STAG2

Last updated
STAG2
Structure of SA2 (blue) and RAD21 (green) (PDB 4PK7).png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases STAG2 , SA-2, SA2, SCC3B, bA517O1.1, stromal antigen 2, NEDXCF, MKMS, HPE13
External IDs OMIM: 300826 MGI: 1098583 HomoloGene: 38206 GeneCards: STAG2
Orthologs
SpeciesHumanMouse
Entrez

10735

20843

Ensembl

ENSG00000101972

ENSMUSG00000025862

UniProt

Q8N3U4

O35638

RefSeq (mRNA)

NM_001077712
NM_001290713
NM_021465
NM_001358225

RefSeq (protein)

NP_001071180
NP_001277642
NP_067440
NP_001345154

Location (UCSC) Chr X: 123.96 – 124.42 Mb Chr X: 41.24 – 41.37 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Cohesin subunit SA-2 (SA2) is a protein that in humans is encoded by the STAG2 gene. [5] [6] SA2 is a subunit of the Cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. In somatic cells cohesin is formed of SMC3, SMC1, RAD21 and either SA1 or SA2 whereas in meiosis, cohesin is formed of SMC3, SMC1B, REC8 and SA3.

Contents

STAG2 is frequently mutated in a range of cancers [7] and several other disorders.

Function

SA2 is part of the cohesin complex, which is a structure that holds the sister chromatids together after DNA replication. [8] STAG2 has been shown to interact with STAG1. [9] Cohesion folds by DNA loop extrusion and this cohesion consists of SMC1, SMC3, RAD21, and either STAG1 or STAG2. [10] SA2 interacts with a ring-like structure composed of SMC1A, SMC3, and RAD21, to form the core of the cohesin complex. [11] The ring-like structure binds chromosomes together until degradation of the cohesin complex is finished during cell division. [12] This allows for the replicated chromosomes to separate into two new cells. Another role of STAG2 is to encode the stromal antigen 2 protein, which is involved in chromatin organization, transcription, DNA repair and control of downstream gene expression. [13]

Structure

Of the cohesin complex, STAG2 is the subunit where the most variants have been reported in cancer. [14] This is thought to be because this gene is located in the X chromosome, therefore only one mutation is needed to inactivate it. [15] Xq25 duplication syndrome, is an X-linked neurodevelopmental disorder that results in delayed development and intellectual disability associated with abnormal behavior and dysmorphic facial features, and the whole STAG2 gene can develop STAG2 encephalopathy. [16] This has all the symptoms of epilepsy with eyelid myoclonia and absences (EMA), and was formally named Jeavons syndrome (JS). [17]

Mutations

One result of mutations in STAG2 can result in one third of non-muscle-invasive bladder cancer to have complete loss of SA2 protein. [18] The loss of this protein has been shown to indicate the prognosis of disease and survival. it has been shown there was a delay in maturation of oligodendrocytes and transcription of myelination-related genes was reduced. Cohesion is needed in proper gene expression in specific cells and an implication the myelination is affected in a negative way. [10] Mutations of STAG2 occur frequently in many cancers, which indicates this protein has a role in cancer. Mutations of the STAG2 gene are frequently seen in multiple adult and pediatric cancers. STAG has been found to be the only gene of 12 that is mutated significantly in at least four types of cancers. [12]

Related Research Articles

<span class="mw-page-title-main">Spindle checkpoint</span> Cell cycle checkpoint

The spindle checkpoint, also known as the metaphase-to-anaphase transition, the spindle assembly checkpoint (SAC), the metaphase checkpoint, or the mitotic checkpoint, is a cell cycle checkpoint during mitosis or meiosis that prevents the separation of the duplicated chromosomes (anaphase) until each chromosome is properly attached to the spindle. To achieve proper segregation, the two kinetochores on the sister chromatids must be attached to opposite spindle poles. Only this pattern of attachment will ensure that each daughter cell receives one copy of the chromosome. The defining biochemical feature of this checkpoint is the stimulation of the anaphase-promoting complex by M-phase cyclin-CDK complexes, which in turn causes the proteolytic destruction of cyclins and proteins that hold the sister chromatids together.

