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Mitotic catastrophe, a type of programmed cell death, or PCD that takes place when a cell is destroyed as a result of an aberrant chromosome segregation early in mitosis, or as a result of DNA damage later during the metaphase/ anaphase transition. This PCD is believed to be caused by apoptosis and demonstrates signs of apoptosis. The death signal transmissions are partially similar with that of apoptosis. Mitotic catastrophe may result from a combination of deficient cell-cycle checkpoints, in particular DNA structure checkpoints and the spindle assembly checkpoint, and cellular damage Defective cell cycle checkpoint can result in the formation of giant multinucleated cells with condensed chromosomes. Hence, mitotic catastrophe also refers to the process when cells attempt to divide without proper repair of DNA damage due to faulty cell cycle checkpoint. The inability to arrest the cell cycle before or at mitosis leads to aberrant chromosome segregation, which ends the activation of the apoptotic default pathway and cellular demise. Since aneuploidization participates in oncogenesis, some scientists consider mitotic catastrophe to be a molecular strategy to deal with cancer by preventing aneuploidization.

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Mitotic catastrophe triggered by DNA synthesis inhibition in Chk1-deficient DT40 cells. Condensed chromosomes are visualised in red using an antibody specific for histone H3 phosphorylated on serine 10, whilst the mitotic spindle is visualised in green using an antibody specific for alpha-tubulin.

There are two distinguishable subtypes of mitotic catastrophe. First, mitotic catastrophe can kill the cell during or close to the metaphase, in a p53-independent manner. Second, mitotic catastrophe can happen after mitosis doesn’t complete, during the activation of the polyploidy checkpoint . Mitotic catastrophe can be regulated by many molecules, especially cell-cycle-specific kinases such as CDK1, polo-like kinases and Aurora, cell-cycle checkpoint proteins, P53, survivin and caspases and members of the Bcl-2 family .

Discovery

In 1989, Lisa Moiz and her collaborators observed mitotic catastrophe in Schizosaccharomyces pombe Some cells are sensitive to their surrounding temperature and can change their cellular morphology because of a specific temperature. This cdc2-3w weel-50 double mutant of fission yeast, the mutant strains in Schizosaccharomyces, displayed gross abnormalities of chromosome segregation and it was associated with the failure of the mutants to undergo complete mitosis so that tetraploid and polypoid occurred . They called this cellular situation mitotic catastrophe. This is the first time that mitotic catastrophe was discovered.

Definition

During recent years, the term of “mitotic catastrophe” has been widely used to describe a kind of cell death that affects mammalian cells. But no accurate and accepted definition of mitotic catastrophe has been made. Igor Rominson, a senior scientist of Ordway Research Institute, defined mitotic catastrophe in morphological terms as a type of cell death resulting from abnormal mitosis, which usually ends in the formation of large cells with multiple micronuclei and decondensed chromatin . It shows some phenotypic characteristic of apoptosis such as hypercondensed chromatin aggregates.

Morphological characteristics

There is no complete description of morphological characteristics of mitotic catastrophe. However, the major morphological trait is the formation of a macro cell that contains several nuclei and condensed chromatin. There has been a debate that the chromosome condensation in apoptosis is the same as that in mitotic catastrophe. It is clear that if a cell fails to block its process of cell cycle, the segregation of chromosome abnormalities will happen. These abnormal cell divisions will sequentially lead the formation of polypoid cells in the next round of mitosis. This is the basis of oncogenesis.

Regulation factors

Cdk1/cyclin B1 complex

The cyclin-dependent kinase1 (Cdk1) interacts with its obligate allosteric activator, cyclin B1 to form an active heterodimer, the so-called mitosis-promoting factor . Progression from G2 toM phase is driven by the activation of the Cdk1/cyclin B1 complex. In this way,cells entry mitosis phase. The aberrant mitotic entry, before the completion of DNA replication, can result in mitotic catastrophe. This needs the activation of Cdk1. Increased nuclear cyclin B1 has been found in numerous examples of mitotic catastrophe. Prolonged Cdk1 activation resulted from prolonged inhibition of the APC can also result in mitotic catastrophe associated with centrosome overduplication.

DNA damage sensors and Chk2

Mitotic catastrophe can be avoided by an intact DNA structure checkpoint. Usually, DNA damage such as double-strand breaks or pyrimidine dimmers is perceived by sensors including RAD1 RAD9 and so on, then relayed to kinases. But kinase Chk2 can stop the cell cycle. Chk2 is a negative regulator of mitotic catastrophe in human cells. The inhibition of Chk2 prevents the activation of a DNA structure check point, which will arrest the cell cycle. Polyploid cells will arrest at the early prophase of the cell cycle, correlating with a sudden loss of cyclin B1 and then undergo mitotic catastrophe .

Application in cancer treatment

After failure to activate the G2/M checkpoints, cells with DNA damage activate an apoptotic program that leads to the formation of mitotic catastrophe during metaphase of the cell cycle. Suppression of the apoptotic program may cause the abnormal cell division, resulting into the creation of tetraploid cells. These cells can generate aneuploid offspring. Since mitotic catastrophe happens when a cell is destroyed during mitosis by aberrant chromosome segregation and DNA damage, and cells in mitotic catastrophe are likely to create aneuploid cells, posing a risk of oncogenesis. Because the mechanisms of mitotic catastrophe often triggered in cancer cells and tissues in response to anti-cancer drugs, chemotherapeuticals induce cell death via these routes during the course of mitosis Hence, mitotic catastrophe is also in the league of processes which participate in prevention of cancer. It can be stimulated by ionizing radiations (IR), chemotherapeutic drugs or hyperthermia and is caused by malfunctioning of cell cycle checkpoints . How the mitotic catastrophe is induced could be important for cancer treatment.