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Year : 2019  |  Volume : 3  |  Issue : 4  |  Page : 243-246

Advances on the metabolism of cohesin in age-related chromosomal aneuploidy

Department of Obstetrics, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China

Date of Submission20-Jul-2019
Date of Web Publication2-Jan-2020

Correspondence Address:
Bin Zhang
Department of Obstetrics, Obstetrics and Gynecology Hospital of Fudan University, 419 Fangxie Road, Shanghai 200011
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2096-2924.274547

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Age-related chromosomal aneuploidy is associated with the reduction of cohesin in meiosis. There are many complicated factors affecting the metabolism of cohesion, including the hyperactive separase, abnormal Shugoshin protein degradation, oxidative damage, increased intracellular pH in oocytes, abnormal metabolism of spindle assembly checkpoint, anaphase-promoting complex, and age-related reproductive hormones, which are summarized in the review.

Keywords: Advanced Age; Aneuploidy; Chromosome; Cohesin

How to cite this article:
Tian LY, Zhang B. Advances on the metabolism of cohesin in age-related chromosomal aneuploidy. Reprod Dev Med 2019;3:243-6

How to cite this URL:
Tian LY, Zhang B. Advances on the metabolism of cohesin in age-related chromosomal aneuploidy. Reprod Dev Med [serial online] 2019 [cited 2021 Aug 1];3:243-6. Available from: https://www.repdevmed.org/text.asp?2019/3/4/243/274547

  Introduction Top

Age-related chromosomal aneuploidy is associated with the reduction of cohesin in meiosis; however, the specific mechanism is still unknown. Cohesin is an evolutionarily highly conserved protein complex that is known for its role in maintaining the cohesion of sister chromatids in somatic and germ cells.[1] Cohesin is present in both mitosis and meiosis; however, the meiosis-specific subunits endow the cohesin complex with specific functions for numerous events, such as chromosomal axis formation, centromeric cohesion for sister kinetochore geometry, homologous association, and recombination.[2]

During meiosis, the cohesin complex consists of the following four subunits: two of the subunits are structural maintenance of chromosome complex (SMC): SMC1 and SMC3, the third is a stromal antigen: STAG3, and the fourth is a kleisin protein: recombination gene 8 (REC8);[3] the interaction between the four subunits forms a ring-shaped structure.[4] The cohesin complex is loaded onto DNA to form cohesion and develop dynamically with the cell cycle, undergoing processes such as establishment, maintenance, and dissolution to complete the separation of homologous chromosome and sister chromatid. The binding and localization of cohesin in chromosomes are not the same in different organisms, and the distribution of similar organisms in mitosis and meiosis is also different.[5]

Cohesin has been loaded onto chromatin with the help of SCC2/SCC4 complex before S phase in meiosis,[6] and its functional activity is affected by various factors after loading. Establishment of cohesion acetylates SMC to form SCC, allowing cohesin to establish cohesion and control sister chromatid, while increased histone deacetylase 8 (HDAC8) activity leads to a decrease in SMC3 acetylation.[7] In addition, Wings apart-like protein (WAPL) can prevent the formation of SCC,[8] due to the action of WAPL and precocious dissociation of sister (PDS5), and cohesin interacts with DNA in an unstable manner until the acetylation of two key lysines on SMC3 (K105 and K106); this makes it difficult for SMC–SCC to interface with WAPL/PDS5 and prevents the release of DNA from the complex, therefore the binding of cohesin to chromatin tends to be stable.[9],[10],[11] PDS5, WAPL, and SA form a rigid scaffold that is localized on SCC1 and anchors the N-terminal domain of SCC1 (SCC1N) to the head of SMC1 ATPase. The SMC–SCC interface is disrupted by the relative motion driven by ATP and WAPL. PDS5 binds to the dissociated SCC1N and extends the open state of cohesin, releasing DNA and leading to chromosome separation.[12] The metabolic process of cohesion [Figure 1] requires the coordination of multiple factors, and chromosomal aneuploidy can be generated when there is any changes in the activity of key components. The incidence of aneuploidy in the offspring of advanced maternal age is gradually increasing, and the relationship between these factors and the specific mechanism of action need to be studied in depth.
Figure 1: The metabolic process of cohesion.

