| 2005 |
Phosphorylation of SA2 (STAG2) by Polo-like kinase 1 (Plk1) is essential for dissociation of cohesin from chromosome arms during prophase and prometaphase. Non-phosphorylatable SA2 mutants expressed at physiological levels in human cells phenocopied Plk1 depletion, preventing cohesin arm dissociation in early mitosis, while SA2 phosphorylation was not required for cohesin cleavage by separase. Multiple mitosis-specific phosphorylation sites on SA2 were identified by mass spectrometry. |
Mass spectrometry identification of phosphorylation sites; stable expression of non-phosphorylatable SA2 mutants in human cells; biochemical in vitro experiments; phenotypic analysis of mitosis |
PLoS biology |
High |
15737063
|
| 2011 |
Mutational inactivation of STAG2 in a near-diploid human cell line causes chromatid cohesion defects and aneuploidy. Conversely, targeted correction of endogenous mutant STAG2 alleles in aneuploid glioblastoma cell lines enhanced chromosomal stability, establishing STAG2 loss as a direct cause of aneuploidy in cancer. |
Targeted gene inactivation (AAV-mediated) in near-diploid human cells; targeted correction of endogenous STAG2 mutations in glioblastoma cell lines; chromosome counting and cohesion assays |
Science (New York, N.Y.) |
High |
21852505
|
| 2009 |
Cohesin-SA2 and cohesin-SA1 have distinct and non-redundant roles in cohesion: SA2-depleted cells lose centromere cohesion prematurely while telomere cohesion remains normal, whereas SA1-depleted cells specifically lose sister telomere cohesion. |
RNAi depletion of SA1 or SA2 in human cells; fluorescence imaging of telomere and centromere cohesion; phenotypic analysis of chromosome morphology |
The Journal of cell biology |
High |
19822671
|
| 2011 |
CTCF interacts directly with the cohesin subunit SA2 via specific sites in the C-terminal tail of CTCF; all other cohesin components are recruited through their interaction with SA2. CTCF mutants lacking these SA2-binding sites lose insulation activity and disrupt imprinted gene expression, demonstrating that SA2 is the direct CTCF-cohesin interface. |
Co-immunoprecipitation; in vivo expression of CTCF C-terminal deletion and point mutants; reporter assays for insulator function; analysis of imprinted gene expression (IGF2-H19) |
Molecular and cellular biology |
High |
21444719
|
| 2013 |
Cohesin-SA2 (not SA1) is the primary complex co-recruited with the cohesin-loading factor NIPBL to DNA damage sites in an S/G2-phase-specific manner; the diverged C-terminal region of SA2 confers this activity. Depletion of SA2 but not SA1 decreased sister chromatid homologous recombination repair and affected repair pathway choice, establishing cohesin-SA2 as the functionally specialized complex for DNA damage site recruitment and HR repair. |
Laser micro-irradiation and live-cell imaging; siRNA depletion of SA1 vs. SA2; domain-swap chimera experiments (SA1 C-terminus replaced with SA2 C-terminus); sister chromatid HR repair assays; intra-S checkpoint assays |
Molecular and cellular biology |
High |
24324008
|
| 2017 |
SA2 (STAG2) is a sequence-independent DNA-binding protein that binds both dsDNA and ssDNA (with higher affinity for ssDNA), can switch between 1D diffusion mode on dsDNA and stable binding at ssDNA gaps, and specifically recognizes DNA replication and DSB repair intermediates (ssDNA overhangs, flaps, forks, gaps, and double-stranded ends) but not centromeric or telomeric sequences. SA2 loss leads to a defect in homologous recombination-mediated DSB repair. |
Single-molecule atomic force microscopy; single-molecule fluorescence microscopy (DNA tightrope assay); fluorescence anisotropy binding measurements; HR repair assays after SA2 loss |
The Journal of biological chemistry |
High |
29175904
|
| 2018 |
Cohesin-SA2 localizes to CTCF sites and additionally to enhancers lacking CTCF, where it promotes cell-type-specific enhancer–promoter contacts. Cohesin-SA1 preferentially stabilizes TAD boundaries together with CTCF. Loss of SA2 rewires local chromatin contacts and alters gene expression at tissue-specific loci that cannot be rescued by SA1. |
