Affinage

STAG3

Cohesin subunit SA-3 · UniProt Q9UJ98

Length
1225 aa
Mass
139.0 kDa
Annotated
2026-04-28
42 papers in source corpus 17 papers cited in narrative 17 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

STAG3 is a meiosis-specific cohesin subunit essential for chromosome axis formation, sister chromatid cohesion, homolog synapsis, and DNA double-strand break repair during prophase I of mammalian meiosis. STAG3 physically interacts with SMC1/SMC3 and all three meiotic α-kleisins (REC8, RAD21L, RAD21), and is required for the stability and chromosomal loading of meiosis-specific cohesin complexes; loss of STAG3 abolishes axial element assembly, disrupts pericentromeric heterochromatin clustering, and causes meiotic arrest and infertility in both sexes (PMID:11483963, PMID:24992337, PMID:24797474, PMID:27172213). Co-expression of STAG3 with REC8 in somatic cells is sufficient to reconstitute nuclear import, chromatin loading, and functional sister chromatid cohesion regulated by Wapl and sororin (PMID:29724914). In somatic cells, STAG3 transcription is silenced by E2F6-dependent recruitment of PRC2/Ezh2, which deposits repressive histone marks at the promoter during early embryonic differentiation (PMID:16236716, PMID:23880518).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2000 High

    Identification of STAG3 as a testis-specific stromalin-domain protein localizing to the synaptonemal complex established the first evidence for a meiosis-specific cohesin subunit dedicated to chromosome pairing.

    Evidence cDNA cloning, sequence analysis, and immunolocalization in mouse spermatocytes

    PMID:10698974

    Open questions at the time
    • No biochemical interaction with cohesin ring subunits demonstrated
    • No functional loss-of-function data
  2. 2001 High

    Demonstration that STAG3 physically associates with SMC1 and SMC3 and localizes to the interchromatid domain at metaphase I confirmed STAG3 as a bona fide cohesin subunit rather than merely a synaptonemal complex structural protein.

    Evidence Reciprocal co-immunoprecipitation of STAG3 with SMC1/SMC3; immunofluorescence in meiotic cells

    PMID:11483963

    Open questions at the time
    • Kleisin partner identity unknown
    • No loss-of-function model available
  3. 2005 High

    Discovery that E2F6 directly represses STAG3 transcription in somatic cells via H3K9 and H3K27 methylation at its promoter explained how meiotic cohesin genes are silenced outside the germline.

    Evidence ChIP for E2F6 and histone marks at STAG3 promoter in E2f6−/− MEFs; rescue by E2F6 re-expression

    PMID:16236716

    Open questions at the time
    • Upstream signals activating STAG3 in germ cells not identified
    • Relationship between H3K9me and H3K27me in repression hierarchy unclear
  4. 2013 High

    Demonstration that PRC2/Ezh2 SET-domain activity is required for STAG3 silencing, while Dnmt3b is dispensable, resolved the epigenetic hierarchy: Polycomb-mediated histone methylation initiates repression, with DNA methylation following secondarily.

    Evidence Ezh2 SET-domain deletion and Dnmt3b KO in embryoid body differentiation; RT-qPCR and ChIP

    PMID:23880518

    Open questions at the time
    • Whether PRC1 also contributes to STAG3 silencing not tested
    • Mechanism of germline-specific derepression unknown
  5. 2014 High

    Four independent Stag3 knockout studies collectively established that STAG3 is the indispensable STAG subunit for meiosis: its loss destabilizes all meiotic cohesin subunits (SMC1β, REC8, RAD21L), abolishes axial element formation, prevents synapsis, impairs DSB repair, and causes meiotic arrest in both sexes.

    Evidence Stag3 KO and hypomorphic mouse models; immunofluorescence for SYCP3, SYCP1, HORMAD1, RAD51, DMC1; genetic epistasis with Smc1β, Rec8, Rad21l mutants

    PMID:24608227 PMID:24797474 PMID:24797475 PMID:24992337

    Open questions at the time
    • Whether residual RAD21-STAG3 cohesin has any meiotic function not fully resolved
    • Mechanism by which STAG3 stabilizes kleisin protein levels (transcriptional vs. post-translational) unclear
  6. 2015 High

    Work in fission yeast showed that CK1 phosphorylation of the STAG3 homolog Rec11 drives meiotic axis assembly by promoting the Rec11–Rec10 interaction independently of cohesion, revealing that STAG proteins have a cohesion-independent structural role in axis formation that is conserved from yeast to mammals.

