STAG2 (Stromal Antigen 2)

2013-09-01   Suning Chen , Stefan Nagel , Hans G Drexler , Roderick AF MacLeod 

Identity

HGNC
LOCATION
Xq25
LOCUSID
ALIAS
SA-2,SA2,SCC3B,bA517O1.1
FUSION GENES

DNA/RNA

Atlas Image
Figure 1. Clustering of GATA3 TFBS in STAG2 regulatory region. Schema showing multiple GATA3 TFBS present in the regulatory intron of STAG2. For additional TFBS see: SABiosciences

Description

The STAG2 gene consists of 35 exons spanning 142 Kbp, located at chromosome Xq25.

Transcription

Transcription takes place in a centromere --> telomere orientation (plus strand). Transcription of STAG2 gene generates 19 different mRNA transcripts, the longest is 6045 bp containing 34 exons (ENST00000371160).
There are multiple transcription factor binding sites (TFBS) for GATA3 present in the regulatory first intron of STAG2 summarized above (Fig. 1).

Pseudogene

There are no known pseudogenes.

Proteins

Description

The STAG2 gene encodes two alternative isoforms:
- A: Q8N3U4-1, 1231 aa, 141.3 KDa
- B: Q8N3U4-2, 1268 aa, 145.7 KDa
Atlas Image
Figure 2. Domain structure of STAG2 and amino acid sequence.

Expression

STAG2 mRNA is expressed in cells from most tissues. Peak expression occurs in T-cell and early erythroid compartments, and in the uterus. Lowest expression is found in brain, heart, liver, lung and testis. STAG2 is also overexpressed in T-/B-cell acute lymphoblastic leukemia (ALL) and in other hematopoietic neoplasias, followed by small cell lung cancer, neuroblastoma and medulloblastoma.
It has been reported that the expression of STAG2 protein is lost in some cancer types such as glioblastoma, Ewings sarcoma, and melanoma (Solomon et al., 2011), colorectal carcinomas, gastric carcinomas and prostate carcinomas (Kim et al., 2012).

Localisation

Nucleus albeit reportedly with transmembrane potential.

Function

STAG2 forms the cohesin complex together with SMC1, SMC3, and SCC1. The cohesin complex is a ring-like structure and is required for cohesion of sister chromatids after DNA replication. The complex is cleaved at the metaphase-anaphase transition and dissociates from chromatin for separation of sister chromatids (Xiao et al., 2011). While STAG2 mediates centromere cohesion, that of telomeres is mediated by the homologous STAG1 (Canudas et al., 2009; Remeseiro et al., 2012).
Cohesin also plays a major part in the organization of interphase chromatin, including the orchestration of gene expression in relation to cell cycle where STAG2 also plays a key role along with the universal transcriptional repressor CCCTC-binding factor (CTCF). CTCF-cohesin interactions require contact between STAG2 and C-terminal CTCF which facilitate recruitment of other cohesion complex proteins and formation of the cohesion ring. This interaction is also needed for CTCF to function as a transcriptional insulator.

Homology

Two paralogs are known: STAG1 and STAG3 which can replace STAG2 in the cohesion complex.
Atlas Image
Figure 3. Cohesin complex showing ring structure. Diagram showing ring structure of cohesin complex (modified from Hagstrom and Meyer, 2003, and Remeseiro and Losada, 2013).

Mutations

Note

Recurrent STAG2 gene mutations were reported in glioblastoma, melanoma and Ewings sarcoma (Solomon et al., 2011). Recently, STAG2 gene was found frequently mutated in myeloid neoplasms, including acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), chronic myelogenous leukemia (CML) and classical myeloproliferative neoplasms (MPN) (Kon et al., 2013). Other studies observed lower frequencies of STAG2 mutation (Chung et al., 2012; Kim et al., 2012).
It remains unclear whether mutations affecting STAG2 operate to induce aneuploidy (Solomon et al., 2011; Kolodner et al., 2011), or simply to abrogate expression (Rocquain et al., 2010; Kon et al., 2013).

Implicated in

Entity name
Myeloid neoplasms
Note
Mutation and deletion of the STAG2 gene was identified in 5.8% (13/224) of MDS, 10.2% (9/88) of CMML, 6.4% (10/157) of AML, 3.1% (2/64) of CML, and 1.3% (1/77) of MPN: the STAG2 alterations were mostly exclusive with alterations involving other components of cohesin complex (SMC1, SMC3, and RAD21) and were significantly associated with mutations in TET2, ASXL1, and EZH2 (Kon et al., 2013).
Entity name
t(X;11)(q25;p13)
Disease
T-ALL: only two T-ALL cell lines described so far.
Cytogenetics
t(X;11)(q25;p13) in MOLT-14 cells and t(X;1;11)(q25;p13;p13) in PER-117 cells. The rearrangement is fully cryptic (see below).
Atlas Image
Figure 4. Cytogenetic analysis of t(X;11) effecting juxtaposition of STAG2 and LMO2. Image shows FISH analysis of t(X;11)(q25;p13) in a T-ALL cell line (DSM ACC 437). Note that this translocation is cryptic in G-banding (Fig. A). FISH using BAC and fosmid clones (Fig. B, C) places breakpoints in MOLT-14 and another T-ALL cell line PER-117, both inside the first (regulatory) intron of STAG2. In both cell lines expression of STAG2 is lost, attributable to divestment of this region which includes a deeply conserved cluster of regulatory motifs, including transcription factor binding sites and DNaseI sensitive sites. Upregulation of LMO2 in both cell lines occurred, concomitant with acquisition of the upstream STAG2 region. Fig. D: Genomic map of Xq25 showing breakpoints in regulatory region in relation to clones used for FISH. Figure redrawn and updated from Chen et al. (2011).
Oncogenesis
t(X;11)(q25;p13) results in simultaneous upregulation of LMO2 and silencing of STAG2 by juxtaposition of the far upstream region of LMO2 with the first regulatory intron of STAG2 (Chen et al., 2011).