ChIP-seq for SA1, SA2, CTCF; Hi-C genome-wide chromosome conformation capture; RNA-seq after SA2 depletion; comparison of isogenic SA2-depleted vs. wild-type human cells |
Nature structural & molecular biology |
High |
29867216
|
| 2019 |
STAG2 is essential for DNA replication fork progression; STAG2 inactivation causes replication fork stalling and collapse, disrupts the interaction between the cohesin ring and the replication machinery, and prevents establishment of SMC3 acetylation. As a consequence, STAG2 loss confers synthetic lethality with DSB repair genes and sensitivity to PARP and ATR inhibitors. |
DNA fiber assays for replication fork progression; co-immunoprecipitation of cohesin with replication machinery; SMC3 acetylation assays; CRISPR-based isogenic cell lines; drug sensitivity assays (PARP, ATR inhibitors) |
Nature communications |
High |
30975996
|
| 2019 |
Stag2 deletion in hematopoietic stem and progenitor cells (HSPCs) reduces chromatin accessibility and transcription of lineage-specification genes (including Ebf1 and Pax5), leading to increased self-renewal and impaired differentiation (particularly B cell lineage commitment). ChIP-seq shows that Stag2 and Stag1 share most binding sites, but a subset of Stag2 sites are unoccupied by Stag1 even in Stag2-deficient cells. |
Conditional Stag2 knockout in murine HSPCs; ChIP-seq for Stag1 and Stag2; ATAC-seq for chromatin accessibility; RNA-seq; hematopoietic differentiation assays |
Cell stem cell |
High |
31495782
|
| 2019 |
Cohesin-SA2 facilitates Polycomb domain compaction through PRC1 recruitment and promotes long-range interaction networks between distant Polycomb-bound promoters in mouse embryonic stem cells. Cohesin-SA1 disrupts these networks while preserving TAD borders. |
ChIP-seq for SA1, SA2, PRC1/2 components; Hi-C; RNA-seq after selective depletion of SA1 or SA2 in mESCs |
Cell reports |
High |
31216471
|
| 2018 |
STAG2 deficiency causes spontaneous genomic DNA damage that activates robust interferon expression via the cGAS-STING cytosolic DNA-sensing pathway, leading to JAK-STAT signaling and broad ISG expression that confers resistance to viral infection including rotavirus. |
Genome-wide CRISPR-Cas9 screen for rotavirus host factors; STAG2 knockout in cell lines and human intestinal enteroids; measurement of DNA damage, IFN expression, cGAS-STING pathway activation; JAK-STAT and ISG analysis |
Nature communications |
High |
29662124
|
| 2017 |
STAG1 displays a strong synthetic lethal interaction with STAG2 in cancer cells. Mechanistically, STAG1 loss abrogates sister chromatid cohesion specifically in STAG2-mutated cells (not wild-type), leading to mitotic catastrophe and apoptosis. Restoration of STAG2 expression in STAG2-mutant cells alleviates the dependency on STAG1. |
CRISPR/shRNA-based STAG1 inactivation in isogenic STAG2-mutant vs. wild-type bladder cancer and Ewing sarcoma cell lines; sister chromatid cohesion assays; cell viability and mitosis assays; STAG2 re-expression rescue experiments |
eLife |
High |
28691904
|
| 2014 |
STAG2 depletion does not impair bipolar spindle formation but causes excessive centromere stretch and hyperstabilization of kinetochore-microtubule (kMT) attachments, along with mislocalization of Bub1 kinase, Bub3, and the chromosome passenger complex. Strategic destabilization of kMT attachments in STAG2-mutant tumor cells by overexpression of MCAK/KIF2C and Kif2B decreased lagging chromosomes and chromosome missegregation. |
STAG2 depletion in human cells; live-cell imaging of mitosis; immunofluorescence for kinetochore proteins and CPC; kMT attachment destabilization by MCAK/Kif2B overexpression; chromosome segregation assays |
Journal of cell science |
Medium |
25074805
|
| 2015 |
The C-terminus of Sororin (last 12 amino acid residues) is required for Sororin to bind the cohesin subunit SA2. Deletion of the last 12 residues inhibits Sororin–SA2 interaction and causes precocious chromosome separation, identifying SA2 as the cohesin anchor for Sororin in sister chromatid cohesion protection. |
