Mitotic catastrophe

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A cell that has been treated with taxol and had a catastrophic mitosis. The cell has become multinucleated after an unsuccessful mitosis. RPE cell that has been treated with taxol and undergone mitotic catastrophe.png
A cell that has been treated with taxol and had a catastrophic mitosis. The cell has become multinucleated after an unsuccessful mitosis.

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. [1] [2] 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. [3] It is a mechanism that is being researched as a potential therapeutic target in cancers, and numerous approved therapeutics induce mitotic catastrophe. [4]

Contents

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. [2] [3] 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. [3] This oncosuppression is accomplished by initiating a form of cell death such as apoptosis or necrosis or by inducing cellular senescence. [3]

Mechanism to prevent cancer development

Diagram showing events that can lead to mitotic catastrophe and the potential outcomes. Mitotic Catastrophe Diagram version 2.png
Diagram showing events that can lead to mitotic catastrophe and the potential outcomes.

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 develop of tumors) that occurs when cells undergo and detect a defective mitosis has occurred. [5] This definition of this mechanism has been described by the International Nomenclature Committee on Cell Death. [6] [5] 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. [5] [3] The function of this mechanism is to prevent cells from accruing genomic instability which can lead to tumorigenesis. [3] [6]

When the cell undergoes cell death during mitosis this is known as mitotic death. [3] 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. [3] Mitotic catastrophe can also lead to the cell being fated for cell death by apoptosis or necrosis following interphase of the cell cycle. [3] 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. [3] 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. [3]

Mechanism of cellular death

Another usage of the term mitotic catastrophe is to describe a mode of cell death that occurs during mitosis. [2] 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. [2] Cells that undergo mitotic catastrophe death can lack activation of pathways of the traditional death pathways such as apoptosis. [7] 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. [5] [7]

Causes

Prolonged spindle assembly checkpoint activation

Mitotic checkpoint (also known as spindle assembly checkpoint) prevents the cell progressing from metaphase to anaphase if not all of the chromosomes are properly attached by mitotic spindles. Spindle chromosomes-en.png
Mitotic checkpoint (also known as spindle assembly checkpoint) prevents the cell progressing from metaphase to anaphase if not all of the chromosomes are properly attached by mitotic spindles.

Cells have a mechanism to prevent improper segregation of chromosomes known as the spindle assembly checkpoint or mitotic checkpoint. [3] 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. [6] If the mitotic spindles are not properly attached to the kinetochores then the spindle assembly checkpoint will prevent the transition from metaphase to anaphase. [6] This mechanism is important to ensure that the DNA within the cell is divided equally between the two daughter cells. [3] When the spindle assembly checkpoint is activated, it arrests the cell in mitosis until all chromosomes are properly attached and aligned. [3] If the checkpoint is activated for a prolonged period it can lead to mitotic catastrophe. [3]

Prolonged activation of the spindle assembly checkpoint inhibits the anaphase promoting complex. [8] Normally, activation of the anaphase promoting complex leads to the separation of sister chromatids and the cell exiting mitosis. [9] The mitotic checkpoint complex acts as a negative regulator of the anaphase promoting complex. [9] 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. [9] When the mitotic checkpoint complex is formed, it binds to the anaphase promoting complex and prevents its ability to promote cell cycle progression. [9]

Errors in mitosis

Expression of cyclin levels during different phases of the cell cycle. Cyclin B promotes progression to mitosis and once the cell is in mitosis normally prevents the cell from exiting mitosis prematurely. Cyclin Expression.svg
Expression of cyclin levels during different phases of the cell cycle. Cyclin B promotes progression to mitosis and once the cell is in mitosis normally prevents the cell from exiting mitosis prematurely.

