{"gene":"STAG3","run_date":"2026-06-10T07:46:42","timeline":{"discoveries":[{"year":2001,"finding":"STAG3 physically interacts with SMC1 and SMC3, the structural maintenance of chromosomes proteins that are subunits of the mitotic cohesin complex, establishing STAG3 as a cohesin subunit specific to meiosis I sister chromatid arm cohesion.","method":"Co-immunoprecipitation; immunofluorescence localization in meiotic cells","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP identifying binding partners, supported by immunofluorescence showing arm-specific localization in meiosis I; replicated across multiple subsequent studies","pmids":["11483963"],"is_preprint":false},{"year":2000,"finding":"STAG3 is expressed specifically in testis and associates with the synaptonemal complex during pachytene, consistent with a cohesin-like role in chromosome pairing and maintenance of synaptonemal complex structure during meiosis.","method":"Immunolocalization in testis sections; cDNA cloning and expression analysis","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct immunolocalization experiment with functional context, single lab but consistent with subsequent mechanistic studies","pmids":["10698974"],"is_preprint":false},{"year":2014,"finding":"STAG3 is required for the stability and chromosomal axis localization of all meiosis-specific cohesin subunits (SMC1β, RAD21L, REC8); in Stag3 knockout mice, these subunits are reduced in protein level and fail to load onto chromosome axes, while the mitotic cohesin complex remains intact. Loss of STAG3 also disrupts DNA repair, homolog synapsis, pericentromeric heterochromatin clustering, and centromere cohesion, causing early prophase I arrest and apoptosis in both sexes.","method":"Knockout mouse model; immunofluorescence on meiotic spreads; western blot","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotypes, multiple orthogonal methods (western blot, immunofluorescence), replicated across multiple independent KO studies","pmids":["24992337"],"is_preprint":false},{"year":2014,"finding":"STAG3 deficiency in mice (both sexes) causes failure of bona fide axial element formation, absence of SYCP3 axial elements (which form only dot-like structures near centromeres), diffuse HORMAD1 distribution, near-complete absence of SYCP1, and impaired centromeric and telomeric sister chromatid cohesion. Centromere and telomere clustering still occurs in the absence of STAG3. The phenotype is more severe than any other single meiotic cohesin knockout, establishing STAG3 as the key meiotic STAG cohesin.","method":"Knockout mouse model; immunofluorescence on meiotic chromosome spreads","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with multiple marker readouts, independently published in same issue as a replicate study","pmids":["24797474"],"is_preprint":false},{"year":2014,"finding":"STAG3 stabilizes REC8-containing cohesin complexes; in mice with a hypomorphic Stag3 allele (severely reduced STAG3), the three α-kleisins (REC8, RAD21L, RAD21) show different dosage-dependent requirements for STAG3, and STAG3-REC8 cohesin complexes have a critical role in supporting meiotic chromosome structure, axis compaction, synapsis, and recombination.","method":"Hypomorphic mouse allele; immunofluorescence; western blot","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — hypomorphic allele with dose-response analysis, multiple orthogonal methods, published concurrently with independent KO study","pmids":["24797475"],"is_preprint":false},{"year":2014,"finding":"Male mice devoid of Stag3 exhibit meiotic arrest at a zygonema-like stage with shortening of chromosome axial/lateral elements, partial loss of centromeric cohesion at early prophase, and the ability to initiate but not complete RAD51- and DMC1-mediated double-strand break repair, demonstrating STAG3 as a crucial cohesin subunit in mammalian male gametogenesis.","method":"Knockout mouse model; immunofluorescence on meiotic spreads; RAD51/DMC1 foci analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO with defined molecular phenotype using multiple markers, independent from other 2014 studies","pmids":["24608227"],"is_preprint":false},{"year":2016,"finding":"Genetic epistasis analysis using double knockout mice shows that STAG3/REC8 cohesins are the primary cohesin complex required for centromeric cohesion and chromosome axis formation, while STAG3/RAD21L cohesins are required for normal pericentromeric heterochromatin clustering. STAG3 interacts directly with each α-kleisin subunit (REC8, RAD21L, RAD21) in primary spermatocytes.","method":"Double knockout mouse models; immunofluorescence on meiotic spreads; genetic epistasis","journal":"G3 (Bethesda, Md.)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple double KO combinations plus direct interaction data, single lab but multiple orthogonal approaches","pmids":["27172213"],"is_preprint":false},{"year":2005,"finding":"E2F6, a retinoblastoma-independent transcriptional repressor, is required to silence STAG3 (and SMC1β) in somatic cells. E2F6 binds in vivo to the STAG3 promoter through a conserved binding site, and this repression involves histone H3 methylation on lysine 9 and lysine 27.","method":"cDNA microarray comparing wild-type vs. E2f6-/- MEFs; ChIP at STAG3 promoter; re-expression rescue experiment; histone methylation analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP, rescue experiment, and microarray in combination; single lab with multiple orthogonal methods","pmids":["16236716"],"is_preprint":false},{"year":2013,"finding":"E2F6-mediated repression of Stag3 (and Smc1β) in somatic cells requires the enzymatic (SET domain) activity of Ezh2, a PRC2 complex component, and occurs independently of the de novo methyltransferase Dnmt3b. Repression is established at the transition from ESCs to epiblast stem cells, coinciding with promoter DNA methylation, though Dnmt3b is not the driver.","method":"Ezh2 SET domain deletion; Dnmt3b knockout embryoid bodies; ChIP; RT-qPCR","journal":"Epigenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function of Ezh2 with defined transcriptional readout, single lab, multiple methods","pmids":["23880518"],"is_preprint":false},{"year":2015,"finding":"In fission yeast, casein kinase 1 (CK1) phosphorylates the meiotic cohesin subunit Rec11/SA3 (the fission yeast ortholog of STAG3). This phosphorylation mediates interaction with the chromosome axis component Rec10/Red1/SCP2, thereby promoting linear element (meiotic chromosome axis) assembly and meiotic recombination, independently of sister chromatid cohesion. Expression of Rec11-Rec10 fusion protein bypasses the requirement for CK1 or cohesin phosphorylation for this process. STAG3, the mammalian functional homolog of Rec11, is also phosphorylated during meiosis.","method":"In vitro phosphorylation assay; kinase mutants; fission yeast genetics; linear element immunofluorescence; Rec11-Rec10 fusion bypass