Co-immunoprecipitation of Sororin deletion mutants with SA2; chromosome separation assays in cells expressing C-terminal truncations of Sororin |
Cell cycle (Georgetown, Tex.) |
Medium |
25608232
|
| 2002 |
STAG2 (and Rad21) are present in meiotic cells and associate with chromosomes during diplotene stage of meiosis, suggesting that a cohesin complex containing Rad21 and STAG2 cooperates with the STAG3-specific meiotic complex to maintain sister chromatid cohesion during meiosis—not solely the STAG3 complex. |
Immunofluorescence localization of STAG2 and Rad21 during mouse spermatogenesis and oogenesis; co-localization analysis with STAG3 |
EMBO reports |
Medium |
12034751
|
| 2017 |
A familial germline STAG2 missense mutation (p.Ser327Asn) disrupts STAG2 binding to SCC1 and other cohesin subunits/regulators when expressed in human cells in vivo, causing a cohesinopathy. S327 is located at a conserved site crucial for binding SCC1 and cohesin regulators. Paradoxically, recombinant STAG2 p.Ser327Asn binds normally to SCC1, WAPL, and SGO1 in vitro, suggesting unknown in vivo mechanisms regulate the STAG2–SCC1 interaction. |
Co-immunoprecipitation of mutant vs. wild-type STAG2 with cohesin subunits in human cells; in vitro binding assays with recombinant proteins; cell cycle analysis; gene expression profiling of patient-derived cells |
NPJ genomic medicine |
Medium |
29263825
|
| 2020 |
SA1 (STAG1) and SA2 (STAG2) directly bind to RNA (ssRNA, dsRNA, RNA:DNA hybrids, and R-loops) as well as to dsDNA regions containing RNA. SA1 and SA2 binding sites from ChIP-seq significantly overlap with R-loop sites from DRIP-seq, and the majority of R-loop-localized SA1/SA2 are also sites where other cohesin complex subunits bind. |
Atomic force microscopy (AFM); single-molecule DNA tightrope assay; fluorescence anisotropy; bulk biochemical RNA/DNA binding assays; overlap analysis of ChIP-seq and DRIP-seq data |
Nucleic acids research |
High |
32352519
|
| 2021 |
STAG2-containing cohesin complexes occupy enhancer and PRC2-marked regulatory regions. STAG2 loss leads to compensatory increase in cohesin-STAG1 complexes, but not at enhancer-rich regions, resulting in reprogramming of cis-chromatin interactions. This alters the oncogenic program driven by EWS/FLI1 (via altered enhancer-promoter contacts) and disrupts PRC2-mediated gene repression, converging to enhance metastatic potential of Ewing sarcoma. |
ChIP-seq for STAG1, STAG2, H3K27ac; Hi-C; RNA-seq in STAG2 knockout Ewing sarcoma cells; xenograft metastasis assays |
Cancer cell |
High |
34129824
|
| 2021 |
STAG2 loss-of-function strongly alters CTCF-anchored dynamic loop extrusion and dramatically decreases promoter-enhancer interactions—particularly at genes regulated by EWSR1-FLI1 at GGAA microsatellite neo-enhancers—without significantly changing EWSR1-FLI1, CTCF/cohesin, or H3K27ac binding patterns. Down-modulation of cis-mediated EWSR1-FLI1 activity by STAG2-LOF is associated with enhanced migration and invasion. |
ChIP-seq; Hi-C; RNA-seq in isogenic Ewing sarcoma cells with/without STAG2 LOF; migration/invasion assays |
Cancer cell |
High |
33930311
|
| 2022 |
STAG2 depletion in melanoma cells leads to TAD expansion and enhanced H3K27ac-associated DNA loop formation at sites where STAG2 binding switches to STAG1. IRF9 is identified as a direct target of STAG2 regulation; STAG2 loss activates IRF9 via altered 3D genome organization, which in turn enhances type I interferon signaling and increases PD-L1 expression, potentially promoting immune evasion. |
RNA-seq; STAG2 ChIP-seq; H3K27ac HiChIP; STAG1 ChIP-seq; STAG2 CRISPR KO in melanoma cells; PD-L1 expression analysis |
Nature communications |
High |
35388001
|
| 2023 |
PAXIP1 is required for stability of cohesin (including STAG2) on chromatin and for its localization to glucocorticoid receptor (GR)-occupied sites. PAXIP1 and STAG2 converge to maintain 3D genome architecture (enhancer-promoter interactions) required for GR-driven transcription; PAXIP1/STAG2 depletion alters the GR transcriptome without changing the GR cistrome, establishing a PAXIP1-STAG2 co-regulator axis for stress hormone signaling. |