Bibliography

Pubmed IDLast YearTitleAuthors
198226712009Differential regulation of telomere and centromere cohesion by the Scc3 homologues SA1 and SA2, respectively, in human cells.Canudas S et al
216471582011Novel non-TCR chromosome translocations t(3;11)(q25;p13) and t(X;11)(q25;p13) activating LMO2 by juxtaposition with MBNL1 and STAG2.Chen S et al
221328722012Somatic mutation of STAG2, an aneuploidy-related gene, is rare in acute leukemias.Chung NG et al
128383442003Condensin and cohesin: more than chromosome compactor and glue.Hagstrom KA et al
226680122012Mutational and expressional analyses of STAG2 gene in solid cancers.Kim MS et al
218524772011Cancer. Aneuploidy drives a mutator phenotype in cancer.Kolodner RD et al
239555992013Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms.Kon A et al
232193702013Cohesin, a chromatin engagement ring.Remeseiro S et al
206871022010Alteration of cohesin genes in myeloid diseases.Rocquain J et al
218525052011Mutational inactivation of STAG2 causes aneuploidy in human cancer.Solomon DA et al
214447192011Specific sites in the C terminus of CTCF interact with the SA2 subunit of the cohesin complex and are required for cohesin-dependent insulation activity.Xiao T et al

Other Information

Locus ID:

NCBI: 10735
MIM: 300826
HGNC: 11355
Ensembl: ENSG00000101972

Variants:

dbSNP: 10735
ClinVar: 10735
TCGA: ENSG00000101972
COSMIC: STAG2

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000101972ENST00000218089Q8N3U4
ENSG00000101972ENST00000371144Q8N3U4
ENSG00000101972ENST00000371145Q8N3U4
ENSG00000101972ENST00000371157Q8N3U4
ENSG00000101972ENST00000371160Q8N3U4
ENSG00000101972ENST00000394477B1AMS9
ENSG00000101972ENST00000394478B1AMT0
ENSG00000101972ENST00000428941B1AMT2
ENSG00000101972ENST00000435103B1AMT1
ENSG00000101972ENST00000435215B1AMT3
ENSG00000101972ENST00000455404B1AMT4
ENSG00000101972ENST00000458176E7ERE6
ENSG00000101972ENST00000458700B1AMS8

Expression (GTEx)

0
5
10
15
20
25
30
35
40
45
50

Pathways

PathwaySourceExternal ID
Cell cycleKEGGko04110
Cell cycleKEGGhsa04110
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
SUMOylationREACTOMER-HSA-2990846
SUMO E3 ligases SUMOylate target proteinsREACTOMER-HSA-3108232
SUMOylation of DNA damage response and repair proteinsREACTOMER-HSA-3108214
Cell CycleREACTOMER-HSA-1640170
Cell Cycle, MitoticREACTOMER-HSA-69278
S PhaseREACTOMER-HSA-69242
Establishment of Sister Chromatid CohesionREACTOMER-HSA-2468052
M PhaseREACTOMER-HSA-68886
Mitotic PrometaphaseREACTOMER-HSA-68877
Resolution of Sister Chromatid CohesionREACTOMER-HSA-2500257
Mitotic Metaphase and AnaphaseREACTOMER-HSA-2555396
Mitotic AnaphaseREACTOMER-HSA-68882
Separation of Sister ChromatidsREACTOMER-HSA-2467813
Mitotic Telophase/CytokinesisREACTOMER-HSA-68884
Cohesin Loading onto ChromatinREACTOMER-HSA-2470946
MeiosisREACTOMER-HSA-1500620
Meiotic synapsisREACTOMER-HSA-1221632

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
157370632005Dissociation of cohesin from chromosome arms and loss of arm cohesion during early mitosis depends on phosphorylation of SA2.190
218525052011Mutational inactivation of STAG2 causes aneuploidy in human cancer.165
157370642005Shugoshin prevents dissociation of cohesin from centromeres during mitosis in vertebrate cells.139
252237342014Genomic landscape of Ewing sarcoma defines an aggressive subtype with co-association of STAG2 and TP53 mutations.130
251869492014The genomic landscape of pediatric Ewing sarcoma.129
250102052014The genomic landscape of the Ewing Sarcoma family of tumors reveals recurrent STAG2 mutation.117
214447192011Specific sites in the C terminus of CTCF interact with the SA2 subunit of the cohesin complex and are required for cohesin-dependent insulation activity.88
241217912013Recurrent inactivation of STAG2 in bladder cancer is not associated with aneuploidy.86
198226712009Differential regulation of telomere and centromere cohesion by the Scc3 homologues SA1 and SA2, respectively, in human cells.73
241217892013Frequent truncating mutations of STAG2 in bladder cancer.61

Citation

Suning Chen ; Stefan Nagel ; Hans G Drexler ; Roderick AF MacLeod

STAG2 (Stromal Antigen 2)

Atlas Genet Cytogenet Oncol Haematol. 2013-09-01

Online version: http://atlasgeneticsoncology.org/gene/52377/stag2