<span class="mw-page-title-main">Separase</span>

Separase, also known as separin, is a cysteine protease responsible for triggering anaphase by hydrolysing cohesin, which is the protein responsible for binding sister chromatids during the early stage of anaphase. In humans, separin is encoded by the ESPL1 gene.

SMC complexes represent a large family of ATPases that participate in many aspects of higher-order chromosome organization and dynamics. SMC stands for Structural Maintenance of Chromosomes.

<span class="mw-page-title-main">Cohesin</span> Protein complex that regulates the separation of sister chromatids during cell division

Cohesin is a protein complex that mediates sister chromatid cohesion, homologous recombination, and DNA looping. Cohesin is formed of SMC3, SMC1, SCC1 and SCC3. Cohesin holds sister chromatids together after DNA replication until anaphase when removal of cohesin leads to separation of sister chromatids. The complex forms a ring-like structure and it is believed that sister chromatids are held together by entrapment inside the cohesin ring. Cohesin is a member of the SMC family of protein complexes which includes Condensin, MukBEF and SMC-ScpAB.

<span class="mw-page-title-main">NIPBL</span> Protein-coding gene in the species Homo sapiens

Nipped-B-like protein (NIPBL), also known as SCC2 or delangin is a protein that in humans is encoded by the NIPBL gene. NIPBL is required for the association of cohesin with DNA and is the major subunit of the cohesin loading complex. Heterozygous mutations in NIPBL account for an estimated 60% of case of Cornelia de Lange Syndrome.

<span class="mw-page-title-main">SMC1A</span> Protein-coding gene in humans

Structural maintenance of chromosomes protein 1A (SMC1A) is a protein that in humans is encoded by the SMC1A gene. SMC1A is a subunit of the cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. In somatic cells, cohesin is formed of SMC1A, SMC3, RAD21 and either SA1 or SA2 whereas in meiosis, cohesin is formed of SMC3, SMC1B, REC8 and SA3.

<span class="mw-page-title-main">RAD21</span> Protein-coding gene in humans

Double-strand-break repair protein rad21 homolog is a protein that in humans is encoded by the RAD21 gene. RAD21, an essential gene, encodes a DNA double-strand break (DSB) repair protein that is evolutionarily conserved in all eukaryotes from budding yeast to humans. RAD21 protein is a structural component of the highly conserved cohesin complex consisting of RAD21, SMC1A, SMC3, and SCC3 [ STAG1 (SA1) and STAG2 (SA2) in multicellular organisms] proteins, involved in sister chromatid cohesion.

<span class="mw-page-title-main">SMC3</span> Protein-coding gene in humans

Structural maintenance of chromosomes protein 3 (SMC3) is a protein that in humans is encoded by the SMC3 gene. SMC3 is a subunit of the Cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. Cohesin is formed of SMC3, SMC1, RAD21 and either SA1 or SA2. In humans, SMC3 is present in all cohesin complexes whereas there are multiple paralogs for the other subunits.

<span class="mw-page-title-main">WAPAL</span> Protein-coding gene in the species Homo sapiens

Wings apart-like protein homolog (WAPL) is a protein that in humans is encoded by the WAPAL gene. WAPL is a key regulator of the Cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. Cohesin is formed of SMC3, SMC1, RAD21 and either SA1 or SA2. Cohesin has a ring-like arrangement and it is thought that it associates with the chromosome by entrapping it whether as a loop of DNA, a single strand or a pair of sister chromosomes. WAPL forms a complex with PDS5A or PDS5B and releases cohesin from DNA by opening the interface between SMC3 and RAD21.

<span class="mw-page-title-main">Shugoshin 1</span> Protein-coding gene in the species Homo sapiens

Shugoshin 1 or Shugoshin-like 1, is a protein that in humans is encoded by the SGO1 gene.

<span class="mw-page-title-main">SMC6</span> Protein-coding gene in the species Homo sapiens

Structural maintenance of chromosomes protein 6 is a protein that in humans is encoded by the SMC6 gene.