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. [3] For instance, cells can undergo a process called mitotic slippage where cells exit mitosis too early before the process of mitosis is finished. [10] In this case, the cell finishes mitosis in the presence of spindle assembly checkpoint signaling which would normally prevent the cell from exiting mitosis. [3] This phenomenon is caused by improper degradation of cyclin B1 and can result in chromosome missegregation events. [3] Cyclin B1 is a major regulator of the cell cycle and guides the cells progression from G2 to M phase. [11] Cyclin B1 works with its binding partner CDK1 to control this progression and the complex is known as the mitotic promoting factor. [11] While the mitotic promoting factor is utilized to guide the cells entry into mitosis, its destruction also guides the cells exit from mitosis. [11] Normally, cyclin B1 degradation is initiated by the anaphase promoting complex after all of the kinetochores have been properly attached by mitotic spindle fibers. [11] 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. [11]

An example of a normal mitosis on the left and a multipolar mitosis on the right. Microtubules are in red and the centrosomes are in yellow. Normal and multipolar mitosis.tif
An example of a normal mitosis on the left and a multipolar mitosis on the right. Microtubules are in red and the centrosomes are in yellow.

Tetraploid or otherwise aneuploid cells are at higher risk of mitotic catastrophe. [4] Tetraploid cells are cells that have duplicated their genetic material, but have not undergo cytokinesis to split into two daughter cells and thus remain as one cell. [12] Aneuploid cells are cells that have an incorrect number of chromosomes including whole additions of chromosomes or complete losses of chromosomes. [13] Cells with an abnormal number of chromosomes are more likely to have chromosome segregation errors that result in mitotic catastrophe. [4] Cells that become aneuploid often are prevented from further cell growth and division by the activation of tumor suppressor pathways such as p53 which drives the cell to a non-proliferating state known as cellular senescence. [4] Given that aneuploid cells can often become tumorigenic, this mechanism prevents the propagation of these cells and thus prevents the development of cancers in the organism. [3]

Cells that undergo multipolar divisions, or in other words split into more than 2 daughter cells, are at a higher risk of mitotic catastrophe as well. [3] While many of the progeny of multipolar divisions do not survive do to highly imbalanced chromosome numbers, most of the cells that survive and undergo a subsequent mitosis are likely to experience mitotic catastrophe. [3] These multipolar divisions occur due to the presence of more than two centrosomes. [14] Centrosomes are cellular organelles that acts to organize the mitotic spindle assembly in the cell during mitosis and thus guide the segregation of chromosomes during mitosis. [15] Normally, cells will have two centrosomes that guide sister chromatids to opposite poles of the dividing cell. [16] However, when there are more than two centrosomes present in mitosis they can pull chromosomes in incorrect directions resulting in daughter cells that are inviable. [12] Many cancers have excessive numbers of centrosomes, but to prevent inviable daughter cells, the cancer cells have developed mechanisms to cluster their centrosomes. [12] When the centrosomes are clustered to two poles of the dividing cell, the chromosomes are segregated properly and two daughter cells are formed. [12] Thus, cancers that are able to adapt to a higher number of centrosomes are able to are able to prevent mitotic catastrophe and propagate in the presence of their extra centrosomes. [3]

DNA damage

High levels of DNA damage that are not repaired before the cell enters mitosis can result in a mitotic catastrophe. [3] Cells that have a compromised G2 checkpoint do not have the ability to prevent progression through the cell cycle even when there is DNA damage present in the cell's genome. [3] The G2 checkpoint normally functions to stop cells that have damaged DNA from progressing to mitosis. [17] The G2 checkpoint can be compromised if tumor suppressor p53 is no longer present in the cell. [3] The response to DNA damage present during mitosis is different from the response to DNA damage detected during the rest of the cell cycle. [3] Cells can detect DNA defects during the rest of the cell cycle and either repair them if possible or undergo apoptosis of senescence. [3] Given that when this happens the cell does not progress into mitosis it is not considered a mitotic catastrophe. [3]

Mitotic catastrophe in cancer

Prevention of genomic instability

Video of a cell treated with taxol undergoing mitotic catastrophe.

