Genetics, Mitosis

Cellular

The entirety of a cell’s DNA is called its genome. During cell division, the whole genome is replicated exactly and distributed to 2 daughter cells. A human cell typically has about 2 meters of DNA. Due to the enormous length, the DNA must be highly condensed to fit into the nucleus of each cell. The highly condensed packages of DNA are termed chromosomes when the cell has completed the synthesis phase and is ready to undergo mitosis. Various proteins aid the DNA in folding compactly into subunits of nucleosomes and chromatin. Human somatic cells have 2 sets of 23 chromosomes for a total of 46 chromosomes - 22 sets of autosomes and 1 set of sex chromosomes. A single set of chromosomes is inherited from each parent.[4][5][6] DNA packaging is discussed in different StatPearls reviews - Genetics, DNA Packaging, Genetics, and Histone Code.

Mechanism

The mitotic phase is usually the shortest part of any cell cycle. The largest portion of the cell cycle, interphase, makes up 90% of a cell's life cycle and is the stage for growing and performing the cellular functions specific to that cell. The interphase is further divided into two G phases- G1 and G2- and an S phase. During these phases, the cell grows by producing various proteins and cytoplasmic organelles. During the S phase, the cell replicates its genome in preparation for cell division or mitosis. Mitosis occurs during the M phase, which occurs after interphase.[7]

Phases

Mitosis is conventionally divided into 5 phases: prophase, metaphase, anaphase and telophase, and cytokinesis. In interphase, a nuclear envelope surrounds the nucleus, the DNA is replicated in the S phase, and the sister chromatids join together at the central portion of the chromosome - the centromere. To organize the chromosome motion in the cell to help make division efficient as well as ensure all material is present in both daughter cells, the cell has centrosomes at each pole of the cell. Centrosomes organize the fibers of the mitotic spindle during mitosis, that will help pull the sister chromatids apart.

In prophase, the chromatin fibers condense into chromosomes that are visible through a light microscope. Each replicated chromosome appears as two identical sister chromatids joined at their centromeres, and the mitotic spindle begins to form. Also, the centrosomes begin to move to opposite poles of the cell, and they are propelled by the lengthening microtubules between them.

In prometaphase, the nuclear envelope falls apart; microtubules can invade the nuclear area and bind to some of the chromosomes. The microtubules bind at the kinetochores, specialized protein structures at the centromere. Not all microtubules interact with kinetochores. Some microtubules interact with microtubules extending from the other side of the cell.

In metaphase, the centrosomes have migrated to opposite poles of the cell. The chromosomes have all lined up at the metaphase plate in the middle of the cell, and all chromosomes are attached to microtubules through their kinetochores. The metaphase plate is an imaginary line equidistant from the spindle's 2 poles.

In anaphase, the shortest stage of mitosis, the sister chromatids break apart, and the chromosomes begin moving to opposite ends of the cell. By the end of anaphase, the 2 halves of the cell have an equivalent collection of chromosomes.

In telophase, 2 daughter nuclei form. The nuclear envelope begins to reappear. DNA begins to de-condense while spindle microtubules begin to depolymerize. Mitosis, the division of one nucleus into 2, is now complete. Lastly, cytokinesis, which is the division of the cytoplasm, takes place, and the cell divides into 2 separate cells. In animal cells, this is accomplished through a cleavage furrow that pinches the cell in 2.

Regulation 

Throughout mitosis, certain checkpoints are essential to the continuation of the process. If certain conditions are not met, mitosis halts. If any of these checkpoints are bypassed without being completed, certain pathologies, such as cancer, can occur.[8][9]

There are three main checkpoints: the G1/S checkpoint, G2/M, and metaphase/anaphase checkpoint. During the G1/S checkpoint, also known as the restriction checkpoint, primary influencers of cell cycle progression include growth factors, DNA damage, cell size, and cell nutrition. The G2/M checkpoint, also known as the DNA replication checkpoint, is influenced by improper DNA replication or DNA damage. The third checkpoint, also known as the spindle apparatus checkpoint, is influenced by the attachment of the mitotic spindle to all chromosomes. Only when all sister chromatids have been bound will mitosis proceed into anaphase.[10]