experiment","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro phosphorylation assay combined with genetic epistasis and reconstitution bypass experiment; two independent studies (PMID 25579976 and 25993311) replicate the Rec11 phosphorylation finding","pmids":["25579976","25993311"],"is_preprint":false},{"year":2018,"finding":"When expressed in HEK293 somatic cells, the meiotic kleisin REC8 has no affinity for STAG1 or STAG2 and remains cytoplasmic; however, co-expression of STAG3 is sufficient for REC8 to enter the nucleus, load onto chromatin, and functionally replace its mitotic counterpart RAD21 during sister chromatid cohesion and dissolution. REC8-STAG3 cohesin physically interacts with PDS5, WAPL, and sororin, and is susceptible to WAPL-dependent ring opening and sororin-mediated protection.","method":"Somatic cell reconstitution (HEK293); co-immunoprecipitation; immunofluorescence for nuclear localization and chromatin loading; cohesion/dissolution assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution in somatic cells with functional assays, Co-IP for binding partners, nuclear localization experiment with defined consequence; single lab but multiple orthogonal methods","pmids":["29724914"],"is_preprint":false},{"year":2019,"finding":"In-frame deletion variants in the STAG3 armadillo-type fold domain (p.293_295del and p.297_298insAsp) are pathogenic: mutant STAG3 and REC8 fail to enter the nucleus, and co-immunoprecipitation shows absence of interaction between mutant STAG3 and REC8 or SMC1A in an in vitro cell model.","method":"Fluorescence localization in transfected cells; co-immunoprecipitation of mutant vs. wild-type STAG3 with REC8 and SMC1A","journal":"Frontiers in genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and localization in cell model with disease variants; single lab, single study","pmids":["31803224"],"is_preprint":false},{"year":2017,"finding":"STAG3 uniquely accumulates on the spindle apparatus and colocalizes with microtubule fibers during mouse oocyte meiotic maturation. Morpholino-mediated depletion of Stag3 disrupts spindle assembly, chromosome alignment, kinetochore-microtubule attachment, reduces acetylated tubulin levels, and decreases microtubule resistance to depolymerizing drugs, resulting in increased aneuploidy in eggs.","method":"Morpholino knockdown in mouse oocytes; immunofluorescence for spindle and chromosome markers; tubulin acetylation western blot; cold-stable microtubule assay; FISH for aneuploidy","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple cellular readouts in oocytes; single lab with several orthogonal assays","pmids":["27906670"],"is_preprint":false},{"year":2010,"finding":"In human oocytes, cohesin subunits REC8, STAG3, SMC1β and SMC3 co-localize with the lateral element of the synaptonemal complex at prophase I, are present at centromeres and along chromosomal arms (absent from chiasmata) at metaphase I, and persist at centromeric domains from anaphase I through metaphase II, supporting roles in sister chromatid cohesion throughout human female meiosis.","method":"Immunofluorescence on human oocytes at multiple meiotic stages; co-localization with SYCP3 and shugoshin 1","journal":"Human reproduction (Oxford, England)","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct immunolocalization across multiple meiotic stages in human material, consistent with findings in mouse models; single lab","pmids":["20634189"],"is_preprint":false},{"year":2016,"finding":"Loss of STAG3 (or STAG2) expression in BRAF(V600E)-mutant melanoma cells confers resistance to BRAF inhibitors. Knockdown of STAG3 decreased sensitivity of melanoma cells and xenograft tumors to BRAFi, providing evidence for a tumor suppressor role for STAG3 in the context of MAPK signaling.","method":"shRNA knockdown in melanoma cell lines; xenograft mouse tumor model; analysis of patient tumor samples with acquired BRAFi resistance","journal":"Nature medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in cell lines and xenograft with defined pharmacological phenotype, patient sample correlates; single lab","pmids":["27500726"],"is_preprint":false},{"year":2023,"finding":"STAG3 mRNA undergoes N6-methyladenosine (m6A) modification in colorectal cancer cells, mediated by the methyltransferase METTL3 and read by the m6A reader IGF2BP2, which stabilizes STAG3 protein expression. Knockdown of METTL3 decreases both m6A levels and protein expression of STAG3, inhibiting cell proliferation and migration; these effects are rescued by STAG3 overexpression.","method":"m6A RNA immunoprecipitation (MeRIP); RIP and pulldown assays for IGF2BP2-STAG3 mRNA interaction; METTL3/IGF2BP2 knockdown and STAG3 overexpression rescue; CCK-8, clone formation, wound healing, flow cytometry; xenograft mouse model","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (MeRIP, RIP, pulldown, functional assays, in vivo) in single lab establishing m6A regulation axis","pmids":["37828232"],"is_preprint":false}],"current_model":"STAG3 is a meiosis-specific stromal antigen (SA) subunit of the cohesin complex that directly binds SMC1, SMC3, and all three meiotic α-kleisins (REC8, RAD21L, RAD21), forming the structural scaffold required for meiotic chromosome axis assembly, sister chromatid arm and centromere cohesion, homolog synapsis, and DNA double-strand break repair; its HEAT/armadillo-repeat domain mediates kleisin binding, its nuclear entry is obligately required for REC8 nuclear import, it is regulated by CK1-mediated phosphorylation (conserved from fission yeast Rec11/SA3 to mammals), and its expression in somatic cells is silenced via E2F6-PRC2 (Ezh2)-dependent histone H3K9/K27 methylation, while in cancer contexts its mRNA stability is post-transcriptionally controlled by METTL3/IGF2BP2-mediated m6A modification."},"narrative":{"mechanistic_narrative":"STAG3 is a meiosis-specific stromal antigen subunit of the cohesin complex that provides the structural scaffold for meiotic chromosome architecture, synapsis, and recombination [PMID:24992337, PMID:24797474]. It physically associates with the SMC1/SMC3 core and binds each of the three meiotic α-kleisins (REC8, RAD21L, RAD21) in spermatocytes, and these distinct STAG3-kleisin complexes carry out specialized tasks: STAG3/REC8 cohesin drives centromeric cohesion and chromosome axis formation, while STAG3/RAD21L cohesin supports pericentromeric heterochromatin clustering [PMID:11483963, PMID:27172213]. STAG3 is required for the stability and axial loading of all meiosis-specific cohesin subunits without disturbing mitotic cohesin, and its loss abolishes bona fide axial element (SYCP3) assembly, blocks SYCP1-dependent synapsis, impairs centromeric and telomeric sister chromatid cohesion, and permits initiation but not completion of RAD51/DMC1-mediated double-strand break repair, causing prophase I arrest and apoptosis in both sexes [PMID:24992337, PMID:24797474, PMID:24608227]. A key non-redundant