    Evidence In vitro CK1 phosphorylation; Rec11-Rec10 fusion bypass; genetic epistasis in S. pombe

    PMID:25979576 PMID:25993311

    Open questions at the time
    • Mammalian CK1 phosphorylation sites on STAG3 not mapped
    • Whether a similar phosphorylation-dependent axis-loading mechanism operates in mammals not tested
  7. 2016 High

    Double-mutant analysis in mice demonstrated that STAG3–REC8 complexes are the primary cohesins for centromeric cohesion and axis formation, while STAG3–RAD21L complexes specifically mediate pericentromeric heterochromatin clustering, functionally partitioning the roles of different STAG3-containing cohesin variants.

    Evidence Stag3/Rad21L and Stag3/Rec8 double KO mice; co-immunoprecipitation; meiotic spread analysis

    PMID:27172213

    Open questions at the time
    • Role of STAG3–RAD21 (somatic kleisin) complexes in meiosis remains poorly understood
    • Genomic binding profiles of different STAG3-containing complexes not determined
  8. 2018 High

    Reconstitution of REC8–STAG3 cohesin in somatic cells demonstrated that STAG3 is both necessary and sufficient for REC8 nuclear import and chromatin loading, and that the resulting complex is regulated by the canonical Wapl/sororin cohesion cycle, bridging meiotic and mitotic cohesin biology.

    Evidence Ectopic co-expression in HEK293 cells; chromatin fractionation; cohesion assay; Wapl/sororin knockdown

    PMID:29724914

    Open questions at the time
    • Whether STAG3–REC8 cohesin adopts a distinct ring topology or chromatin binding mode not addressed structurally
    • Sororin regulation in actual meiotic cells not validated
  9. 2019 Medium

    Disease-associated in-frame deletions in STAG3 (residues 293–298) were shown to abolish interactions with both REC8 and SMC1A and prevent nuclear import, mapping a critical interface for cohesin complex assembly.

    Evidence Fluorescence localization and co-immunoprecipitation of mutant STAG3 proteins in cells

    PMID:31803224

    Open questions at the time
    • No structural model of the STAG3–kleisin interface available
    • Only two variants tested; broader structure–function map lacking
    • Single-lab study without independent replication
  10. 2024 Medium

    A preprint reported that STAG3 localizes to centrosomes in embryonic stem cells independently of cohesin and interacts with RISC component TNRC6C to regulate mRNA stability, suggesting a cohesin-independent cytoplasmic function in post-transcriptional gene regulation.

    Evidence (preprint) siRNA knockdown in mESCs; mass spectrometry interactome; RNA-seq; proximity ligation assay

    PMID:bio_10.1101_2024.05.31.595485

    Open questions at the time
    • Not yet peer-reviewed
    • Centrosomal localization not confirmed in meiotic germ cells
    • Mechanism linking centrosome association to mRNA regulation not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: the structural basis of STAG3's selective interaction with meiotic kleisins, whether CK1-dependent phosphorylation regulates mammalian STAG3 axis loading, the genomic binding profiles distinguishing STAG3–REC8 from STAG3–RAD21L complexes, and whether the cytoplasmic mRNA-regulatory role observed in stem cells operates in germ cells.
  • No crystal or cryo-EM structure of STAG3 or STAG3–kleisin interface
  • Mammalian CK1 phosphorylation of STAG3 not validated
  • ChIP-seq for distinct STAG3-containing complexes not performed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 6
Localization
GO:0005694 chromosome 7 GO:0005634 nucleus 3 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-1640170 Cell Cycle 7 R-HSA-1474165 Reproduction 4 R-HSA-4839726 Chromatin organization 2
Partners
PDS5RAD21RAD21LREC8SMC1ASMC1BSMC3WAPL
Complex memberships
Meiotic cohesin (STAG3-RAD21L-SMC1-SMC3)Meiotic cohesin (STAG3-REC8-SMC1-SMC3)