Genomic instability is one of the hallmarks of cancer cells and promotes genetic changes (both large chromosomal changes as well as individual nucleotide changes) in cancer cells which can lead to increased levels of tumor progression through genetic variation in the tumor cell. [18] Cancers with a higher level of genomic instability have been shown to have worse patient outcomes than those cancers which have lower levels of genomic instability. [19] Cells have gained mechanisms that resist increased genomic instability in cells. [3] Mitotic catastrophe is one way in which cells prevent the propagation of genomically unstable cells. [3] If mitotic catastrophe fails for cells whose genome has become unstable they can propagate uncontrollably and potentially become tumorigenic. [6]

The level of genomic instability is different across cancer types with epithelial cancers being more genomically unstable than cancers of hematological or mesenchymal origin. [20] Mesothelioma, small-cell lung cancer, breast, ovarian, non-small cell lung cancer, and liver cancer exhibit high levels of genomic instability while acute lymphoblastic leukemia, myelodysplasia, and myeloproliferative disorder have lower levels of instability. [20]

Anticancer therapeutics

Chemical structure of Paclitaxel (Taxol), an anticancer therapeutic that can induce mitotic catastrophe. Taxol.svg
Chemical structure of Paclitaxel (Taxol), an anticancer therapeutic that can induce mitotic catastrophe.

Promotion of mitotic catastrophe in cancer cells is an area of cancer therapeutic research that has garnered interest and is seen as a potential target to overcome resistance developed to current chemotherapies. [4] Cancer cells have been found to be more sensitive to mitotic catastrophe induction than non-cancerous cells in the body. [3] Tumors cells often have inactivated the machinery that is required for apoptosis such as the p53 protein. [4] This is usually achieved by mutations in the p53 protein or by loss of the chromosome region that contains the genetic code for it. [21] p53 acts to prevent the propagation of tumor cells and is considered a major tumor suppressor protein. [21] p53 works by either halting progression through the cell cycle when uncontrolled cell division is sensed or it can promote cell death through apoptosis in the presence of irreparable DNA damage. [21] Mitotic catastrophe can occur in a p53 independent fashion and thus presents a therapeutic avenue of interest. [4] Furthermore, doses of DNA damaging drugs lower than lethal levels have been shown to induce mitotic catastrophe. [4] This would allow for administration of a drug while the patient has fewer side effects. [3]

Cancer therapies can induce mitotic catastrophe by either damaging the cells DNA or inhibiting spindle assembly. [4] Drugs, known as spindle poisons, affect the polymerization or depolymerization of microtubule spindles and thus interfere with the correct formation of the mitotic spindles. [4] When this happens, the spindle assembly checkpoint becomes activated and the transition from metaphase to anaphase is inhibited. [4]

Cancer drugs that induce mitotic catastrophe
DrugApproved uses / clinical trial phase / research useMechanism of action
Paclitaxel [4] Approved use: AIDS-related Kaposi sarcoma, breast cancer, non-small cell lung cancer, and ovarian cancer [22] Promotes microtubule spindle assembly and prevents the detachment of microtubules preventing the cell from properly entering or exiting mitosis. [23]
Docetaxel [4] Approved use: Breast cancer, non-small cell lung cancer, prostate cancer, head and neck squamous cell carcinoma, stomach adenocarcinoma, and gastroesophageal junction adenocarcinoma [24]
Vinblastin [4] Approved use: Breast cancer, Choriocarcinoma, Hodgkin lymphoma, Kaposi sarcoma, mycosis fungoides, non-Hodgkin lymphoma, testicular germ cell tumors [25] Depolymerizes microtubules [4]
Vinkristine [4] Approved use: Acute lymphoblastic leukemia, lymphomas, neuroblastoma, sarcomas, and central nervous system tumors [26]
Monastrol [3] Research use EG5 Inhibitor which perturbs the movement of chromosomes during mitosis. [3] This perturbation results in cells dying in mitosis or in the subsequent interphase. [27]
ARRY-520 (Filanesib) [3] Phase III clinical trial: multiple myeloma [27]
VX-680 [3] Pre-clinical research [28] AURKA / AURKB inhibitor which disrupts the movement of chromosomes and the cytoskeleton during mitosis
MLN8237 [4] Phase I clinical trial: pediatric recurrent atypical teratoid rhabdoid tumors and pediatric advanced solid tumors

Failed clinical trial for adult lymphomas and lung cancer [29]

See also

Related Research Articles

<span class="mw-page-title-main">Cell cycle</span> Series of events and stages that result in cell division

The cell cycle, or cell-division cycle, is the series of events that take place in a cell that causes it to divide into two daughter cells. These events include the duplication of its DNA and some of its organelles, and subsequently the partitioning of its cytoplasm, chromosomes and other components into two daughter cells in a process called cell division.