function is nuclear delivery of its kleisin partner: STAG3 binding through its armadillo-type fold domain is obligately required for REC8 nuclear entry, chromatin loading, and engagement of the cohesin regulators PDS5, WAPL, and sororin, and in-frame deletions in this domain abolish STAG3-REC8/SMC1A interaction and block nuclear import as a cause of human meiotic disease [PMID:29724914, PMID:31803224]. Cohesin axis function is gated by CK1-mediated phosphorylation of the STAG3 ortholog Rec11, which promotes its interaction with the axis component Rec10 and linear element assembly independently of cohesion [PMID:25579976, PMID:25993311]. In somatic cells STAG3 is transcriptionally silenced by E2F6 acting with PRC2/Ezh2 through H3K9/K27 methylation [PMID:16236716, PMID:23880518]. In cancer contexts STAG3 behaves as a context-dependent factor, with loss conferring BRAF-inhibitor resistance in melanoma and METTL3/IGF2BP2-mediated m6A modification stabilizing its mRNA to promote colorectal cancer proliferation [PMID:27500726, PMID:37828232].","teleology":[{"year":2000,"claim":"Established STAG3 as a testis-restricted protein localizing to the synaptonemal complex, framing it as a candidate meiotic cohesin rather than a ubiquitous cohesin subunit.","evidence":"cDNA cloning, expression analysis, and immunolocalization in testis sections","pmids":["10698974"],"confidence":"Medium","gaps":["No direct binding partners identified","Functional requirement not tested by loss-of-function"]},{"year":2001,"claim":"Showed STAG3 physically associates with the cohesin core SMC1/SMC3 and localizes to chromosome arms in meiosis I, placing it inside the cohesin complex as a meiosis-specific arm-cohesion subunit.","evidence":"Co-immunoprecipitation and immunofluorescence in meiotic cells","pmids":["11483963"],"confidence":"High","gaps":["Kleisin partner not yet defined","Mechanism of arm-specific localization unresolved"]},{"year":2005,"claim":"Identified how STAG3 is kept off in somatic tissue, showing E2F6 binds the STAG3 promoter and represses it via H3K9/K27 methylation.","evidence":"Microarray of E2f6-/- MEFs, promoter ChIP, and rescue/histone methylation analysis","pmids":["16236716"],"confidence":"High","gaps":["Enzymatic effector of the methylation not yet defined","Developmental timing of silencing not established"]},{"year":2010,"claim":"Extended the cohesin localization model to human female meiosis, showing STAG3 co-localizes with REC8/SMC1β/SMC3 at lateral elements, arms, and centromeres across meiotic stages.","evidence":"Immunofluorescence of human oocytes at multiple meiotic stages with SYCP3 and shugoshin 1","pmids":["20634189"],"confidence":"Medium","gaps":["Descriptive localization without functional perturbation in human cells","Single lab"]},{"year":2013,"claim":"Defined the enzymatic basis of somatic silencing, showing E2F6 repression of Stag3 requires the Ezh2 SET domain and is independent of Dnmt3b.","evidence":"Ezh2 SET-domain deletion and Dnmt3b-KO embryoid bodies with ChIP and RT-qPCR","pmids":["23880518"],"confidence":"Medium","gaps":["Driver of associated promoter DNA methylation unidentified","Direct E2F6-PRC2 recruitment mechanism not shown"]},{"year":2014,"claim":"Knockout and hypomorphic mouse studies established STAG3 as the master meiotic STAG subunit required for stability and axial loading of all meiotic cohesins, axial element formation, synapsis, cohesion, and DSB repair, with kleisin-specific dosage requirements.","evidence":"Multiple independent Stag3 KO and hypomorphic mouse models with meiotic spread immunofluorescence, western blot, and RAD51/DMC1 foci analysis","pmids":["24992337","24797474","24797475","24608227"],"confidence":"High","gaps":["Molecular basis for differential kleisin dependence not resolved","Direct contribution to DSB repair step blocked not mechanistically defined"]},{"year":2016,"claim":"Genetic epistasis separated the functions of distinct STAG3-kleisin cohesins, assigning centromeric cohesion/axis formation to STAG3/REC8 and pericentromeric heterochromatin clustering to STAG3/RAD21L, and confirmed direct STAG3 binding to all three α-kleisins.","evidence":"Double-knockout mouse combinations, meiotic spread immunofluorescence, and interaction assays in primary spermatocytes","pmids":["27172213"],"confidence":"High","gaps":["Structural determinants of kleisin selectivity not defined","Mechanism coupling RAD21L cohesin to heterochromatin clustering unknown"]},{"year":2017,"claim":"Revealed a non-canonical STAG3 association with the oocyte spindle, where depletion disrupts spindle assembly, kinetochore-microtubule attachment, and tubulin stability, linking STAG3 to chromosome segregation fidelity.","evidence":"Morpholino knockdown in mouse oocytes with spindle/chromosome immunofluorescence, tubulin acetylation, cold-stable microtubule assay, and FISH aneuploidy scoring","pmids":["27906670"],"confidence":"Medium","gaps":["Whether spindle effect is cohesin-dependent or a separate role unclear","Direct STAG3-microtubule interaction not demonstrated"]},{"year":2015,"claim":"Demonstrated regulatory control of cohesin axis function by CK1 phosphorylation of the STAG3 ortholog Rec11, which licenses Rec10 binding and linear element assembly independently of cohesion.","evidence":"In vitro phosphorylation assays, kinase mutants, fission yeast genetics, and a Rec11-Rec10 fusion bypass experiment (two independent studies)","pmids":["25579976","25993311"],"confidence":"High","gaps":["Mammalian STAG3 phosphosites and the equivalent axis partner not mapped","Functional consequence of STAG3 phosphorylation in mammals untested"]},{"year":2018,"claim":"Reconstitution in somatic cells showed STAG3 is necessary and sufficient to import its kleisin REC8 into the nucleus and load it onto chromatin, where REC8-STAG3 cohesin engages PDS5, WAPL, and sororin and substitutes for mitotic RAD21.","evidence":"HEK293 reconstitution with Co-IP, nuclear localization/chromatin loading immunofluorescence, and cohesion/dissolution assays","pmids":["29724914"],"confidence":"High","gaps":["Import signal/mechanism for the STAG3-REC8 complex not mapped","Reconstitution in somatic cells may not fully recapitulate meiotic regulation"]},{"year":2019,"claim":"Connected STAG3 to human meiotic disease, showing armadillo-domain in-frame deletions abolish STAG3 binding to REC8 and SMC1A and block nuclear entry of both proteins.","evidence":"Localization and Co-IP of mutant versus wild-type STAG3 with REC8 and SMC1A in a cell model","pmids":["31803224"],"confidence":"Medium","gaps":["Single study without structural validation","Variant effects not tested in patient germ cells"]},{"year":2023,"claim":"Established post-transcriptional control of STAG3 in cancer, showing METTL3-deposited m6A read by IGF2BP2 stabilizes STAG3 mRNA to drive colorectal cancer proliferation and migration.","evidence":"MeRIP, RIP/pulldown, METTL3/IGF2BP2 knockdown with STAG3 rescue, functional