FACS-based genome-wide CRISPR screen; ChIP-seq for GR, STAG2, cohesin; Hi-C; RNA-seq; STAG2 and PAXIP1 co-depletion in lung cancer cells; epistasis experiments |
Nucleic acids research |
High |
37070193
|
| 2023 |
STAG2 knockout increases DSBs and chromosomal aberrations by reducing homologous recombination repair. Mechanistically, STAG2 deficiency restores expression of KMT5A, which methylates H4K20 (H4K20me0 to H4K20me1), thereby decreasing recruitment of BRCA1-BARD1 to chromatin and impairing HR. STAG2 loss confers hypersensitivity to ATM inhibitor, PARP inhibitor, and their combination. |
STAG2 CRISPR KO; HR repair assays; γH2AX and chromosomal aberration quantification; KMT5A expression and H4K20 methylation analysis; BRCA1-BARD1 chromatin recruitment assays; drug sensitivity assays |
Advanced science (Weinheim, Baden-Wurttemberg, Germany) |
Medium |
37985839
|
| 2020 |
In mice, Stag2 ablation in the nervous system (conditional KO in oligodendrocytes) impairs myelination: Stag2-cKO oligodendrocytes show delayed maturation and downregulation of myelination-related genes. Mechanistically, STAG2-cohesin generates promoter-anchored chromatin loops at myelination-promoting genes to facilitate their transcription; Stag2 loss reduces these promoter-anchored loops at downregulated myelination genes. |
Conditional Stag2 KO mice; RNA-seq of oligodendrocytes; ChIP-seq/HiChIP for cohesin and chromatin loops; histological analysis of myelination; behavioral and survival assessment |
eLife |
High |
35959892
|
| 2024 |
STAG2 is uniquely tumor-suppressive among all core and auxiliary cohesin components in oncogenic KRAS-driven lung tumorigenesis in vivo. PAXIP1 and PAGR1 are epistatic to STAG2 in this context: their tumor-suppressive effects are highly correlated with STAG2, and STAG2 inactivation elicits gene expression, chromatin accessibility, and 3D genome conformation changes shared with PAXIP1-deficient cells, establishing a STAG2-PAXIP1/PAGR1 tumor-suppressive axis. |
Somatic CRISPR-Cas9 genome editing with tumor barcoding in autochthonous KRAS-driven lung cancer mouse model; epistasis in vivo; RNA-seq; ATAC-seq; Hi-C in lung cancer cell lines |
The Journal of experimental medicine |
High |
39652422
|
| 2016 |
Loss of STAG2 in melanoma cells inhibits CTCF-mediated expression of DUSP6, leading to reactivation of MAPK signaling (ERK1/2), which confers resistance to BRAF inhibitors. STAG2 knockdown decreased sensitivity of BRAF(V600E)-mutant melanoma cells and xenograft tumors to BRAFi. |
shRNA knockdown of STAG2 or STAG3 in BRAF(V600E) melanoma cell lines; xenograft models; CTCF ChIP; DUSP6 expression analysis; ERK phosphorylation assays; sequencing of BRAFi-resistant patient tumors |
Nature medicine |
Medium |
27500726
|
| 2016 |
Many tumor-derived STAG2 missense mutations retain the ability to interact with the cohesin ring, but the presence of mutant STAG2 reduces the ability of regulatory subunits WAPL, PDS5A, and PDS5B to interact with the core cohesin ring. Nonsense STAG2 mutations cause cohesion defects and some anaphase defects, while missense mutations do not impair cohesion or chromosome segregation, suggesting distinct functional consequences of different mutation classes. |
AAV-mediated introduction of nine tumor-derived STAG2 mutations into the endogenous locus; co-immunoprecipitation of WAPL, PDS5A, PDS5B; sister chromatid cohesion assays; anaphase analysis; chromosome counting |
PLoS genetics |
High |
26871722
|
| 2013 |
STAG2 loss in bladder cancer cells (knockdown) does not increase aneuploidy, while STAG2 reintroduction into non-expressing bladder cancer cells led to reduced colony formation, indicating a tumor suppressor role through mechanisms independent of aneuploidy prevention. |
siRNA knockdown of STAG2 in bladder cancer cells with karyotype analysis; stable re-expression of STAG2 in STAG2-negative cells; colony formation assays |
Nature genetics |
Medium |
24121791
|
| 2020 |