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 STAG3 physically interacts with SMC1 and SMC3 (structural maintenance of chromosome proteins) and functions as a sister chromatid arm cohesin specific to mammalian meiosis I, localizing to the interchromatid domain in metaphase I and to the axial/lateral element of the synaptonemal complex in prophase I. Co-immunoprecipitation; immunofluorescence localization in meiotic cells Nature cell biology High 11483963
2000 STAG3 contains a stromalin conservative domain (SCD) and localizes to the synaptonemal complex specifically in testis, suggesting a cohesin-like role in chromosome pairing and synaptonemal complex maintenance during pachytene. cDNA cloning; immunolocalization in spermatocytes; sequence analysis FASEB journal High 10698974
2014 STAG3 is required for the stability and chromosomal axis loading of all meiosis-specific cohesin subunits (SMC1β, RAD21L, REC8); loss of STAG3 reduces protein levels of these subunits and disrupts their localization to chromosome axes, causing aberrant DNA repair, failed homolog synapsis, disrupted pericentromeric heterochromatin clustering, and early prophase I arrest in both sexes. Stag3 knockout mouse; immunofluorescence; meiotic spread analysis; genetic epistasis with Smc1β, Rec8, Rad21l mutants PLoS genetics High 24992337
2014 STAG3 deficiency causes complete failure of axial element (AE) formation in meiosis — SYCP3 forms only dot-like structures, HORMAD1 is diffusely distributed, and SYCP1 is largely absent — demonstrating STAG3 is the key STAG cohesin for meiotic chromosome architecture, centromeric and telomeric sister chromatid cohesion. STAG3-deficient mouse (both sexes); immunofluorescence of synaptonemal complex proteins; meiotic spread analysis The EMBO journal High 24797474
2014 STAG3 preferentially stabilizes REC8-containing cohesin complexes; three α-kleisins (REC8, RAD21L, RAD21) show different dosage-dependent requirements for STAG3, and STAG3-REC8 complexes have a critical role in meiotic chromosome axis compaction and synapsis. Stag3 hypomorphic mouse allele; immunofluorescence; co-immunoprecipitation of cohesin subunits; meiotic phenotype analysis The EMBO journal High 24797475
2014 In male Stag3 knockout mice, meiotic arrest occurs at zygonema with shortened axial elements, partial loss of centromeric cohesion, and inability to complete RAD51- and DMC1-mediated DSB repair, establishing STAG3 as a crucial cohesin subunit for mammalian gametogenesis. Stag3 knockout mouse; immunofluorescence; meiotic spread analysis for RAD51, DMC1, axial element markers Human molecular genetics High 24608227
2005 E2F6 transcriptionally represses STAG3 (and SMC1β) in somatic cells by binding their promoters and mediating histone H3 methylation on lysine 9 and lysine 27; loss of E2f6 derepresses these meiotic genes in mouse embryonic fibroblasts. cDNA microarray in E2f6-/- MEFs; chromatin immunoprecipitation (ChIP); E2F6 re-expression rescue The Journal of biological chemistry High 16236716
2013 E2f6-mediated repression of Stag3 and Smc1β during embryonic development requires the enzymatic (SET domain) activity of Ezh2 (PRC2), but not the de novo methyltransferase Dnmt3b; repression is established at the transition from ESCs to epiblast stem cells and accompanied by promoter DNA methylation. Ezh2 SET domain deletion; Dnmt3b knockout; embryoid body differentiation; RT-qPCR; ChIP Epigenetics High 23880518
2015 In fission yeast, casein kinase 1 (CK1/Hhp1/Hhp2) phosphorylates the STAG3 functional homolog Rec11/SA3, which promotes loading of linear element proteins Rec10/Rec27 and thereby drives meiotic DSB formation and recombination; the mammalian STAG3 is also phosphorylated during meiosis, indicating conservation. In vitro phosphorylation screen; genetic analysis of CK1 mutants; immunofluorescence; biochemical fractionation in S. pombe PLoS genetics Medium 25993311
