin [#1, #6, #5]. ATPase activity is an emergent property of the dimer\\u2014neither SMC2 nor SMC4 alone hydrolyzes ATP, and reconstitution requires equimolar mixing [#2]. The complex binds DNA and compacts it by constraining the duplex to retrace its own path and sequestering chiral loops; this chiral DNA compaction depends on ATP binding but not on ATP hydrolysis, as an ATPase-dead mutant retains the activity, while the nucleotide cycle drives coupled head-engagement and hinge-opening conformational transitions [#2, #3, #13]. Condensin loading is cell-cycle regulated: the bulk of the complex is sequestered in the cytoplasm during interphase and associates with chromosomes at mitosis [#1]. During interphase, MCPH1 restrains condensin II by blocking the SMC2\\u2013kleisin (NCAPH2) interface, a control bypassed by an SMC2\\u2013NCAPH2 fusion [#9], and during mitosis AURKA phosphorylates SMC2 at T574 to disrupt the SMC2/SMC4 interaction and chromosomal binding when pre-rRNA levels fall, with a T574A mutant rescuing the resulting segregation catastrophe [#12]. Beyond condensation, SMC2 has interphase functions in the DNA damage response, cooperating transcriptionally with MYCN, and its own expression is directly activated by WNT/\\u03b2-catenin\\u00b7TCF4 signaling [#10, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established SMC2 as a nuclear protein genetically required for chromosome condensation and segregation, defining its core cellular role before any molecular mechanism was known.\",\n      \"evidence\": \"Temperature-sensitive mutant analysis and in vivo co-IP in yeast\",\n      \"pmids\": [\"7698648\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the obligate partner subunit or biochemical activity\", \"Multimeric assembly inferred from co-IP, not reconstituted\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identified the human SMC2(hCAP-E)\\u2013SMC4(hCAP-C) heterodimer and its association with CNAP1 as the condensin complex, and showed chromosome association is mitosis-specific with interphase cytoplasmic sequestration.\",\n      \"evidence\": \"Reciprocal co-IP of endogenous proteins, subcellular fractionation, and immunofluorescence in HeLa cells\",\n      \"pmids\": [\"10958694\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how condensin is loaded or activated at mitosis\", \"Mechanism of cytoplasmic sequestration unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrated that ATPase activity is emergent from the SMC2/SMC4 dimer and that the complex binds DNA and promotes chiral knotting, providing the first biochemical activity for the scaffold.\",\n      \"evidence\": \"In vitro reconstitution of purified yeast proteins with ATPase, DNA-binding, and topology assays\",\n      \"pmids\": [\"12719426\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate ATP binding from hydrolysis in the compaction mechanism\", \"Physiological relevance of high molar ratios untested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolved the mechanism of DNA compaction\\u2014constraining DNA to retrace its path and sequester loops\\u2014and showed ATP hydrolysis is dispensable for chiral compaction.\",\n      \"evidence\": \"ATPase-dead mutagenesis, topoisomerase-trapping, linking-number measurement, and EM of protein-DNA species in vitro\",\n      \"pmids\": [\"16100111\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role of ATP hydrolysis in the cell remained undefined\", \"Did not connect filament/ring species to in vivo condensin states\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Provided structural basis for SMC2\\u2013SMC4 dimerization by crystallizing the hinge\\u2013hinge interface.\",\n      \"evidence\": \"Crystallization and SAD-phased X-ray diffraction of the human SMC2 hinge domain\",\n      \"pmids\": [\"20823528\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reported as preliminary with no full refined structure\", \"Single domain only; full-length architecture not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Characterized the SMC2/SMC4 coiled coils as highly flexible, dynamically interconverting polymers in which heads can engage the distal hinge, refining the mechanical model of condensin.\",\n      \"evidence\": \"High-speed AFM in liquid (2016) and cross-linking MS with molecular modelling of chicken condensin (2015)\",\n      \"pmids\": [\"26904946\", \"25716199\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of head-hinge engagement not tested by mutagenesis\", \"Histone H2A/H4 contacts inferred from cross-links only\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Placed SMC2 downstream of an oncogenic transcriptional input by showing WNT/\\u03b2-catenin\\u00b7TCF4 directly activates the SMC2 promoter and that SMC2 supports tumor proliferation.\",\n      \"evidence\": \"ChIP, promoter reporter/deletion assays, and siRNA knockdown in a xenograft model\",\n      \"pmids\": [\"23095742\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not link transcriptional regulation to a specific condensin output\", \"Single tumor context\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed interphase regulation of SMC2-containing condensin II by MCPH1 acting through the SMC2\\u2013kleisin interface, establishing a cohesin-like control logic.\",\n      \"evidence\": \"Mouse ESC Mcph1 deletion, SMC2\\u2013NCAPH2 fusion rescue, Hi-C, and CDK1-inhibition epistasis\",\n      \"pmids\": [\"34850681\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of MCPH1 blockade of the SMC2 interface not resolved\", \"Does not address condensin I regulation\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Uncovered a non-condensation, interphase role for SMC2 in the DNA damage response through cooperation with MYCN.\",\n      \"evidence\": \"siRNA knockdown, apoptosis assays, and transcriptional co-regulation analysis in MYCN-amplified neuroblastoma cells\",\n      \"pmids\": [\"24553121\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DNA-binding role versus transcriptional cofactor role not separated\", \"No mechanism for SMC2\\u2013MYCN physical cooperation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Confirmed maternal SMC2 is essential in vivo for chromosome condensation in oocytes and for embryonic development past the one-cell stage.\",\n      \"evidence\": \"Oocyte-specific conditional knockout mouse with condensation and DNA-damage assays\",\n      \"pmids\": [\"37642322\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not dissect which condensin complex or partner mediates the meiotic role\", \"Developmental arrest mechanism downstream of condensation defect unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected SMC2 activity to nucleolar/rRNA status via AURKA phosphorylation of T574 that disrupts SMC2/SMC4 binding to DNA, with pre-rRNA acting as a protective signal.\",\n      \"evidence\": \"Proteomics, in vitro kinase assay, phospho-specific antibody, and SMC2 T574A rescue of Pol I-inhibition-induced mitotic catastrophe\",\n      \"pmids\": [\"41203590\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which pre-rRNA shields T574 not defined\", \"Single lab; physiological frequency of this regulation unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Coupled discrete steps of the ATPase cycle to defined conformational states, showing head engagement upon ATP binding drives hinge opening and that kleisin re-associates with the SMC2 head after ADP release.\",\n      \"evidence\": \"Solution AFM with nucleotide variation and coarse-grained MD simulation of yeast condensin (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.12.16.628603\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mutagenesis validation of the proposed cycle\", \"Preprint, not peer-reviewed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the ATP-binding-driven conformational cycle is mechanically converted into the loop sequestration and chiral compaction observed biochemically, and how interphase regulatory inputs (MCPH1, AURKA, transcription) are integrated on the same SMC2 scaffold, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model linking nucleotide state to DNA-loop geometry\", \"Cross-talk between mitotic and interphase regulatory mechanisms uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [2, 3, 13]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1, 11]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [\"condensin\", \"condensin II\"],\n    \"partners\": [\"SMC4\", \"NCAPH2\", \"MCPH1\", \"AURKA\", \"CNAP1\", \"MYCN\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}