<span class="mw-page-title-main">PDS5B</span> Protein-coding gene in the species Homo sapiens

Sister chromatid cohesion protein PDS5 homolog B(PDS5B) is a protein that in humans is encoded by the PDS5B gene. It is a regulatory subunit of the Cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. The core cohesin complex is formed of SMC3, SMC1, RAD21 and either SA1 or SA2. PDS5 associates with WAPL to stimulate the release of cohesin from DNA but during DNA replication PDS5 promotes acetylation of SMC3 by ESCO1 and ESCO2.

<span class="mw-page-title-main">SMC5</span> Protein-coding gene in the species Homo sapiens

Structural maintenance of chromosomes protein 5 is a protein encoded by the SMC5 gene in human.

<span class="mw-page-title-main">REC8</span> Protein-coding gene in the species Homo sapiens

Meiotic recombination protein REC8 homolog is a protein that in humans is encoded by the REC8 gene.

<span class="mw-page-title-main">STAG1</span> Protein-coding gene in the species Homo sapiens

Cohesin subunit SA-1 (SA1) is a protein that in humans is encoded by the STAG1 gene. SA1 is a subunit of the Cohesin complex which mediates sister chromatid cohesion, homologous recombination and DNA looping. In somatic cells cohesin is formed of SMC3, SMC1, RAD21 and either SA1 or SA2 whereas in meiosis, cohesin is formed of SMC3, SMC1B, REC8 and SA3. There is a nonprofit community formed for those with a STAG1 Gene mutation at www.stag1gene.org.

<span class="mw-page-title-main">SMC2</span> Protein-coding gene in the species Homo sapiens

Structural maintenance of chromosomes protein 2 (SMC-2), also known as chromosome-associated protein E (CAP-E), is a protein that in humans is encoded by the SMC2 gene. SMC2 is part of the SMC protein family and is a core subunit of condensin I and II, large protein complexes involved in chromosome condensation, overall organization. Several studies have demonstrated the necessity of SMC2 for cell division and proliferation.

Sister chromatid cohesion refers to the process by which sister chromatids are paired and held together during certain phases of the cell cycle. Establishment of sister chromatid cohesion is the process by which chromatin-associated cohesin protein becomes competent to physically bind together the sister chromatids. In general, cohesion is established during S phase as DNA is replicated, and is lost when chromosomes segregate during mitosis and meiosis. Some studies have suggested that cohesion aids in aligning the kinetochores during mitosis by forcing the kinetochores to face opposite cell poles.

<span class="mw-page-title-main">SMC1B</span> Protein-coding gene in the species Homo sapiens

Structural maintenance of chromosomes protein 1B (SMC-1B) is a protein that in humans is encoded by the SMC1B gene. SMC proteins engage in chromosome organization and can be broken into 3 groups based on function which are cohesins, condensins, and DNA repair.SMC-1B belongs to a family of proteins required for chromatid cohesion and DNA recombination during meiosis and mitosis. SMC1ß protein appears to participate with other cohesins REC8, STAG3 and SMC3 in sister-chromatid cohesion throughout the whole meiotic process in human oocytes.

<span class="mw-page-title-main">STAG3 (gene)</span> Protein-coding gene in the species Homo sapiens

Stromal antigen 3 is a protein that in humans is encoded by the STAG3 gene. STAG3 protein is a component of a cohesin complex that regulates the separation of sister chromatids specifically during meiosis. STAG3 appears to be paramount in sister-chromatid cohesion throughout the meiotic process in human oocytes and spermatocytes.

