| STAG3 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | STAG3 , stromal antigen 3, SPGF61 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 608489 MGI: 1355311 HomoloGene: 40844 GeneCards: STAG3 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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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.
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]
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]
Meiosis is a special type of cell division of germ cells and apicomplexans in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately result in four cells with only one copy of each chromosome (haploid). Additionally, prior to the division, genetic material from the paternal and maternal copies of each chromosome is crossed over, creating new combinations of code on each chromosome. Later on, during fertilisation, the haploid cells produced by meiosis from a male and a female will fuse to create a cell with two copies of each chromosome again, the zygote.
A couple of homologous chromosomes, or homologs, are a set of one maternal and one paternal chromosome that pair up with each other inside a cell during fertilization. Homologs have the same genes in the same loci, where they provide points along each chromosome that enable a pair of chromosomes to align correctly with each other before separating during meiosis. This is the basis for Mendelian inheritance, which characterizes inheritance patterns of genetic material from an organism to its offspring parent developmental cell at the given time and area.
Nondisjunction is the failure of homologous chromosomes or sister chromatids to separate properly during cell division (mitosis/meiosis). There are three forms of nondisjunction: failure of a pair of homologous chromosomes to separate in meiosis I, failure of sister chromatids to separate during meiosis II, and failure of sister chromatids to separate during mitosis. Nondisjunction results in daughter cells with abnormal chromosome numbers (aneuploidy).
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 metaphase of 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.
Spermatocytes are a type of male gametocyte in animals. They derive from immature germ cells called spermatogonia. They are found in the testis, in a structure known as the seminiferous tubules. There are two types of spermatocytes, primary and secondary spermatocytes. Primary and secondary spermatocytes are formed through the process of spermatocytogenesis.
The synaptonemal complex (SC) is a protein structure that forms between homologous chromosomes during meiosis and is thought to mediate synapsis and recombination during prophase I during meiosis in eukaryotes. It is currently thought that the SC functions primarily as a scaffold to allow interacting chromatids to complete their crossover activities.
Synapsis is the pairing of two chromosomes that occurs during meiosis. It allows matching-up of homologous pairs prior to their segregation, and possible chromosomal crossover between them. Synapsis takes place during prophase I of meiosis. When homologous chromosomes synapse, their ends are first attached to the nuclear envelope. These end-membrane complexes then migrate, assisted by the extranuclear cytoskeleton, until matching ends have been paired. Then the intervening regions of the chromosome are brought together, and may be connected by a protein-RNA complex called the synaptonemal complex. During synapsis, autosomes are held together by the synaptonemal complex along their whole length, whereas for sex chromosomes, this only takes place at one end of each chromosome.
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.
A bivalent is one pair of chromosomes in a tetrad. A tetrad is the association of a pair of homologous chromosomes physically held together by at least one DNA crossover. This physical attachment allows for alignment and segregation of the homologous chromosomes in the first meiotic division. In most organisms, each replicated chromosome elicits formation of DNA double-strand breaks during the leptotene phase. These breaks are repaired by homologous recombination, that uses the homologous chromosome as a template for repair. The search for the homologous target, helped by numerous proteins collectively referred as the synaptonemal complex, cause the two homologs to pair, between the leptotene and the pachytene phases of meiosis I.
Chromosome segregation is the process in eukaryotes by which two sister chromatids formed as a consequence of DNA replication, or paired homologous chromosomes, separate from each other and migrate to opposite poles of the nucleus. This segregation process occurs during both mitosis and meiosis. Chromosome segregation also occurs in prokaryotes. However, in contrast to eukaryotic chromosome segregation, replication and segregation are not temporally separated. Instead segregation occurs progressively following replication.
Serine/threonine-protein kinase PLK1, also known as polo-like kinase 1 (PLK-1) or serine/threonine-protein kinase 13 (STPK13), is an enzyme that in humans is encoded by the PLK1 gene.
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.
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.
Cohesin subunit SA-2 (SA2) is a protein that in humans is encoded by the STAG2 gene. 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.
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.
Meiotic recombination protein REC8 homolog is a protein that in humans is encoded by the REC8 gene.
The meiotic recombination checkpoint monitors meiotic recombination during meiosis, and blocks the entry into metaphase I if recombination is not efficiently processed.
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.
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. SMC1B protein appears to participate with other cohesins REC8, STAG3 and SMC3 in sister-chromatid cohesion throughout the whole meiotic process in human oocytes.
Achiasmate Meiosis refers to meiosis without chiasmata, which are structures that are necessary for recombination to occur and that usually aid in the segregation of non-sister homologs. The pachytene stage of prophase I typically results in the formation of chiasmata between homologous non-sister chromatids in the tetrad chromosomes that form. The formation of a chiasma is also referred to as crossing over. When two homologous chromatids cross over, they form a chiasma at the point of their intersection. However, it has been found that there are cases where one or more pairs of homologous chromosomes do not form chiasmata during pachynema. Without a chiasma, no recombination between homologs can occur.
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