Cell Types 

It is important to recognize that cells can progress through the cell cycle in different manners. Cells can withdraw from the active cell cycle and exist in a non-proliferating or quiescent state. These cells are said to be in the G0 phase. During G1, remain in G1 or leave the active cell cycle and enter the G0 phase. Different cell types are classified below on their characteristic cell cycle progressions. [11]

Labile cell types are cells that are constantly proliferating via stem cells in order to replace cells that have died or sloughed off. Some examples of labile cell types include skin epithelium, gastrointestinal epithelium, salivary gland tissue, and hematopoietic cell types. It is important to recognize that chemotherapy used in cancer treatments has toxic effects on healthy cells, especially cells undergoing rapid renewal.[12]

Quiescent or stable cell types are normally in a non-dividing state but may enter the cell cycle in response to certain stimuli. Examples of stable cell types include lymphocytes, hepatocytes, endothelial cells, and others. 

Finally, permanent cell types are unable to proliferate and are considered non-dividing. Examples of permanent cell types include cardiac and skeletal muscle. [13]

Clinical Significance

Cancer cells can bypass these checkpoints and divide indefinitely. They do not stop growing even when all growth factors have been depleted. The abnormal behavior of cells can have harmful effects on the body. It starts with a single cell in a specific tissue, transforming from a normal cell to a cancer cell. Normally, the body can identify a cancer cell by the proteins on its surface and destroy it. However, if a cancer cell evades destruction, it can form a mass of cancerous cells called a tumor. If the tumor stays in the same place, it is called a benign tumor and can usually be removed with surgery. However, a malignant tumor is one that can spread to other tissues of the body and impair the functions of more than one organ. An individual with a malignant tumor is said to have cancer. The spread of cancer cells from one location to another is called metastasis.

Individuals can have a somatic or inherited mutation in certain tumor suppressor genes that will increase their risk of developing cancers. These "tumor suppressor genes" are very often cell cycle regulators that will act as a stop sign to halt cell division in the case of DNA damage, etc. Some relevant tumor suppressors are mentioned below. 

A well-known tumor suppressor, Rb, is associated with the development of retinoblastoma. The two most common symptoms are leukocoria and strabismus. Leukocoria means "white pupil" and refers to an abnormal pupillary reflex that can be better seen in photography. Strabismus refers to a misalignment of the eyes.[14][15][16][17]

Another well-known tumor suppressor is p53, which is seen to be mutated in around 50% of human cancers. It normally responds to stresses such as damage, oncogenic activation, and more, leading to cell cycle arrest. When mutated, normal cellular responses to these stressors are less effective, and the cell can continue to progress through cell division. Le Fraumeni syndrome is caused by a germline mutation in the TP53 gene encoding the p53 protein. It genetically predisposes carriers to osteosarcoma, soft tissue sarcomas, premenopausal breast cancers, adrenal cortical carcinomas, and brain tumors.[18][19][20]

Adenomatous polyposis coli (APC) is a tumor suppressor involved in the pathogenesis of colorectal cancer. Germline mutations in APC lead to a classical form of familial adenomatous polyposis (FAP). FAP is characterized by hundreds of colonic polyps or adenomas, which have a high tendency to undergo malignant transformation.[21][22]

It is important to recognize that cancer can develop through mechanisms other than loss of tumor suppressor genes, such as mutations in DNA repair genes, proto-oncogenes, growth factor receptors, and others. 

A localized tumor can be treated with high-energy radiation, which damages DNA in cancer cells much more than in normal cells. This is because cancer cells have lost the ability to repair DNA. In order to treat metastatic tumors, chemotherapy is used. Chemotherapy is when drugs that are toxic to dividing cells are administered through the circulatory system. One example is the drug Taxol, or paclitaxel, which causes microtubule stabilization, preventing depolymerization leading to cell cycle arrest.[23]

Other errors in mitosis that can contribute to disease include aneuploidy or an improper number of chromosomes within cells. Aneuploidy is a common characteristic of tumors with chromosomal instability, as well as other diseases. Aneuploidy can be caused by nondisjunction or the failure of chromosomes to separate, which can lead to somatic mosaicism in cells undergoing mitosis. Mosaicism can be a component of certain diseases, such as Turner syndrome.[10][24]

Mitosis is a process constantly occurring in the human body. It is important to understand the process at the molecular level because many conditions, such as cancer and others, can arise when mitosis is interfered with in any way.