assays, and xenografts","pmids":["37828232"],"confidence":"Medium","gaps":["Downstream effectors of STAG3 in colorectal cancer not defined","Relationship to its meiotic cohesin function unclear"]},{"year":null,"claim":"How phosphorylation, m6A regulation, and the somatic versus meiotic and cancer-context roles of STAG3 are mechanistically integrated, and the structural basis of its kleisin selectivity, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of STAG3-kleisin contacts","Mammalian STAG3 phosphoregulation not functionally tested","Mechanistic link between cohesin role and oncogenic/tumor-suppressive behavior absent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[10,11]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[12]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,2,3,13]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[10,11]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[2,3,5]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[10]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7,8]}],"complexes":["meiotic cohesin complex","synaptonemal complex (lateral element associated)"],"partners":["SMC1","SMC3","REC8","RAD21L","RAD21","PDS5","WAPL","SMC1A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UJ98","full_name":"Cohesin subunit SA-3","aliases":["SCC3 homolog 3","Stromal antigen 3","Stromalin-3"],"length_aa":1225,"mass_kda":139.0,"function":"Meiosis specific 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 meiosis-specific cohesin complex probably replaces mitosis specific cohesin complex when it dissociates from chromatin during prophase I","subcellular_location":"Nucleus; Chromosome; Chromosome, centromere","url":"https://www.uniprot.org/uniprotkb/Q9UJ98/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/STAG3","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/STAG3","total_profiled":1310},"omim":[{"mim_id":"619673","title":"SPERMATOGENIC FAILURE 62; SPGF62","url":"https://www.omim.org/entry/619673"},{"mim_id":"619672","title":"SPERMATOGENIC FAILURE 61; SPGF61","url":"https://www.omim.org/entry/619672"},{"mim_id":"619533","title":"RAD21 COHESIN COMPLEX COMPONENT-LIKE 1; RAD21L1","url":"https://www.omim.org/entry/619533"},{"mim_id":"617332","title":"TELOMERE REPEAT-BINDING BOUQUET FORMATION PROTEIN 1; TERB1","url":"https://www.omim.org/entry/617332"},{"mim_id":"617012","title":"POLIOVIRUS RECEPTOR-RELATED IMMUNOGLOBULIN DOMAIN-CONTAINING PROTEIN; PVRIG","url":"https://www.omim.org/entry/617012"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoli","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"testis","ntpm":49.8}],"url":"https://www.proteinatlas.org/search/STAG3"},"hgnc":{"alias_symbol":["SA3"],"prev_symbol":[]},"alphafold":{"accession":"Q9UJ98","domains":[{"cath_id":"-","chopping":"921-1057","consensus_level":"high","plddt":86.814,"start":921,"end":1057},{"cath_id":"1.25.40","chopping":"672-828","consensus_level":"medium","plddt":92.9542,"start":672,"end":828}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UJ98","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UJ98-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UJ98-F1-predicted_aligned_error_v6.png","plddt_mean":77.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=STAG3","jax_strain_url":"https://www.jax.org/strain/search?query=STAG3"},"sequence":{"accession":"Q9UJ98","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UJ98.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UJ98/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UJ98"}},"corpus_meta":[{"pmid":"11483963","id":"PMC_11483963","title":"Mammalian STAG3 is a cohesin specific to sister chromatid arms in meiosis I.","date":"2001","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/11483963","citation_count":210,"is_preprint":false},{"pmid":"10698974","id":"PMC_10698974","title":"STAG3, a novel gene encoding a protein involved in meiotic chromosome pairing and location of STAG3-related genes flanking the Williams-Beuren syndrome deletion.","date":"2000","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/10698974","citation_count":117,"is_preprint":false},{"pmid":"24992337","id":"PMC_24992337","title":"Meiosis-specific cohesin component, Stag3 is essential for maintaining centromere chromatid cohesion, and required for DNA repair and synapsis between homologous chromosomes.","date":"2014","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24992337","citation_count":107,"is_preprint":false},{"pmid":"24797474","id":"PMC_24797474","title":"Meiotic cohesin STAG3 is required for chromosome axis formation and sister chromatid cohesion.","date":"2014","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/24797474","citation_count":89,"is_preprint":false},{"pmid":"20634189","id":"PMC_20634189","title":"Dynamics of cohesin proteins REC8, STAG3, SMC1 beta and SMC3 are consistent with a role in sister chromatid cohesion during meiosis in human oocytes.","date":"2010","source":"Human reproduction (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/20634189","citation_count":89,"is_preprint":false},{"pmid":"24797475","id":"PMC_24797475","title":"STAG3-mediated stabilization of REC8 cohesin complexes promotes chromosome synapsis during meiosis.","date":"2014","source":"The EMBO 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SA3 and its symbiote.","date":"2003","source":"Journal of industrial microbiology & biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/12545389","citation_count":21,"is_preprint":false},{"pmid":"35176428","id":"PMC_35176428","title":"Novel STAG3 variant associated with primary ovarian insufficiency and non-obstructive azoospermia in an Iranian consanguineous family.","date":"2022","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/35176428","citation_count":19,"is_preprint":false},{"pmid":"29724914","id":"PMC_29724914","title":"Studying meiotic cohesin in somatic cells reveals that Rec8-containing cohesin requires Stag3 to function and is regulated by Wapl and sororin.","date":"2018","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/29724914","citation_count":18,"is_preprint":false},{"pmid":"23880518","id":"PMC_23880518","title":"E2f6-mediated repression of the meiotic Stag3 and Smc1β genes during early embryonic development requires Ezh2 and not the de novo methyltransferase Dnmt3b.","date":"2013","source":"Epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/23880518","citation_count":16,"is_preprint":false},{"pmid":"37828232","id":"PMC_37828232","title":"METTL3/IGF2BP2 axis affects the progression of colorectal cancer by regulating m6A modification of STAG3.