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The subunits that affect the metabolism of cohesin in yeast and human have many similarities. Currently, researches on this process are more comprehensive in fission yeast. Thus, we compare the homologs of fission yeast with humans in [Table 1].
Table 1: Comparison of cohesion in fission yeast and human

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The meiosis cell cycle consists of a single DNA replication followed by two rounds of chromosome segregation, meiosis I (MI) and meiosis II (MII). The result is a halving of the number of chromosomes, producing haploid gametes. In the early stage of MI, sister chromatids are assembled into a chromosomal axis, on which a synaptonemal complex is assembled. Then, homologous chromosomes undergoing pairing and cross-recombination, producing bivalent chromosomes, and then makes physical connection between the chromosomes, which has an important role in the localization of homologous chromosome separation in the late MI.[1] Sister chromatids are tightly bound by the cohesion; the separation or reduction of the cohesin would result in the loss of cohesion and the separation of homologs and chromatids at MI and sister chromatid at MII will arrive earlier.[13]

Cohesin continuously plays a role in chromosome segregation during meiosis.[14] As gestational age increases, cohesin-related diseases increase significantly,[15] which is often manifested as the chromosomal aneuploidy of offspring in clinic.[16] The factors that affect cohesin metabolism are complex and various, which will be reviewed in detail as follows.

  Hyperactive Separase Top

Separase belongs to the clan CD family of cysteine proteases [17] and cleaves the kleisin subunit of cohesin (REC8, RAD21L in meiosis). The separase activation starts after birth and lasts until old age, which paves the way for metaphase/anaphase transition during the cell cycle by irreversible cleavage of cohesion complex subunit. Both over and low levels of separase expression associate with several medical consequences.[18],[19] If the activity of the separase persists in a low level during a life time, it will lead to a age-related loss of cohesin.[20] Overexpression of separase induces chromosomes to separate prematurely and lag at anaphase.[20] The cleavage of the kleisin subunit by separase depends mainly on its degree of phosphorylation and activity.[21] It binds to the securin by the cyclin-dependent kinase (Cdk1), while the latter contracts with phosphorylated separase through regulated cyclin B1 subunit. After activation of the separase, the cohesin ring is opened by cleavage, allowing REC8 to be removed from the chromosomal arm, and the cohesion is released, leading to the separation of sister chromatids.[22]

  Degradation of Shugoshin Top

First found in fission yeast and budding yeast, shugoshin (the guardian of genome in Japanese) plays multiple and distinct roles in ensuring the accuracy of chromosomal segregation during meiosis.[23] Shugoshin protein (SGO) maintains chromosomal stability by recruiting protein phosphatase 2A (PP2A) to dephosphorylate cohesin and securin.

SGO1 and SGO2 are involved in chromosomal segregation. SGO1 plays an important role in the formation of sister kinetochore mono-orientation. Recruitment of aurora kinase Ipl1 to the centromere mediated by SGO1 contributes to one-way separation during MI.[24] SGO1 can also compete with WAPL for binding to the site of SA2-SCC1, which protects the stability of cohesion.[25] This direct antagonism between SGO1 and WAPL augments centromeric cohesion protection.[26] SGO2 cooperates with PP2A to protect the REC8 within centromere from cleavage by separase in MI. During oocyte aging, reduced levels of SGO2 can lead to the loss of cohesin, which, in turn, amplifies the loss of SGO2.[27] It has been reported that the REC8 is preserved in the centromere of SGO1-depleted oocytes, whereas disappeared in SGO2-depleted oocytes, which indicated that only SGO2 plays a major role in protecting cohesion.[28] However, taking the C57B16/J mouse strain as the research object, it was found that there was no change in SGO2 in oocytes, indeed observed a loss of cohesion with the increase of age, suggesting that individuals with high incidence of chromosome aneuploidy had a certain genetic basis.[29]

  Oxidative Damage Top

Oxidative damage is characterized by an imbalance between pro-oxidants and antioxidants in species including reactive oxygen species (ROS) and nitrogen species,[30] observing that oxidative damage increases with age in different organisms and cells.

The increase of oxidative damage is largely caused by ROS in aged cells. The separation errors are significantly increased by knocking out the superoxide dismutase (SOD), which is the ROS scavenger of cytoplasm or mitochondria.[31] However, an additional expression of SOD1 (cytosol/nucleus) or SOD2 (mitochondria) in oocytes may alleviate this phenomenon.[32] Peroxides such as oxygen-free radicals accumulating in advanced oocytes [33] and proteolytic activity reducing after exposure to oxidative damage in the form of hydrogen peroxide or 4-hydroxynonenal [34] both cause an increase of chromosomal aneuploidy in oocytes. Caloric restriction and antioxidants (melatonin) have a positive role in maintaining the cohesion between sister chromatid in advanced maternal age,[35] but has not been confirmed whether it has adverse effects on other systems. Maintaining the quality of oocytes and reducing age-related loss of cohesion remains a major challenge.

