Separase is a protein that is a cornerstone of cell division. Separase is also known as Separin or Esp1. It allows for replicated chromosomes to be separated from their sister chromatids and pulled to opposite ends of the cell by the mitotic spindle. This allows for microfilaments to dissect the cell in half causing two genetically identical daughter cells from the single mother cell in mitosis or haploid cells in Meiosis. The sister chromatids are held together by a protein called Cohesin. Separase catalyses and breaks down cohesin allowing the sister chromatids to break apart, which in turn allows the mitotic spindle to draw the chromatids to either sides of the cell. Separase is crucial to the cell division process, not only does it physically separate the sister chromatids, it triggers the start of the anaphase period of cell division. Separase causes the cell to replicate accurately and on some occasions cause some problems if the protein is present or absent in excess quanitities. Separase is a large part of the cell cycle as its initiation begins the anaphase cycle of the M phase in the cell cycle and without the division of the sister chromatids, cell division cannot occur.
Role of Separase in cell division
Separase has an extremely important role in cell division, it allows the chromatids to be pulled to opposite sides of the cell by the Mitotic spindle. Cohesin holds the chromatids together to allow them to replicate, separase catalyses the cohesin holding the chromatids together allowing for separation. It has been found DNA does not stimulate but mediates cohesin breakdown by allowing separase to interact with Cohesin. (Sun, Kucej, Fan, Yu, Sun, Zou. 2009) There are 2 main roles separase undertake in their use, the first is to ‘separate sister-chromatid attachments, and the second is the dissociation of cohesin from the chromasomes’ (Uhlmann, Lottspeich, Nasmyth, 1999). Separase is the marker for the end of the G2 phase and the initiation of the M phase. Separase must be inhibited before the cell cylce reaches the anaphase, separase initiates the anaphase but it must be inhibited before anaphase begins otherwise there will be complications in the cell division process (Huang, Andreu-Vieyra, Wang, Cooney, Matzuk, Zhang, 2009). Huang et.al also state there are 'two inhibitory mechanisms which exist in vertebrates that block the protease activity. One mechanism is through binding and inhibition by securin, and another is phosphorylation on Ser1126 in humans' (2009). The purpose of separase is to separate the chromatids by catylising and breaking down the cohesin.
Driving factors of Separase
Sun et.al. have hypothesised that separase is not stimulated by DNA but is mediated by DNA (2009). Separase also requires other proteins that have catalysed other proteins. ‘The dissolution of sister-chromatid cohesion is catalysed by separase, after the destruction of securing by the anaphase-promoting complex/cylosome’ (Yuan, Li, Huo, Yan, Yang, Ward, Jin, Yao, 2009). In order for Separase to have the desired affect, it must work in order and conjunction with other proteins. Aurora B is the regulator of Separase, which forces the separase protein to be accumulated during the M phase and then degraded at the end of telophase (Yuan et.al. 2009). Yuan et.al. has also discovered the Aurora B kinase helps coordinate the association of separase with the chromosome to begin degradation of cohesin (2009). Separase can not catalyse the cohesin without other proteins first acting upon each other to regulate the pathway for separase.
Possible complications caused by Separase
The accuracy of transmission of chromosomes is crucial to prevent complications arising. Complications arise if there is an over abundance of or a lack of a protein, in this case, the seperase protein. One of the major complications of seperase during cell division is aneuploidy. Aneuploidy happens to be a major cause of cancers as chromosomes are not separated equally leading to a malfunction in the cell. Huang et.al have discovered a small amount of overexpression of separase does not cause harm, but too much can have serious complications (2009), Zhang et.al have also researched the area of separase overexpression and have found it ‘induces premature separation of chromatids, lagging chromatids and anaphase bridges’ (2008). An underexpression of separase will not allow the mitotic spindle to pull the sister chromatids apart, which may result in pulling the spindle towards the middle of the cell or the chromatids may not be separated leading to a mutated cell. Huang et.al have also hypothesised the deregulation of separase may cause infertility in humans (2009). It is crucial to have the right amount of separase to catalyse the cohesin, too little or too much will cause complications, which may eventually lead to cancer. 'Results have collectively suggested separase is an oncogene, whose overexpression is sufficient to cause aneuploidy and tumorigenesis in a p53 mutant background'(Zhang et.al, 2008). A normal amount of separase will lead to proper cell division, health and function.
- Huang X, Andreu-Vieyra CV, Wang M, Cooney AJ, Matzuk MM, Zhang P. 2009. Preimplantation mouse embryos depend on inhibitory phophorylation of separase to prevent chromosome missegregation. Molecular and Cell Biology 29(6):1498-505
- Sun Y, Kucej M, Fan HY, Yu H, Sun QY, Zou H. 2009. Seperase is recruited to mitotic chromosomes to dissolve sister chromatid cohesion in a DNA dependent manner. Cell. 137(1):123-32
- Uhlmann F, Lottspeich F, Nasmyth K. 1999. Sister-chromatid separation at anaphase is promoted by cleavage of the cohesion subunit. Nature. 400:37-42
- Yuan K, Li N, Huo Y, Yan F, Yang Y, Ward T, jin C, Yao X, 2009. Recruitment of separase to mitotic chromosomes is regulated by Aurora B. Cell cycle. 8(9)
- Zhang N, Ge G, Meyer R, Sethi S, Basu D, Pradhan S, Zhao YJ, Li XN, Cai WW, El-Naggar AK, Baladandayuthapani V, Kittrell FS, Rao PH, Medina D, Pati D, 2008. Overexpression of Separase induces aneuploidy and mammary tumorigenesis. Proc Natl Acad Sci USA. 105(35):13033-8