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/37828232","citation_count":15,"is_preprint":false},{"pmid":"16790336","id":"PMC_16790336","title":"Production of an antimicrobial substance against Cryptococcus neoformans by Paenibacillus brasilensis Sa3 isolated from the rhizosphere of Kalanchoe brasiliensis.","date":"2006","source":"Microbiological research","url":"https://pubmed.ncbi.nlm.nih.gov/16790336","citation_count":14,"is_preprint":false},{"pmid":"34828315","id":"PMC_34828315","title":"A Long Contiguous Stretch of Homozygosity Disclosed a Novel STAG3 Biallelic Pathogenic Variant Causing Primary Ovarian Insufficiency: A Case Report and Review of the Literature.","date":"2021","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/34828315","citation_count":11,"is_preprint":false},{"pmid":"11599053","id":"PMC_11599053","title":"Evaluation of the Stag3 gene and the synaptonemal complex in a rat model (as/as) for male infertility.","date":"2001","source":"Molecular reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/11599053","citation_count":10,"is_preprint":false},{"pmid":"31115363","id":"PMC_31115363","title":"The association of stromal antigen 3 (STAG3) sequence variations with spermatogenic impairment in the male Korean population.","date":"2020","source":"Asian journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/31115363","citation_count":10,"is_preprint":false},{"pmid":"34497033","id":"PMC_34497033","title":"Biallelic loss of function variants in STAG3 result in primary ovarian insufficiency.","date":"2021","source":"Reproductive biomedicine online","url":"https://pubmed.ncbi.nlm.nih.gov/34497033","citation_count":8,"is_preprint":false},{"pmid":"30420384","id":"PMC_30420384","title":"Retinoic acid-induced CYP51 nuclear translocation promotes meiosis prophase I process and is correlated to the expression of REC8 and STAG3 in mice.","date":"2018","source":"Biology open","url":"https://pubmed.ncbi.nlm.nih.gov/30420384","citation_count":6,"is_preprint":false},{"pmid":"29277047","id":"PMC_29277047","title":"Association of the common SNPs in RNF212, STAG3 and RFX2 gene with male infertility with azoospermia in Chinese population.","date":"2017","source":"European journal of obstetrics, gynecology, and reproductive biology","url":"https://pubmed.ncbi.nlm.nih.gov/29277047","citation_count":5,"is_preprint":false},{"pmid":"11320322","id":"PMC_11320322","title":"Purification, crystallization and preliminary X-ray analysis of two crystal forms of ribonuclease Sa3.","date":"2001","source":"Acta crystallographica. Section D, Biological crystallography","url":"https://pubmed.ncbi.nlm.nih.gov/11320322","citation_count":5,"is_preprint":false},{"pmid":"38391498","id":"PMC_38391498","title":"The Role of Prophage ϕSa3 in the Adaption of Staphylococcus aureus ST398 Sublineages from Human to Animal Hosts.","date":"2024","source":"Antibiotics (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/38391498","citation_count":3,"is_preprint":false},{"pmid":"33980954","id":"PMC_33980954","title":"Analysis of STAG3 variants in Chinese non-obstructive azoospermia patients with germ cell maturation arrest.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33980954","citation_count":3,"is_preprint":false},{"pmid":"39932630","id":"PMC_39932630","title":"Novel STAG3 variant causes oligoasthenoteratozoospermia with high sperm aneuploidy rate.","date":"2025","source":"Journal of assisted reproduction and genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39932630","citation_count":3,"is_preprint":false},{"pmid":"35503298","id":"PMC_35503298","title":"New STAG3 gene variant as a cause of premature ovarian insufficiency.","date":"2022","source":"Revista colombiana de obstetricia y ginecologia","url":"https://pubmed.ncbi.nlm.nih.gov/35503298","citation_count":2,"is_preprint":false},{"pmid":"26648292","id":"PMC_26648292","title":"[Rab23 enhances invasion of Sa3 cutaneous squamous cell carcinoma cells via up-regulating the expression of Rac1].","date":"2015","source":"Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26648292","citation_count":2,"is_preprint":false},{"pmid":"38554835","id":"PMC_38554835","title":"Statistical modelling, optimization, and mechanistic exploration of novel ureolytic Enterobacter hormaechei IITISM-SA3 in cadmium immobilization under microbial inclusive and cell-free conditions through microbially induced calcite precipitation.","date":"2024","source":"Environmental pollution (Barking, Essex : 1987)","url":"https://pubmed.ncbi.nlm.nih.gov/38554835","citation_count":1,"is_preprint":false},{"pmid":"22086009","id":"PMC_22086009","title":"Expression of scFv SA3 against hepatoma fused with enhanced green fluorescent protein and its targeted ability in vivo.","date":"2011","source":"Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/22086009","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23644,"output_tokens":4368,"usd":0.068226,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12253,"output_tokens":4323,"usd":0.08467,"stage2_stop_reason":"end_turn"},"total_usd":0.152896,"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\": 2001,\n      \"finding\": \"STAG3 physically interacts with SMC1 and SMC3, the structural maintenance of chromosomes proteins that are subunits of the mitotic cohesin complex, establishing STAG3 as a cohesin subunit specific to meiosis I sister chromatid arm cohesion.\",\n      \"method\": \"Co-immunoprecipitation; immunofluorescence localization in meiotic cells\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP identifying binding partners, supported by immunofluorescence showing arm-specific localization in meiosis I; replicated across multiple subsequent studies\",\n      \"pmids\": [\"11483963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"STAG3 is expressed specifically in testis and associates with the synaptonemal complex during pachytene, consistent with a cohesin-like role in chromosome pairing and maintenance of synaptonemal complex structure during meiosis.\",\n      \"method\": \"Immunolocalization in testis sections; cDNA cloning and expression analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct immunolocalization experiment with functional context, single lab but consistent with subsequent mechanistic studies\",\n      \"pmids\": [\"10698974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"STAG3 is required for the stability and chromosomal axis localization of all meiosis-specific cohesin subunits (SMC1β, RAD21L, REC8); in Stag3 knockout mice, these subunits are reduced in protein level and fail to load onto chromosome axes, while the mitotic cohesin complex remains intact. Loss of STAG3 also disrupts DNA repair, homolog synapsis, pericentromeric heterochromatin clustering, and centromere cohesion, causing early prophase I arrest and apoptosis in both sexes.\",\n      \"method\": \"Knockout mouse model; immunofluorescence on meiotic spreads; western blot\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotypes, multiple orthogonal methods (western blot, immunofluorescence), replicated across multiple independent KO studies\",\n      \"pmids\": [\"24992337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"STAG3 deficiency in mice (both sexes) causes failure of bona fide axial element formation, absence of SYCP3 axial elements (which form only dot-like structures near centromeres), diffuse HORMAD1 distribution, near-complete absence of SYCP1, and impaired centromeric and telomeric sister chromatid cohesion. Centromere and telomere clustering still occurs in the absence of STAG3. The phenotype is more severe than any other single meiotic cohesin knockout, establishing STAG3 as the key meiotic STAG cohesin.