2015 CK1-mediated phosphorylation of fission yeast Rec11/SA3 (STAG3 homolog) mediates the interaction with the Rec10/Red1/SCP2 axis component to assemble the meiotic chromosome axis (linear element), independently of sister chromatid cohesion; Rec11-Rec10 fusion protein bypasses the requirement for CK1. In vitro phosphorylation assay; Rec11-Rec10 fusion rescue; genetic epistasis; immunofluorescence in S. pombe Developmental cell High 25979576
2016 STAG3 is the predominant STAG protein in primary spermatocytes and interacts directly with each α-kleisin subunit (REC8, RAD21L, RAD21); genetic double-mutant analysis shows STAG3/REC8 complexes are the primary cohesins required for centromeric cohesion and axis formation, while STAG3/RAD21L cohesins mediate pericentromeric heterochromatin clustering. Stag3/Rad21L and Stag3/Rec8 double knockout mice; immunofluorescence; co-immunoprecipitation; meiotic spread analysis G3 (Bethesda, Md.) High 27172213
2018 When expressed in HEK293 somatic cells, REC8 has no affinity for STAG1 or STAG2 and remains cytoplasmic; co-expression of STAG3 is sufficient for REC8 to enter the nucleus, load onto chromatin, and functionally replace RAD21 in sister chromatid cohesion. REC8-STAG3 cohesin physically interacts with Pds5, Wapl, and sororin, and is susceptible to Wapl-dependent ring opening and sororin-mediated protection. Ectopic expression in HEK293 cells; co-immunoprecipitation; chromatin fractionation; cohesion assay; Wapl/sororin knockdown Journal of cell science High 29724914
2017 STAG3 localizes to the spindle apparatus and colocalizes with microtubule fibers during mouse oocyte meiotic maturation; depletion of STAG3 disrupts spindle assembly, chromosome alignment, reduces acetylated tubulin levels and microtubule stability, impairs kinetochore-microtubule attachment, and causes aneuploidy. Morpholino knockdown in mouse oocytes; immunofluorescence; microtubule depolymerization assay; FISH for aneuploidy Oncotarget Medium 27906670
2016 Loss of STAG3 (or STAG2) in melanoma cells confers resistance to BRAF inhibition; loss of STAG2 specifically inhibits CTCF-mediated expression of DUSP6, leading to reactivation of MAPK/ERK signaling. STAG2/STAG3 knockdown in melanoma cells; xenograft tumor model; gene expression analysis; MAPK signaling readout Nature medicine Medium 27500726
2019 In-frame deletion variants in STAG3 (p.293_295del and p.297_298insAsp) prevent both STAG3 and REC8 from entering the nucleus, and abolish the interaction between mutant STAG3 and REC8 or SMC1A, demonstrating that these residues are required for nuclear import and protein–protein interactions within the meiotic cohesin complex. Fluorescence localization of mutant proteins in cells; co-immunoprecipitation Frontiers in genetics Medium 31803224
2023 METTL3-mediated m6A methylation of STAG3 mRNA is read by IGF2BP2, stabilizing STAG3 protein expression in colorectal cancer cells; knockdown of METTL3 or IGF2BP2 decreases STAG3 protein level, inhibits proliferation and migration, and promotes apoptosis, effects rescued by STAG3 overexpression. m6A RNA immunoprecipitation (MeRIP); RIP assay; pulldown; METTL3/IGF2BP2 knockdown/overexpression; xenograft mouse model Scientific reports Medium 37828232
2024 STAG3 is expressed in mouse embryonic stem cells and primordial germ cell-like cells, where it localizes to the centrosome independently of cohesin and interacts with mRNA localization/stability proteins; STAG3 knockdown destabilizes the centrosome and RISC component TNRC6C, derepressing P-body mRNAs (e.g., DPPA3), indicating a cytoplasmic post-transcriptional gene regulatory role distinct from its nuclear cohesin function. siRNA knockdown in mESCs; mass spectrometry interactome; immunofluorescence; RNA-seq; proximity ligation / co-IP bioRxivpreprint Medium bio_10.1101_2024.05.31.595485