<span class="mw-page-title-main">Mitosis</span> Process in which chromosomes are replicated and separated into two new identical nuclei

Mitosis is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis is an equational division which gives rise to genetically identical cells in which the total number of chromosomes is maintained. Mitosis is preceded by the S phase of interphase and is followed by telophase and cytokinesis, which divide the cytoplasm, organelles, and cell membrane of one cell into two new cells containing roughly equal shares of these cellular components. The different stages of mitosis altogether define the mitotic phase of a cell cycle—the division of the mother cell into two daughter cells genetically identical to each other.

<span class="mw-page-title-main">Cell division</span> Process by which living cells divide

Cell division is the process by which a parent cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukaryotes, there are two distinct types of cell division: a vegetative division (mitosis), producing daughter cells genetically identical to the parent cell, and a cell division that produces haploid gametes for sexual reproduction (meiosis), reducing the number of chromosomes from two of each type in the diploid parent cell to one of each type in the daughter cells. Mitosis is a part of the cell cycle, in which, replicated chromosomes are separated into two new nuclei. Cell division gives rise to genetically identical cells in which the total number of chromosomes is maintained. In general, mitosis is preceded by the S stage of interphase and is followed by telophase and cytokinesis; which divides the cytoplasm, organelles, and cell membrane of one cell into two new cells containing roughly equal shares of these cellular components. The different stages of mitosis all together define the M phase of an animal cell cycle—the division of the mother cell into two genetically identical daughter cells. To ensure proper progression through the cell cycle, DNA damage is detected and repaired at various checkpoints throughout the cycle. These checkpoints can halt progression through the cell cycle by inhibiting certain cyclin-CDK complexes. Meiosis undergoes two divisions resulting in four haploid daughter cells. Homologous chromosomes are separated in the first division of meiosis, such that each daughter cell has one copy of each chromosome. These chromosomes have already been replicated and have two sister chromatids which are then separated during the second division of meiosis. Both of these cell division cycles are used in the process of sexual reproduction at some point in their life cycle. Both are believed to be present in the last eukaryotic common ancestor.

<span class="mw-page-title-main">Centrosome</span> Cell organelle in animal cell helping in cell division

In cell biology, the centrosome is an organelle that serves as the main microtubule organizing center (MTOC) of the animal cell, as well as a regulator of cell-cycle progression. The centrosome provides structure for the cell. The centrosome is thought to have evolved only in the metazoan lineage of eukaryotic cells. Fungi and plants lack centrosomes and therefore use other structures to organize their microtubules. Although the centrosome has a key role in efficient mitosis in animal cells, it is not essential in certain fly and flatworm species.

<span class="mw-page-title-main">Prophase</span> First phase of cell division in both mitosis and meiosis

Prophase is the first stage of cell division in both mitosis and meiosis. Beginning after interphase, DNA has already been replicated when the cell enters prophase. The main occurrences in prophase are the condensation of the chromatin reticulum and the disappearance of the nucleolus.

<span class="mw-page-title-main">Spindle apparatus</span> Feature of biological cell structure

In cell biology, the spindle apparatus is the cytoskeletal structure of eukaryotic cells that forms during cell division to separate sister chromatids between daughter cells. It is referred to as the mitotic spindle during mitosis, a process that produces genetically identical daughter cells, or the meiotic spindle during meiosis, a process that produces gametes with half the number of chromosomes of the parent cell.

<span class="mw-page-title-main">Spindle checkpoint</span> Cell cycle checkpoint

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.