<span class="mw-page-title-main">Frank Uhlmann</span>

Frank Uhlmann FRS is a group leader at the Francis Crick Institute in London.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000101972 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000025862 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Carramolino L, Lee BC, Zaballos A, Peled A, Barthelemy I, Shav-Tal Y, et al. (August 1997). "SA-1, a nuclear protein encoded by one member of a novel gene family: molecular cloning and detection in hemopoietic organs". Gene. 195 (2): 151–159. doi:10.1016/S0378-1119(97)00121-2. PMID   9305759.
  6. ↑ "Entrez Gene: STAG2 stromal antigen 2".
  7. ↑ De Koninck M, Losada A (December 2016). "Cohesin Mutations in Cancer". Cold Spring Harbor Perspectives in Medicine. 6 (12): a026476. doi: 10.1101/cshperspect.a026476 . PMC   5131750 . PMID   27742736.
  8. ↑ Mehta GD, Kumar R, Srivastava S, Ghosh SK (August 2013). "Cohesin: functions beyond sister chromatid cohesion". FEBS Letters. 587 (15): 2299–2312. doi: 10.1016/j.febslet.2013.06.035 . PMID   23831059.
  9. ↑ Sumara I, Vorlaufer E, Gieffers C, Peters BH, Peters JM (November 2000). "Characterization of vertebrate cohesin complexes and their regulation in prophase". The Journal of Cell Biology. 151 (4): 749–762. doi:10.1083/jcb.151.4.749. PMC   2169443 . PMID   11076961.
  10. 1 2 Cheng N, Li G, Kanchwala M, Evers BM, Xing C, Yu H (August 2022). "STAG2 promotes the myelination transcriptional program in oligodendrocytes". eLife. 11: e77848. doi:10.7554/eLife.77848. PMC   9439679 . PMID   35959892.
  11. ↑ Losada A (June 2014). "Cohesin in cancer: chromosome segregation and beyond". Nature Reviews. Cancer. 14 (6): 389–393. doi:10.1038/nrc3743. PMID   24854081. S2CID   22909640.
  12. 1 2 Arruda NL, Carico ZM, Justice M, Liu YF, Zhou J, Stefan HC, Dowen JM (August 2020). "Distinct and overlapping roles of STAG1 and STAG2 in cohesin localization and gene expression in embryonic stem cells". Epigenetics & Chromatin. 13 (1): 32. doi:10.1186/s13072-020-00353-9. PMC   7418333 . PMID   32778134.
  13. ↑ Athans S, Krishnan N, Ramakrishnan S, Cortes Gomez E, Lage-Vickers S, Rak M, et al. (October 2022). "STAG2 expression is associated with adverse survival outcomes and regulates cell phenotype in muscle-invasive bladder cancer". Cancer Research Communications. 2 (10): 1129–1143. doi:10.1158/2767-9764.CRC-22-0155. PMC   9583756 . PMID   36275363. S2CID   252025964.
  14. ↑ Cosmic. "STAG2 Gene - COSMIC". cancer.sanger.ac.uk. Retrieved 2018-02-13.
  15. ↑ Kim JS, He X, Orr B, Wutz G, Hill V, Peters JM, et al. (February 2016). "Intact Cohesion, Anaphase, and Chromosome Segregation in Human Cells Harboring Tumor-Derived Mutations in STAG2". PLOS Genetics. 12 (2): e1005865. doi:10.1371/journal.pgen.1005865. PMC   4752446 . PMID   26871722.
  16. ↑ Turchi G, Bernardo P, Consales A, Bilo L, Coppola A (April 2020). "Xq25 microduplication syndrome: a further contribution to its definition. A case report and review of the literature". Clinical Dysmorphology. 29 (2): 90–96. doi:10.1097/mcd.0000000000000303. PMID   31609727. S2CID   204703545.
  17. ↑ Gokce-Samar Z, de Bellescize J, Arzimanoglou A, Putoux A, Chatron N, Lesca G, Portes VD (December 2022). "STAG2 microduplication in a patient with eyelid myoclonia and absences and a review of EMA-related reported genes". European Journal of Medical Genetics. 65 (12): 104636. doi:10.1016/j.ejmg.2022.104636. PMID   36216271. S2CID   252792610.
  18. ↑ Gordon NS, Humayun-Zakaria N, Goel A, Abbotts B, Zeegers MP, Cheng KK, et al. (April 2022). "STAG2 Protein Expression in Non-muscle-invasive Bladder Cancer: Associations with Sex, Genomic and Transcriptomic Changes, and Clinical Outcomes". European Urology Open Science. 38: 88–95. doi:10.1016/j.euros.2022.02.004. PMC   9051973 . PMID   35495284.
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