Chronic loss of STAG2 in AML cells leads to loss of smaller chromatin loop domains and formation/maintenance of large domains, altering genome compartmentalization. These structural changes result in deregulated gene expression including the HOXA locus and MAPK signaling pathway, and increase sensitivity to MEK inhibition. |
RNA-seq; ChIP-seq; HiChIP in a chronic STAG2 loss AML cell model; MEK inhibitor sensitivity assays |
Journal of translational medicine |
Medium |
32883299
|
| 2021 |
STAG2 loss in bladder cancer cells reduces short- and mid-range chromatin interactions engaging genes (more so than STAG1-mediated contacts), results in down-regulation of the luminal urothelial gene signature and up-regulation of the basal transcriptional program. Contacts lost upon STAG2 depletion preferentially occur within silent chromatin domains and are associated with de-repression of lineage-specifying genes, suggesting STAG2-mediated looping maintains the basal program in a silent state. |
ChIP-seq for STAG1, STAG2; Hi-C; RNA-seq; STAG2 knockdown in RT112 bladder cancer cells; integration of genomic and gene expression data |
Nucleic acids research |
Medium |
34648034
|
| 2024 |
STAG2 mutations in AML alter cohesin occupancy at specific loci, reduce gene expression and local chromatin activation at affected sites, and disrupt spatial chromatin looping. These effects are not compensated by STAG1-cohesin. STAG2 depletion (not STAG1 depletion) in primary human HSPCs impairs differentiation and maintains HSPC-like gene expression, mimicking STAG2-mutant AML. |
Cohesin ChIP-seq, RNA-seq, and Hi-C in AML patient samples; STAG2 and STAG1 depletion in primary human HSPCs; differentiation assays |
Cell reports |
High |
39084219
|
| 2024 |
In Ewing sarcoma, cohesin-STAG2 facilitates communication between EWS::FLI1-bound GGAA microsatellite neo-enhancers and their target promoters. STAG2 loss severely decreases total chromatin-bound cohesin (NIPBL levels unchanged), alters CTCF-dependent chromatin contacts at STAG2-dependent signature genes unrelated to EWS::FLI1, and STAG1 cannot compensate. A STAG2-dependent gene signature is associated with worse prognosis. |
Capture Hi-C; ChIP-seq for STAG1, STAG2, CTCF, cohesin subunits; RNA-seq in isogenic STAG2-KO Ewing sarcoma cells; patient transcriptomic data analysis |
EMBO reports |
High |
39487368
|
| 2024 |
STAG2 mutation correction in GBM cell lines alters expression of ~10% of genes, predominantly negatively regulated by STAG2. STAG2 correction alters thousands of individual chromatin loops (many gene-proximal) without affecting A/B compartments or TADs. Loops specific to STAG2-mutant cells (governed by STAG1-cohesin) are very large, consistent with greater loop extrusion processivity for STAG1-cohesin vs. STAG2-cohesin. STAG2 mutation activates Polycomb activity, increasing H3K27me3 marks. |
Endogenous STAG2 mutation correction by AAV-mediated targeting in two GBM cell lines; RNA-seq; Hi-C; ChIP-seq for H3K27me3 |
The Journal of biological chemistry |
High |
38705393
|
| 2023 |
STAG2 inactivation in BRAF-mutant thyroid cancer cells decreases c-Myc protein stability via the ERK/AKT/GSK3β feedback pathway, thereby impairing glutamine metabolism by downregulating c-Myc targets SCL1A5, GLS, and GLS2, and conferring sensitivity to glutaminase inhibitor BPTES. |
STAG2 knockdown in BRAF-mutant thyroid cancer cell lines; c-Myc stability assays; ERK/AKT/GSK3β pathway analysis; glutamine deprivation and BPTES sensitivity assays; in vivo xenograft assays |
Cell death & disease |
Medium |
37479689
|
| 2017 |
STAG2 loss promotes telomere recombination as an alternative mechanism of telomere maintenance. Despite loss of centromere cohesion, STAG2-mutant tumor cells maintain cohesion at chromosome arms and telomeres. STAG2 silencing in normal human telomerase-negative cells leads to increased telomere recombination, delayed telomere shortening, and postponed senescence onset. |
STAG2 silencing (shRNA and CRISPR) in normal human fibroblasts and tumor cell lines; telomere FISH; sister chromatid exchange assays at telomeres; telomerase inhibitor sensitivity; senescence assays |
Cancer research |
Medium |
28819029
|