<span class="mw-page-title-main">Kinetochore</span> Protein complex that allows microtubules to attach to chromosomes during cell division

A kinetochore is a disc-shaped protein structure associated with duplicated chromatids in eukaryotic cells where the spindle fibers attach during cell division to pull sister chromatids apart. The kinetochore assembles on the centromere and links the chromosome to microtubule polymers from the mitotic spindle during mitosis and meiosis. The term kinetochore was first used in a footnote in a 1934 Cytology book by Lester W. Sharp and commonly accepted in 1936. Sharp's footnote reads: "The convenient term kinetochore has been suggested to the author by J. A. Moore", likely referring to John Alexander Moore who had joined Columbia University as a freshman in 1932.

<span class="mw-page-title-main">Micronucleus</span> Small nucleus in the cells of some organisms

A micronucleus is a small nucleus that forms whenever a chromosome or a fragment of a chromosome is not incorporated into one of the daughter nuclei during cell division. It usually is a sign of genotoxic events and chromosomal instability. Micronuclei are commonly seen in cancerous cells and may indicate genomic damage events that can increase the risk of developmental or degenerative diseases.

<span class="mw-page-title-main">Cell cycle checkpoint</span> Control mechanism in the eukaryotic cell cycle

Cell cycle checkpoints are control mechanisms in the eukaryotic cell cycle which ensure its proper progression. Each checkpoint serves as a potential termination point along the cell cycle, during which the conditions of the cell are assessed, with progression through the various phases of the cell cycle occurring only when favorable conditions are met. There are many checkpoints in the cell cycle, but the three major ones are: the G1 checkpoint, also known as the Start or restriction checkpoint or Major Checkpoint; the G2/M checkpoint; and the metaphase-to-anaphase transition, also known as the spindle checkpoint. Progression through these checkpoints is largely determined by the activation of cyclin-dependent kinases by regulatory protein subunits called cyclins, different forms of which are produced at each stage of the cell cycle to control the specific events that occur therein.

<span class="mw-page-title-main">G1/S transition</span> Stage in cell cycle

The G1/S transition is a stage in the cell cycle at the boundary between the G1 phase, in which the cell grows, and the S phase, during which DNA is replicated. It is governed by cell cycle checkpoints to ensure cell cycle integrity and the subsequent S phase can pause in response to improperly or partially replicated DNA. During this transition the cell makes decisions to become quiescent, differentiate, make DNA repairs, or proliferate based on environmental cues and molecular signaling inputs. The G1/S transition occurs late in G1 and the absence or improper application of this highly regulated checkpoint can lead to cellular transformation and disease states such as cancer.

<span class="mw-page-title-main">Aurora kinase A</span> Protein-coding gene in the species Homo sapiens

Aurora kinase A also known as serine/threonine-protein kinase 6 is an enzyme that in humans is encoded by the AURKA gene.

Anaphase lag is a consequence of an event during cell division where sister chromatids do not properly separate from each other because of improper spindle formation. The chromosome or chromatid does not properly migrate during anaphase and the daughter cells will lose some genetic information. It is one of many causes of aneuploidy. This event can occur during both meiosis and mitosis with unique repercussions. In either case, anaphase lag will cause one daughter cell to receive a complete set of chromosomes while the other lacks one paired set of chromosomes, creating a form of monosomy. Whether the cell survives depends on which sister chromatid was lost and the background genomic state of the cell. The passage of abnormal numbers of chromosomes will have unique consequences with regards to mosaicism and development as well as the progression and heterogeneity of cancers.

<span class="mw-page-title-main">CHEK1</span> Protein-coding gene in humans

Checkpoint kinase 1, commonly referred to as Chk1, is a serine/threonine-specific protein kinase that, in humans, is encoded by the CHEK1 gene. Chk1 coordinates the DNA damage response (DDR) and cell cycle checkpoint response. Activation of Chk1 results in the initiation of cell cycle checkpoints, cell cycle arrest, DNA repair and cell death to prevent damaged cells from progressing through the cell cycle.

<span class="mw-page-title-main">CDC20</span> Protein-coding gene in the species Homo sapiens

The cell division cycle protein 20 homolog is an essential regulator of cell division that is encoded by the CDC20 gene in humans. To the best of current knowledge its most important function is to activate the anaphase promoting complex (APC/C), a large 11-13 subunit complex that initiates chromatid separation and entrance into anaphase. The APC/CCdc20 protein complex has two main downstream targets. Firstly, it targets securin for destruction, enabling the eventual destruction of cohesin and thus sister chromatid separation. It also targets S and M-phase (S/M) cyclins for destruction, which inactivates S/M cyclin-dependent kinases (Cdks) and allows the cell to exit from mitosis. A closely related protein, Cdc20homologue-1 (Cdh1) plays a complementary role in the cell cycle.

