Mitotic catastrophe has been defined as either a cellular mechanism to prevent potentially cancerous cells from proliferating or as a mode of cellular death that occurs following improper cell cycle progression or entrance. Mitotic catastrophe can be induced by prolonged activation of the spindle assembly checkpoint, errors in mitosis, or DNA damage and operates to prevent genomic instability. It is a mechanism that is being researched as a potential therapeutic target in cancers, and numerous approved therapeutics induce mitotic catastrophe.
Term usage Multiple attempts to specifically define mitotic catastrophe have been made since the term was first used to describe a temperature dependent lethality in the yeast, Schizosaccharomyces pombe, that demonstrated abnormal segregation of chromosomes. The term has been used to define a mechanism of cellular death that occurs while a cell is in mitosis or as a method of oncosuppression that prevents potentially tumorigenic cells from dividing. This oncosuppression is accomplished by initiating a form of cell death such as apoptosis or necrosis or by inducing cellular senescence.
Mechanism to prevent cancer development
One usage of the term mitotic catastrophe is to describe an oncosuppressive mechanism (i.e. a mechanism to prevent the proliferation of cancerous cells and the development of tumors) that occurs when cells undergo and detect a defective mitosis has occurred. This definition of this mechanism has been described by the International Nomenclature Committee on Cell Death. Under this definition, cells that undergo mitotic catastrophe either senesce and stop dividing or undergo a regulated form of cell death during mitosis or another form of cell death in the next G1 phase of the cell cycle. The function of this mechanism is to prevent cells from accruing genomic instability which can lead to tumorigenesis. When the cell undergoes cell death during mitosis this is known as mitotic death. This is characterized by high levels of cyclin B1 still present in the cell at the time of cell death indicating the cell never finished mitosis. Mitotic catastrophe can also lead to the cell being fated for cell death by apoptosis or necrosis following interphase of the cell cycle. However, the timing of cell death can vary from hours after mitosis completes to years later which has been witnessed in human tissues treated with radiotherapy. The least common outcome of mitotic catastrophe is senescence in which the cell stops dividing and enters a permanent cell cycle arrest that prevents the cell from proliferating any further.
Mechanism of cellular death Another usage of the term mitotic catastrophe is to describe a mode of cell death that occurs during mitosis. This cell death can occur due to an accumulation of DNA damage in the presence of improperly functioning DNA structure checkpoints or an improperly functioning spindle assembly checkpoint. Cells that undergo mitotic catastrophe death can lack activation of pathways of the traditional death pathways such as apoptosis. While more recent definitions of mitotic catastrophe do not use it to describe a bona fide cell death mechanism, some publications describe it as a mechanism of cell death.
Causes
Prolonged spindle assembly checkpoint activation
Cells have a mechanism to prevent improper segregation of chromosomes known as the spindle assembly checkpoint or mitotic checkpoint. The spindle assembly checkpoint verifies that mitotic spindles have properly attached to the kinetochores of each pair of chromosomes before the chromosomes segregate during cell division. If the mitotic spindles are not properly attached to the kinetochores then the spindle assembly checkpoint will prevent the transition from metaphase to anaphase. This mechanism is important to ensure that the DNA within the cell is divided equally between the two daughter cells. When the spindle assembly checkpoint is activated, it arrests the cell in mitosis until all chromosomes are properly attached and aligned. If the checkpoint is activated for a prolonged period it can lead to mitotic catastrophe. Prolonged activation of the spindle assembly checkpoint inhibits the anaphase promoting complex. Normally, activation of the anaphase promoting complex leads to the separation of sister chromatids and the cell exiting mitosis. The mitotic checkpoint complex acts as a negative regulator of the anaphase promoting complex. Unattached kinetochores promote the formation of the mitotic checkpoint complex which is composed of four different proteins known as Mad2, Cdc20, BubR1, and Bub3 in humans. When the mitotic checkpoint complex is formed, it binds to the anaphase promoting complex and prevents its ability to promote cell cycle progression.
Errors in mitosis
Some cells can have an erroneous mitosis yet survive and undergo another cell division which puts the cell at a higher likelihood to undergo mitotic catastrophe. For instance, cells can undergo a process called mitotic slippage where cells exit mitosis too early before the process of mitosis is finished. In this case, the cell finishes mitosis in the presence of spindle assembly checkpoint signaling which would normally prevent the cell from exiting mitosis. This phenomenon is caused by improper degradation of cyclin B1 and can result in chromosome missegregation events. Cyclin B1 is a major regulator of the cell cycle and guides the cells progression from G2 to M phase. Cyclin B1 works with its binding partner CDK1 to control this progression and the complex is known as the mitotic promoting factor. While the mitotic promoting factor is utilized to guide the cells entry into mitosis, its destruction also guides the cells exit from mitosis. Normally, cyclin B1 degradation is initiated by the anaphase promoting complex after all of the kinetochores have been properly attached by mitotic spindle fibers. However, when cyclin B1 levels are degraded too fast this can result in the cell exiting mitosis prematurely resulting in potential mitotic errors including missegregation of chromosomes.
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