\",\n      \"method\": \"Knockout mouse model; immunofluorescence on meiotic chromosome spreads\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with multiple marker readouts, independently published in same issue as a replicate study\",\n      \"pmids\": [\"24797474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"STAG3 stabilizes REC8-containing cohesin complexes; in mice with a hypomorphic Stag3 allele (severely reduced STAG3), the three α-kleisins (REC8, RAD21L, RAD21) show different dosage-dependent requirements for STAG3, and STAG3-REC8 cohesin complexes have a critical role in supporting meiotic chromosome structure, axis compaction, synapsis, and recombination.\",\n      \"method\": \"Hypomorphic mouse allele; immunofluorescence; western blot\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — hypomorphic allele with dose-response analysis, multiple orthogonal methods, published concurrently with independent KO study\",\n      \"pmids\": [\"24797475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Male mice devoid of Stag3 exhibit meiotic arrest at a zygonema-like stage with shortening of chromosome axial/lateral elements, partial loss of centromeric cohesion at early prophase, and the ability to initiate but not complete RAD51- and DMC1-mediated double-strand break repair, demonstrating STAG3 as a crucial cohesin subunit in mammalian male gametogenesis.\",\n      \"method\": \"Knockout mouse model; immunofluorescence on meiotic spreads; RAD51/DMC1 foci analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined molecular phenotype using multiple markers, independent from other 2014 studies\",\n      \"pmids\": [\"24608227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Genetic epistasis analysis using double knockout mice shows that STAG3/REC8 cohesins are the primary cohesin complex required for centromeric cohesion and chromosome axis formation, while STAG3/RAD21L cohesins are required for normal pericentromeric heterochromatin clustering. STAG3 interacts directly with each α-kleisin subunit (REC8, RAD21L, RAD21) in primary spermatocytes.\",\n      \"method\": \"Double knockout mouse models; immunofluorescence on meiotic spreads; genetic epistasis\",\n      \"journal\": \"G3 (Bethesda, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple double KO combinations plus direct interaction data, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"27172213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"E2F6, a retinoblastoma-independent transcriptional repressor, is required to silence STAG3 (and SMC1β) in somatic cells. E2F6 binds in vivo to the STAG3 promoter through a conserved binding site, and this repression involves histone H3 methylation on lysine 9 and lysine 27.\",\n      \"method\": \"cDNA microarray comparing wild-type vs. E2f6-/- MEFs; ChIP at STAG3 promoter; re-expression rescue experiment; histone methylation analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, rescue experiment, and microarray in combination; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"16236716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"E2F6-mediated repression of Stag3 (and Smc1β) in somatic cells requires the enzymatic (SET domain) activity of Ezh2, a PRC2 complex component, and occurs independently of the de novo methyltransferase Dnmt3b. Repression is established at the transition from ESCs to epiblast stem cells, coinciding with promoter DNA methylation, though Dnmt3b is not the driver.\",\n      \"method\": \"Ezh2 SET domain deletion; Dnmt3b knockout embryoid bodies; ChIP; RT-qPCR\",\n      \"journal\": \"Epigenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function of Ezh2 with defined transcriptional readout, single lab, multiple methods\",\n      \"pmids\": [\"23880518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In fission yeast, casein kinase 1 (CK1) phosphorylates the meiotic cohesin subunit Rec11/SA3 (the fission yeast ortholog of STAG3). This phosphorylation mediates interaction with the chromosome axis component Rec10/Red1/SCP2, thereby promoting linear element (meiotic chromosome axis) assembly and meiotic recombination, independently of sister chromatid cohesion. Expression of Rec11-Rec10 fusion protein bypasses the requirement for CK1 or cohesin phosphorylation for this process. STAG3, the mammalian functional homolog of Rec11, is also phosphorylated during meiosis.\",\n      \"method\": \"In vitro phosphorylation assay; kinase mutants; fission yeast genetics; linear element immunofluorescence; Rec11-Rec10 fusion bypass experiment\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro phosphorylation assay combined with genetic epistasis and reconstitution bypass experiment; two independent studies (PMID 25579976 and 25993311) replicate the Rec11 phosphorylation finding\",\n      \"pmids\": [\"25579976\", \"25993311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"When expressed in HEK293 somatic cells, the meiotic kleisin REC8 has no affinity for STAG1 or STAG2 and remains cytoplasmic; however, co-expression of STAG3 is sufficient for REC8 to enter the nucleus, load onto chromatin, and functionally replace its mitotic counterpart RAD21 during sister chromatid cohesion and dissolution. REC8-STAG3 cohesin physically interacts with PDS5, WAPL, and sororin, and is susceptible to WAPL-dependent ring opening and sororin-mediated protection.\",\n      \"method\": \"Somatic cell reconstitution (HEK293); co-immunoprecipitation; immunofluorescence for nuclear localization and chromatin loading; cohesion/dissolution assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution in somatic cells with functional assays, Co-IP for binding partners, nuclear localization experiment with defined consequence; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"29724914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In-frame deletion variants in the STAG3 armadillo-type fold domain (p.293_295del and p.297_298insAsp) are pathogenic: mutant STAG3 and REC8 fail to enter the nucleus, and co-immunoprecipitation shows absence of interaction between mutant STAG3 and REC8 or SMC1A in an in vitro cell model.\",\n      \"method\": \"Fluorescence localization in transfected cells; co-immunoprecipitation of mutant vs. wild-type STAG3 with REC8 and SMC1A\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and localization in cell model with disease variants; single lab, single study\",\n      \"pmids\": [\"31803224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"STAG3 uniquely accumulates on the spindle apparatus and colocalizes with microtubule fibers during mouse oocyte meiotic maturation. Morpholino-mediated depletion of Stag3 disrupts spindle assembly, chromosome alignment, kinetochore-microtubule attachment, reduces acetylated tubulin levels, and decreases microtubule resistance to depolymerizing drugs, resulting in increased aneuploidy in eggs.