STAG3 (gene)
| STAG3 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | STAG3, stromal antigen 3, SPGF61 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 608489; MGI: 1355311; HomoloGene: 40844; GeneCards: STAG3; OMA:STAG3 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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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.
Role in meiosis
[edit]STAG3 associates with several key structures throughout meiosis. As shown in spermatocytes, STAG3 interacts with the synaptonemal complex or SC, which facilitates the alignment of sister chromosomes. Furthermore, STAG3 associates with axial elements during prophase, which are responsible for packaging the sister chromosomes via loops. Once the axial elements interact with the SC they are termed as lateral elements. STAG3's involvement with these three complexes suggest its profound role in the cohesion of sister chromatids. Moreover, STAG3 has also been detected in the centromeres and telomeres of sister chromosomes, implying a potential role in telomere cohesion as well.[5]
The role of STAG3 changes once prophase elapses. This is supported by the change in localization of STAG3 between metaphase and anaphase. STAG3 disassociates with the axes, but stays localized in the centromere, during the transition. Once anaphase is achieved, STAG3 is not observed anywhere in the chromosome architecture, further emphasizing its primary function in chromosome alignment and packaging.[5]
Variants
[edit]Deficiencies in STAG3 production can result in severe complications during meiosis. In the aging and age-related disease strain of mice, SAM, many cohesin proteins, including STAG3, are shown in reduced numbers. This supports the widely believed role of cohesin deficiency in aneuploidy as a result of aging.[5]
Infertility is a widely studied outcome of STAG3 deficiency or knockout. In a study, a homozygous knockout of STAG3 gene was made in a strain of mice. The males that had the double knockout had their testis reduced to half the size of the wild type mouse. Female mice also gonad atrophy. In STAG3 deficient female mice, body weight to ovary ratio dropped 10 fold compared to STAG +/- females.[6] While all other cohesin subunits were able to assemble, the loss of STAG3 impaired the synapsis of sister chromosomes, as shortened or no axial elements and SCs were able to be formed,[7] causing the spermatocytes and oocytes to forgo meiosis upon reaching prophase. In STAG3 knockout cells, the presence of other necessary proteins for synaptonemal complex formation, SMC1beta, RAD21L, and REC8, were found in decreased amounts.
A homozygous 1-bp deletion inducing a frameshift mutation in STAG3 causes premature ovarian failure. Loss of function mutations in STAG3 can result in stifling ovary development in utero. Much like the infertile STAG3 knockout male mice models, female mice also experienced meiotic arrest during prophase. Since females are born with a finite amount of oocytes, a significant deficiency in STAG3 can result in a depletion of viable eggs early in life.[8]
In males, variants can result in azoospermia, or not motile sperm. To elaborate, a missense mutation, which resulted in a premature stop codon, leading to a complete loss of function in STAG3 caused infertility in men. Another mutation that has been identified changes a neutral amino acid residue, leucine, to a positively charged amino acid, arginine. This causes debilitating protein misfolding, preventing the protein from taking on the correct conformation, rendering it useless. It has been identified that variants in the STAG3 gene can be inherited in an autosomal recessive manner.[7]
DNA damage repair pathways can also be disrupted by STAG3 depletion. In STAG3 mutants, DMC1 and RAD51, which are responsible for double stranded break invasion during crossing over events, aggregated after the double stranded breaks were supposed to be repaired. Given the lack of dissociation of RAD51 and DMC1, it is assumed that ATR and ATRIP function, which are responsible for double stranded break repair in recombination, is abnormal as result of STAG3 deficiency.[6]
References
[edit]- ^ a b c GRCh38: Ensembl release 89: ENSG00000066923 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000036928 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b c Winters T, McNicoll F, Jessberger R (2014-06-02). "Meiotic cohesin STAG 3 is required for chromosome axis formation and sister chromatid cohesion". The EMBO Journal. 33 (11): 1256–1270. doi:10.1002/embj.201387330. ISSN 0261-4189. PMC 4198028. PMID 24797474.
- ^ a b Hopkins J, Hwang G, Jacob J, Sapp N, Bedigian R, Oka K, Overbeek P, Murray S, Jordan PW (2014-07-03). "Meiosis-Specific Cohesin Component, Stag3 Is Essential for Maintaining Centromere Chromatid Cohesion, and Required for DNA Repair and Synapsis between Homologous Chromosomes". PLOS Genetics. 10 (7): e1004413. doi:10.1371/journal.pgen.1004413. ISSN 1553-7404. PMC 4081007. PMID 24992337.