Source papers

Stage 0 corpus · 42 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Mammalian STAG3 is a cohesin specific to sister chromatid arms in meiosis I. Nature cell biology 210 11483963
2000 STAG3, a novel gene encoding a protein involved in meiotic chromosome pairing and location of STAG3-related genes flanking the Williams-Beuren syndrome deletion. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 117 10698974
2014 Meiosis-specific cohesin component, Stag3 is essential for maintaining centromere chromatid cohesion, and required for DNA repair and synapsis between homologous chromosomes. PLoS genetics 104 24992337
2010 Dynamics of cohesin proteins REC8, STAG3, SMC1 beta and SMC3 are consistent with a role in sister chromatid cohesion during meiosis in human oocytes. Human reproduction (Oxford, England) 89 20634189
2014 Meiotic cohesin STAG3 is required for chromosome axis formation and sister chromatid cohesion. The EMBO journal 86 24797474
2014 STAG3-mediated stabilization of REC8 cohesin complexes promotes chromosome synapsis during meiosis. The EMBO journal 83 24797475
2016 Loss of cohesin complex components STAG2 or STAG3 confers resistance to BRAF inhibition in melanoma. Nature medicine 67 27500726
2019 Mutations in the stromal antigen 3 (STAG3) gene cause male infertility due to meiotic arrest. Human reproduction (Oxford, England) 64 31682730
2019 Sequencing of a 'mouse azoospermia' gene panel in azoospermic men: identification of RNF212 and STAG3 mutations as novel genetic causes of meiotic arrest. Human reproduction (Oxford, England) 63 31125047
2014 STAG3 is a strong candidate gene for male infertility. Human molecular genetics 61 24608227
1997 Purification of ribonucleases Sa, Sa2, and Sa3 after expression in Escherichia coli. Protein expression and purification 51 9367812
2016 Genetic Interactions Between the Meiosis-Specific Cohesin Components, STAG3, REC8, and RAD21L. G3 (Bethesda, Md.) 46 27172213
2015 Phosphorylation of cohesin Rec11/SA3 by casein kinase 1 promotes homologous recombination by assembling the meiotic chromosome axis. Developmental cell 46 25579976
2015 Casein Kinase 1 and Phosphorylation of Cohesin Subunit Rec11 (SA3) Promote Meiotic Recombination through Linear Element Formation. PLoS genetics 46 25993311
2015 STAG3 truncating variant as the cause of primary ovarian insufficiency. European journal of human genetics : EJHG 43 26059840
2020 STAG3 homozygous missense variant causes primary ovarian insufficiency and male non-obstructive azoospermia. Molecular human reproduction 37 32634216
2017 Whole-exome sequencing identifies a homozygous donor splice-site mutation in STAG3 that causes primary ovarian insufficiency. Clinical genetics 36 28393351
2019 Novel STAG3 mutations in a Caucasian family with primary ovarian insufficiency. Molecular genetics and genomics : MGG 31 31363903
2005 Silencing of the meiotic genes SMC1beta and STAG3 in somatic cells by E2F6. The Journal of biological chemistry 29 16236716
2018 Two rare loss-of-function variants in the STAG3 gene leading to primary ovarian insufficiency. European journal of medical genetics 25 30006057
2019 In-Frame Variants in STAG3 Gene Cause Premature Ovarian Insufficiency. Frontiers in genetics 23 31803224
2017 Stag3 regulates microtubule stability to maintain euploidy during mouse oocyte meiotic maturation. Oncotarget 21 27906670
2003 Degradation of polyvinyl alcohol by Sphingomonas sp. SA3 and its symbiote. Journal of industrial microbiology & biotechnology 19 12545389
2022 Novel STAG3 variant associated with primary ovarian insufficiency and non-obstructive azoospermia in an Iranian consanguineous family. Gene 18 35176428
2018 Studying meiotic cohesin in somatic cells reveals that Rec8-containing cohesin requires Stag3 to function and is regulated by Wapl and sororin. Journal of cell science 18 29724914
2013 E2f6-mediated repression of the meiotic Stag3 and Smc1β genes during early embryonic development requires Ezh2 and not the de novo methyltransferase Dnmt3b. Epigenetics 16 23880518
2023 METTL3/IGF2BP2 axis affects the progression of colorectal cancer by regulating m6A modification of STAG3. Scientific reports 14 37828232
2006 Production of an antimicrobial substance against Cryptococcus neoformans by Paenibacillus brasilensis Sa3 isolated from the rhizosphere of Kalanchoe brasiliensis. Microbiological research 14 16790336
2021 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. Genes 11 34828315
2020 The association of stromal antigen 3 (STAG3) sequence variations with spermatogenic impairment in the male Korean population. Asian journal of andrology 10 31115363
2001 Evaluation of the Stag3 gene and the synaptonemal complex in a rat model (as/as) for male infertility. Molecular reproduction and development 10 11599053
2021 Biallelic loss of function variants in STAG3 result in primary ovarian insufficiency. Reproductive biomedicine online 7 34497033
2018 Retinoic acid-induced CYP51 nuclear translocation promotes meiosis prophase I process and is correlated to the expression of REC8 and STAG3 in mice. Biology open 6 30420384
2017 Association of the common SNPs in RNF212, STAG3 and RFX2 gene with male infertility with azoospermia in Chinese population. European journal of obstetrics, gynecology, and reproductive biology 5 29277047
2001 Purification, crystallization and preliminary X-ray analysis of two crystal forms of ribonuclease Sa3. Acta crystallographica. Section D, Biological crystallography 5 11320322
2025 Novel STAG3 variant causes oligoasthenoteratozoospermia with high sperm aneuploidy rate. Journal of assisted reproduction and genetics 3 39932630
2021 Analysis of STAG3 variants in Chinese non-obstructive azoospermia patients with germ cell maturation arrest. Scientific reports 3 33980954
2024 The Role of Prophage ϕSa3 in the Adaption of Staphylococcus aureus ST398 Sublineages from Human to Animal Hosts. Antibiotics (Basel, Switzerland) 2 38391498
2022 New STAG3 gene variant as a cause of premature ovarian insufficiency. Revista colombiana de obstetricia y ginecologia 2 35503298
2015 [Rab23 enhances invasion of Sa3 cutaneous squamous cell carcinoma cells via up-regulating the expression of Rac1]. Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 2 26648292
2024 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. Environmental pollution (Barking, Essex : 1987) 1 38554835
2011 Expression of scFv SA3 against hepatoma fused with enhanced green fluorescent protein and its targeted ability in vivo. Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences 1 22086009