  Increased Intracellular PH in Oocytes Top

It was observed that the intracellular pH (pHi) in oocytes increased with maternal age, which may be the result of decreased activity of HCO3+/Cl exchange and reduced expression of AE2 mRNA in oocytes.[36] Deregulation of pHi in advanced oocytes may damage the protein localization of cohesion subunit, leading to the loss of chromosomal cohesion, but the specific mechanism remains unknown.[27] During the long-term stagnation of meiosis, the peptide bonds within the cohesin ring are cleaved or spontaneously hydrolyzed in an alkaline environment, resulting in an increase in the sister inter-kinetochore, and the increase of this distance will lead to an increased incidence of premature sister chromatid separation.[37]

  Abnormal Spindle Assembly Checkpoint Top

The spindle assembly checkpoint (SAC) is located at the centromere to monitor the attachment of the spindle microtubules to the centromere and the tension of the spindle against the centromeres.[38] Bub1 is a key component in SAC, which helps to recruit SGO1 and SGO2 into centromeres; its loss in oocytes usually leads to an early loss of cohesion between sister chromosomes as well as large number of chromosomal mis-separation during meiosis.

Cohesin maintains cohesion until the final dissolution in the anaphase through the deacetylation of SMC3 and the cleavage of SCC1, which are mediated by HDAC8 and separase.[39] SCC cleaves the kleisin subunit by separase, and the process is controlled by SAC tightly. Active SAC inhibits the proteolysis of the securin and cyclin B mediated by the anaphase-promoting complex (APC).[40] In addition, the effects of SMC complex on chromosomes also depend on the hydrolysis of ATP.[41]

  Abnormal Anaphase-Promoting Complex Top

APC can irreversibly drive the progression of cells from metaphase to anaphase.[42] CDC20 is an activator of APC that inhibits the binding of APC to MAD2 and BubR1 and indirectly inhibits the formation and activity of M-phase checkpoint complexes. Delayed formation of SAC will lead to abnormal chromosome separation. Securin, an inhibitor of separase, is ubiquitinated in a CDC20-dependent manner through APC. Securin promotes the separation of cohesin after the activation of separase and induces the separation of homologous chromosome.[28]

At the anaphase, the degradation of securin is mediated by CDC20, while the activity of CDC20 is regulated by the SAC. There is a lot of intrinsic link between SAC and APC in the formation and function of cohesion. Either the amount or quality change will lead to abnormal chromosomal separation.

  Age-Related Reproductive Hormones Top

There are a lot of age-related reproductive hormones in oocytes, such as luteinizing hormone and follicle-stimulating hormone (FSH), whose levels gradually increase with the age of women. Abnormal increase of FSH levels in follicles may cause aneuploidy indirectly by changing the structure of spindle and inhibiting the role of cohesion.[43] Anti-Müllerian hormone is commonly used as an indicator for monitoring ovarian function in the clinic, but there is no correlation between its content and abnormal chromosomal separation. The change of reproductive hormone levels can affect MI and MII, and MI is more susceptible.[44]

Recent studies have shown that dehydroepiandrosterone can inhibit the apoptosis of follicular cells and delay the decrease of cohesin levels in oocytes.[45] He Yankuntai Capsule (HYKT) can increase the number of follicles, inhibit the apoptosis of oocytes, and improve the meiosis-specific cohesin subunits (REC8 and SMC1β) in aged mice, playing an important role in the improvement of the number and quality of follicles.[46] However, further research is needed to explore the mechanism of abnormal chromosomal separation.

Except those factors mentioned above, oncogene LANA can result in premature chromosomal separation, but its correlation with age has not been proven.[47]

  Conclusion Top

There are many factors affecting the metabolism of cohesin in chromosomal separation, and chromosomal separation in meiosis involves a variety of molecular mechanisms; how these factors coordinate with each other and play a role sufficiently still needs to be further studied.

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Conflicts of interest

There are no conflicts of interest.

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  [Table 1]


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Hyperactive Separase
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