\",\n      \"method\": \"Morpholino knockdown in mouse oocytes; immunofluorescence for spindle and chromosome markers; tubulin acetylation western blot; cold-stable microtubule assay; FISH for aneuploidy\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple cellular readouts in oocytes; single lab with several orthogonal assays\",\n      \"pmids\": [\"27906670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In human oocytes, cohesin subunits REC8, STAG3, SMC1β and SMC3 co-localize with the lateral element of the synaptonemal complex at prophase I, are present at centromeres and along chromosomal arms (absent from chiasmata) at metaphase I, and persist at centromeric domains from anaphase I through metaphase II, supporting roles in sister chromatid cohesion throughout human female meiosis.\",\n      \"method\": \"Immunofluorescence on human oocytes at multiple meiotic stages; co-localization with SYCP3 and shugoshin 1\",\n      \"journal\": \"Human reproduction (Oxford, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct immunolocalization across multiple meiotic stages in human material, consistent with findings in mouse models; single lab\",\n      \"pmids\": [\"20634189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Loss of STAG3 (or STAG2) expression in BRAF(V600E)-mutant melanoma cells confers resistance to BRAF inhibitors. Knockdown of STAG3 decreased sensitivity of melanoma cells and xenograft tumors to BRAFi, providing evidence for a tumor suppressor role for STAG3 in the context of MAPK signaling.\",\n      \"method\": \"shRNA knockdown in melanoma cell lines; xenograft mouse tumor model; analysis of patient tumor samples with acquired BRAFi resistance\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in cell lines and xenograft with defined pharmacological phenotype, patient sample correlates; single lab\",\n      \"pmids\": [\"27500726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"STAG3 mRNA undergoes N6-methyladenosine (m6A) modification in colorectal cancer cells, mediated by the methyltransferase METTL3 and read by the m6A reader IGF2BP2, which stabilizes STAG3 protein expression. Knockdown of METTL3 decreases both m6A levels and protein expression of STAG3, inhibiting cell proliferation and migration; these effects are rescued by STAG3 overexpression.\",\n      \"method\": \"m6A RNA immunoprecipitation (MeRIP); RIP and pulldown assays for IGF2BP2-STAG3 mRNA interaction; METTL3/IGF2BP2 knockdown and STAG3 overexpression rescue; CCK-8, clone formation, wound healing, flow cytometry; xenograft mouse model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (MeRIP, RIP, pulldown, functional assays, in vivo) in single lab establishing m6A regulation axis\",\n      \"pmids\": [\"37828232\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"STAG3 is a meiosis-specific stromal antigen (SA) subunit of the cohesin complex that directly binds SMC1, SMC3, and all three meiotic α-kleisins (REC8, RAD21L, RAD21), forming the structural scaffold required for meiotic chromosome axis assembly, sister chromatid arm and centromere cohesion, homolog synapsis, and DNA double-strand break repair; its HEAT/armadillo-repeat domain mediates kleisin binding, its nuclear entry is obligately required for REC8 nuclear import, it is regulated by CK1-mediated phosphorylation (conserved from fission yeast Rec11/SA3 to mammals), and its expression in somatic cells is silenced via E2F6-PRC2 (Ezh2)-dependent histone H3K9/K27 methylation, while in cancer contexts its mRNA stability is post-transcriptionally controlled by METTL3/IGF2BP2-mediated m6A modification.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"STAG3 is a meiosis-specific stromal antigen subunit of the cohesin complex that provides the structural scaffold for meiotic chromosome architecture, synapsis, and recombination [#2, #3]. It physically associates with the SMC1/SMC3 core and binds each of the three meiotic α-kleisins (REC8, RAD21L, RAD21) in spermatocytes, and these distinct STAG3-kleisin complexes carry out specialized tasks: STAG3/REC8 cohesin drives centromeric cohesion and chromosome axis formation, while STAG3/RAD21L cohesin supports pericentromeric heterochromatin clustering [#0, #6]. STAG3 is required for the stability and axial loading of all meiosis-specific cohesin subunits without disturbing mitotic cohesin, and its loss abolishes bona fide axial element (SYCP3) assembly, blocks SYCP1-dependent synapsis, impairs centromeric and telomeric sister chromatid cohesion, and permits initiation but not completion of RAD51/DMC1-mediated double-strand break repair, causing prophase I arrest and apoptosis in both sexes [#2, #3, #5]. A key non-redundant function is nuclear delivery of its kleisin partner: STAG3 binding through its armadillo-type fold domain is obligately required for REC8 nuclear entry, chromatin loading, and engagement of the cohesin regulators PDS5, WAPL, and sororin, and in-frame deletions in this domain abolish STAG3-REC8/SMC1A interaction and block nuclear import as a cause of human meiotic disease [#10, #11]. Cohesin axis function is gated by CK1-mediated phosphorylation of the STAG3 ortholog Rec11, which promotes its interaction with the axis component Rec10 and linear element assembly independently of cohesion [#9]. In somatic cells STAG3 is transcriptionally silenced by E2F6 acting with PRC2/Ezh2 through H3K9/K27 methylation [#7, #8]. In cancer contexts STAG3 behaves as a context-dependent factor, with loss conferring BRAF-inhibitor resistance in melanoma and METTL3/IGF2BP2-mediated m6A modification stabilizing its mRNA to promote colorectal cancer proliferation [#14, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established STAG3 as a testis-restricted protein localizing to the synaptonemal complex, framing it as a candidate meiotic cohesin rather than a ubiquitous cohesin subunit.\",\n      \"evidence\": \"cDNA cloning, expression analysis, and immunolocalization in testis sections\",\n      \"pmids\": [\"10698974\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct binding partners identified\", \"Functional requirement not tested by loss-of-function\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed STAG3 physically associates with the cohesin core SMC1/SMC3 and localizes to chromosome arms in meiosis I, placing it inside the cohesin complex as a meiosis-specific arm-cohesion subunit.