<span class="mw-page-title-main">BUB1</span> Protein-coding gene in the species Homo sapiens

Mitotic checkpoint serine/threonine-protein kinase BUB1 also known as BUB1 is an enzyme that in humans is encoded by the BUB1 gene.

<span class="mw-page-title-main">TPX2</span> Protein-coding gene in the species Homo sapiens

Targeting protein for Xklp2 is a protein that in humans is encoded by the TPX2 gene. It is one of the many spindle assembly factors that play a key role in inducing microtubule assembly and growth during M phase.

<span class="mw-page-title-main">Mad1</span>

Mad1 is a non-essential protein which in yeast has a function in the spindle assembly checkpoint (SAC). This checkpoint monitors chromosome attachment to spindle microtubules and prevents cells from starting anaphase until the spindle is built up. The name Mad refers to the observation that mutant cells are mitotic arrest deficient (MAD) during microtubule depolymerization. Mad1 recruits the anaphase inhibitor Mad2 to unattached kinetochores and is essential for Mad2-Cdc20 complex formation in vivo but not in vitro. In vivo, Mad1 acts as a competitive inhibitor of the Mad2-Cdc20 complex. Mad1 is phosphorylated by Mps1 which then leads together with other activities to the formation of the mitotic checkpoint complex (MCC). Thereby it inhibits the activity of the anaphase-promoting complex/cyclosome (APC/C). Homologues of Mad1 are conserved in eukaryotes from yeast to mammals.

<span class="mw-page-title-main">G2-M DNA damage checkpoint</span>

The G2-M DNA damage checkpoint is an important cell cycle checkpoint in eukaryotic organisms that ensures that cells don't initiate mitosis until damaged or incompletely replicated DNA is sufficiently repaired. Cells with a defective G2-M checkpoint will undergo apoptosis or death after cell division if they enter the M phase before repairing their DNA. The defining biochemical feature of this checkpoint is the activation of M-phase cyclin-CDK complexes, which phosphorylate proteins that promote spindle assembly and bring the cell to metaphase.

Chromosomal instability (CIN) is a type of genomic instability in which chromosomes are unstable, such that either whole chromosomes or parts of chromosomes are duplicated or deleted. More specifically, CIN refers to the increase in rate of addition or loss of entire chromosomes or sections of them. The unequal distribution of DNA to daughter cells upon mitosis results in a failure to maintain euploidy leading to aneuploidy. In other words, the daughter cells do not have the same number of chromosomes as the cell they originated from. Chromosomal instability is the most common form of genetic instability and cause of aneuploidy.

References

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  20. 1 2 Pikor, Larissa; Thu, Kelsie; Vucic, Emily; Lam, Wan (2013). "The detection and implication of genome instability in cancer". Cancer and Metastasis Reviews. 32 (3): 341–352. doi:10.1007/s10555-013-9429-5. ISSN   0167-7659. PMC   3843371 . PMID   23633034.
  21. 1 2 3 Kanapathipillai, Mathumai (2018-05-23). "Treating p53 Mutant Aggregation-Associated Cancer". Cancers. 10 (6): 154. doi: 10.3390/cancers10060154 . ISSN   2072-6694. PMC   6025594 . PMID   29789497.
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  25. ↑ "Vinblastine Sulfate - NCI". www.cancer.gov. 2011-02-03. Retrieved 2022-11-29.
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  27. 1 2 Garcia-Saez, Isabel; Skoufias, Dimitrios A. (2021-02-01). "Eg5 targeting agents: From new anti-mitotic based inhibitor discovery to cancer therapy and resistance". Biochemical Pharmacology. 184: 114364. doi: 10.1016/j.bcp.2020.114364 . ISSN   0006-2952. PMID   33310050. S2CID   229180081.
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