- ^ a b van der Bijl N, Röpke A, Biswas U, Wöste M, Jessberger R, Kliesch S, Friedrich C, Tüttelmann F (2019-11-04). "Mutations in the stromal antigen 3 (STAG3) gene cause male infertility due to meiotic arrest". Human Reproduction. 34 (11): 2112–2119. doi:10.1093/humrep/dez204. ISSN 0268-1161. PMID 31682730.
- ^ Le Quesne Stabej P, Williams HJ, James C, Tekman M, Stanescu HC, Kleta R, Ocaka L, Lescai F, Storr HL, Bitner-Glindzicz M, Bacchelli C, Conway GS (2015-06-10). "STAG3 truncating variant as the cause of primary ovarian insufficiency". European Journal of Human Genetics. 24 (1): 135–138. doi:10.1038/ejhg.2015.107. ISSN 1018-4813. PMC 4795223. PMID 26059840.
Further reading
[edit]- Quaye L, Dafou D, Ramus SJ, Song H, Gentry-Maharaj A, Maharaj AG, Notaridou M, Hogdall E, Kjaer SK, Christensen L, Hogdall C, Easton DF, Jacobs I, Menon U, Pharoah PD, Gayther SA (May 2009). "Functional complementation studies identify candidate genes and common genetic variants associated with ovarian cancer survival". Human Molecular Genetics. 18 (10): 1869–78. doi:10.1093/hmg/ddp107. PMID 19270026.
- Pezzi N, Prieto I, Kremer L, Pérez Jurado LA, Valero C, Del Mazo J, Martínez-A C, Barbero JL (March 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. 14 (3): 581–92. doi:10.1096/fasebj.14.3.581. PMID 10698974. S2CID 29409521.
- Prieto I, Suja JA, Pezzi N, Kremer L, Martínez-A C, Rufas JS, Barbero JL (August 2001). "Mammalian STAG3 is a cohesin specific to sister chromatid arms in meiosis I". Nature Cell Biology. 3 (8): 761–6. doi:10.1038/35087082. PMID 11483963. S2CID 40898732.
- Notaridou M, Quaye L, Dafou D, Jones C, Song H, Høgdall E, Kjaer SK, Christensen L, Høgdall C, Blaakaer J, McGuire V, Wu AH, Van Den Berg DJ, Pike MC, Gentry-Maharaj A, Wozniak E, Sher T, Jacobs IJ, Tyrer J, Schildkraut JM, Moorman PG, Iversen ES, Jakubowska A, Mędrek K, Lubiński J, Ness RB, Moysich KB, Lurie G, Wilkens LR, Carney ME, Wang-Gohrke S, Doherty JA, Rossing MA, Beckmann MW, Thiel FC, Ekici AB, Chen X, Beesley J, Gronwald J, Fasching PA, Chang-Claude J, Goodman MT, Chenevix-Trench G, Berchuck A, Pearce CL, Whittemore AS, Menon U, Pharoah PD, Gayther SA, Ramus SJ (May 2011). "Common alleles in candidate susceptibility genes associated with risk and development of epithelial ovarian cancer". International Journal of Cancer. 128 (9): 2063–74. doi:10.1002/ijc.25554. PMC 3098608. PMID 20635389.
- Prieto I, Pezzi N, Buesa JM, Kremer L, Barthelemy I, Carreiro C, Roncal F, Martinez A, Gomez L, Fernandez R, Martinez-A C, Barbero JL (June 2002). "STAG2 and Rad21 mammalian mitotic cohesins are implicated in meiosis". EMBO Reports. 3 (6): 543–50. doi:10.1093/embo-reports/kvf108. PMC 1084142. PMID 12034751.
- Barber TD, McManus K, Yuen KW, Reis M, Parmigiani G, Shen D, Barrett I, Nouhi Y, Spencer F, Markowitz S, Velculescu VE, Kinzler KW, Vogelstein B, Lengauer C, Hieter P (March 2008). "Chromatid cohesion defects may underlie chromosome instability in human colorectal cancers". Proceedings of the National Academy of Sciences of the United States of America. 105 (9): 3443–8. Bibcode:2008PNAS..105.3443B. doi:10.1073/pnas.0712384105. PMC 2265152. PMID 18299561.
- Maeshima K, Yoshida K, Shirahige K (September 2008). "[Function of cohesin in transcription]". Tanpakushitsu Kakusan Koso. Protein, Nucleic Acid, Enzyme. 53 (11): 1337–44. PMID 18788457.
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