\",\n      \"evidence\": \"Co-immunoprecipitation and immunofluorescence in meiotic cells\",\n      \"pmids\": [\"11483963\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kleisin partner not yet defined\", \"Mechanism of arm-specific localization unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified how STAG3 is kept off in somatic tissue, showing E2F6 binds the STAG3 promoter and represses it via H3K9/K27 methylation.\",\n      \"evidence\": \"Microarray of E2f6-/- MEFs, promoter ChIP, and rescue/histone methylation analysis\",\n      \"pmids\": [\"16236716\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzymatic effector of the methylation not yet defined\", \"Developmental timing of silencing not established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended the cohesin localization model to human female meiosis, showing STAG3 co-localizes with REC8/SMC1β/SMC3 at lateral elements, arms, and centromeres across meiotic stages.\",\n      \"evidence\": \"Immunofluorescence of human oocytes at multiple meiotic stages with SYCP3 and shugoshin 1\",\n      \"pmids\": [\"20634189\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Descriptive localization without functional perturbation in human cells\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the enzymatic basis of somatic silencing, showing E2F6 repression of Stag3 requires the Ezh2 SET domain and is independent of Dnmt3b.\",\n      \"evidence\": \"Ezh2 SET-domain deletion and Dnmt3b-KO embryoid bodies with ChIP and RT-qPCR\",\n      \"pmids\": [\"23880518\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Driver of associated promoter DNA methylation unidentified\", \"Direct E2F6-PRC2 recruitment mechanism not shown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Knockout and hypomorphic mouse studies established STAG3 as the master meiotic STAG subunit required for stability and axial loading of all meiotic cohesins, axial element formation, synapsis, cohesion, and DSB repair, with kleisin-specific dosage requirements.\",\n      \"evidence\": \"Multiple independent Stag3 KO and hypomorphic mouse models with meiotic spread immunofluorescence, western blot, and RAD51/DMC1 foci analysis\",\n      \"pmids\": [\"24992337\", \"24797474\", \"24797475\", \"24608227\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for differential kleisin dependence not resolved\", \"Direct contribution to DSB repair step blocked not mechanistically defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Genetic epistasis separated the functions of distinct STAG3-kleisin cohesins, assigning centromeric cohesion/axis formation to STAG3/REC8 and pericentromeric heterochromatin clustering to STAG3/RAD21L, and confirmed direct STAG3 binding to all three α-kleisins.\",\n      \"evidence\": \"Double-knockout mouse combinations, meiotic spread immunofluorescence, and interaction assays in primary spermatocytes\",\n      \"pmids\": [\"27172213\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural determinants of kleisin selectivity not defined\", \"Mechanism coupling RAD21L cohesin to heterochromatin clustering unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed a non-canonical STAG3 association with the oocyte spindle, where depletion disrupts spindle assembly, kinetochore-microtubule attachment, and tubulin stability, linking STAG3 to chromosome segregation fidelity.\",\n      \"evidence\": \"Morpholino knockdown in mouse oocytes with spindle/chromosome immunofluorescence, tubulin acetylation, cold-stable microtubule assay, and FISH aneuploidy scoring\",\n      \"pmids\": [\"27906670\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether spindle effect is cohesin-dependent or a separate role unclear\", \"Direct STAG3-microtubule interaction not demonstrated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated regulatory control of cohesin axis function by CK1 phosphorylation of the STAG3 ortholog Rec11, which licenses Rec10 binding and linear element assembly independently of cohesion.\",\n      \"evidence\": \"In vitro phosphorylation assays, kinase mutants, fission yeast genetics, and a Rec11-Rec10 fusion bypass experiment (two independent studies)\",\n      \"pmids\": [\"25579976\", \"25993311\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian STAG3 phosphosites and the equivalent axis partner not mapped\", \"Functional consequence of STAG3 phosphorylation in mammals untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Reconstitution in somatic cells showed STAG3 is necessary and sufficient to import its kleisin REC8 into the nucleus and load it onto chromatin, where REC8-STAG3 cohesin engages PDS5, WAPL, and sororin and substitutes for mitotic RAD21.\",\n      \"evidence\": \"HEK293 reconstitution with Co-IP, nuclear localization/chromatin loading immunofluorescence, and cohesion/dissolution assays\",\n      \"pmids\": [\"29724914\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Import signal/mechanism for the STAG3-REC8 complex not mapped\", \"Reconstitution in somatic cells may not fully recapitulate meiotic regulation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected STAG3 to human meiotic disease, showing armadillo-domain in-frame deletions abolish STAG3 binding to REC8 and SMC1A and block nuclear entry of both proteins.\",\n      \"evidence\": \"Localization and Co-IP of mutant versus wild-type STAG3 with REC8 and SMC1A in a cell model\",\n      \"pmids\": [\"31803224\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study without structural validation\", \"Variant effects not tested in patient germ cells\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established post-transcriptional control of STAG3 in cancer, showing METTL3-deposited m6A read by IGF2BP2 stabilizes STAG3 mRNA to drive colorectal cancer proliferation and migration.\",\n      \"evidence\": \"MeRIP, RIP/pulldown, METTL3/IGF2BP2 knockdown with STAG3 rescue, functional assays, and xenografts\",\n      \"pmids\": [\"37828232\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effectors of STAG3 in colorectal cancer not defined\", \"Relationship to its meiotic cohesin function unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How phosphorylation, m6A regulation, and the somatic versus meiotic and cancer-context roles of STAG3 are mechanistically integrated, and the structural basis of its kleisin selectivity, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of STAG3-kleisin contacts\", \"Mammalian STAG3 phosphoregulation not functionally tested\", \"Mechanistic link between cohesin role and oncogenic/tumor-suppressive behavior absent\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [10, 11]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 2, 3, 13]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10, 11]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [2, 3, 5]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"complexes\": [\"meiotic cohesin complex\", \"synaptonemal complex (lateral element associated)\"],\n    \"partners\": [\"SMC1\", \"SMC3\", \"REC8\", \"RAD21L\", \"RAD21\", \"PDS5\", \"WAPL\", \"SMC1A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}