# Cell Biology/Cell division/Cell cycle

The normal cell cycle consists of 2 major stages. The first is interphase, during which the cell lives and grows larger. The second is Mitotic Phase. Interphase is composed of three subphases. G$_1$ phase (first gap), S phase (synthesis), and G$_2$ phase (second gap). The interphase is the growth of the cell. The normal cell functions of creating proteins and organelles. The Mitotic Phase is composed of Mitosis and Cytokinesis. Mitosis, when the cell divides. Mitosis can be further divided into multiple phases. Cytokinesis, which is when the two daughter cells complete their separation. Mitosis is the division of the nucleus and cytokinesis is the division of the cytoplasm. There is some overlap between there two sub phases. Reproductive cell division is called meiosis, which yields a nonidentical daughter cells that have only one set of chromosomes. In other words, they have half as many chromosomes as the parent cell. Meiosis occurs in gonads, ovaries or testes. Therefore combining two gametes together produce 46 chromosomes.

## From Wikipedia

The cell cycle is the cycle of a biological cell, starting from the time it is first formed from a dividing parent cell until its own division into two cells, consisting of repeated mitotic cell division and interphase (the growth phase). A cell spends the overwhelming majority of its time in the interphase(about 90% of time).

## Background Information

DNA, deoxyribonucleic acid, consists of four nucleic acids, A, T, C, and G. In a cell, the DNA provides the directions for creating all of the proteins necessary for cell viability, health, growth, function, and replication. The unique DNA sequence that encodes each protein is called a gene, and the complete set of genes for an organism or cell is referred to as it's genome. Prokaryotic genomes are often a single long DNA molecule, and Eukaryotic genomes consist of number of DNA molecules. A typical human cell has about 2 m of DNA, which is 250,000 times greater than the cell's diameter. Before a cell divides the DNA is first copied then separated so that each daughter cell ends up with a complete genome. Chromosomes are the packaged DNA molecules. Because of chromosomes, the replication and distribution of so much DNA is manageable. Every eukaryotic species has a characteristic number of chromosomes in each cell nucleus. They contain two sets of each chromosome: one set inherited from each parent. For example human somatic cells (all body cells except the reproductive cells) each contain 46 chromosomes; the reproductive cells, gametes, have half as many chromosomes as somatic cells. The number of chromosomes in somatic cells varies widely among species. Eukaryotic chromosomes are made of chromatin that is a complex of DNA and associated protein molecules. Each single chromosome contains one very long, linear DNA molecule that carries several hundred to a few thousand genes; the associated proteins maintain the structure of the chromosome and help control the gene activity. When a cell is not dividing, each chromosome is a long thins chromatic fiber; however after DNA duplication chromosomes condense. Each chromatin fiber coils and folds. Each duplicated chromosome has two sister chromatids, containing an identical DNA molecule, initially attached along adhesive protein complex; such attachment is called sister chromatid cohesion. In condensed form of chromosome, a center narrow part is called centromere, a specialized region where the two chromatids are closely attached. The other part of a chromatid on either side of the centromere is referred as arm. Once the sister chromatids separate, they are considered individual chromosomes.

## Overview

The mitotic phase includes both mitosis and cytokinesis which is usually the shortest part of the cell cycle. Interphase accounts about 90%of the cycle; during interphase the cell grows and copies its chromosomes in preparation for cell division. Interphase is divided into sub-phases: G$_1$ phase ("first gap"), the S phase ("synthesis"), and G$_2$ phase ("second gap"). The chromosomes are duplicated only during the S phase. During G$_1$ phase cell grows until S phase where the cell prepares for the cell division during G$_2$ phase. Based on human cell, M phase only takes about 1 hour while the S phase occupies about 10-12 hours.
The cell cycle consists of
* G$_1$ phase, the first growth phase
* S phase, during which the DNA is replicated, where S stands for the Synthesis of DNA.
* G$_2$ phase is the second growth phase, also the preparation phase for the next stage
* M phase or mitosis and cytokinesis, the actual division of the cell into two daughter cells
The cell cycle stops at several checkpoints and can only proceed if certain conditions are met, for example, if the cell has reached a certain diameter. Some cells, such as neurons, never divide once they become locked in a G$_0$ phase.

## Mitosis

Mitosis has five stages: prophase, prometaphase, metaphase, anaphase, and telophase. Mitotic spindle starts to form in the cytoplasm during prophase. it is made of microtubules and other associated proteins. while the mitotic spindle assembles, the microtubules of the cytoskeleton disassemble, providing the material used to construct the spindle. In animal cells, the assembly of spindle microtubules starts at the centrosome, the microtubule-organizing center. In plant cells, the centrioles are not present.
During interphase in animal cells, the single centrosome replicates; the two centrosomes remain together near the nucleus and they move apart during prophase and prometaphase of mitosis as spindle microtubules grows. The two centrosomes are located at the opposite end of the cell. Then aster, a radial array of short microtubules, extends from each centrosome. Kinetochore is a structure of proteins associated with specific sections of chromosomal DNA at the centromere. Each of the two sister chromatids of a replicated chromosome contains kinetochore as it face in opposite direction. During prometaphase, kinetochore microtubules form as come of the spindle microtubules attach to the kinetochores. After the microtubules are attached to chromosome's kinetochores, the chromosome begins to move towards the pole from which those microtubules extend. the chromosomes moves in a motion like a tug-of-war. Metaphase plate is the imaginary plane that formed during metaphase the centromeres of all the duplicated chromosomes are on the plane midway between the spindle's two poles. The other microtubules that did not attach to kinetochores overlap and interact with other nonkinetochore microtubules from the opposite pole. The nonkinetochore microtubules are responsible for elongating the whole cell during anaphase. During anaphase, the cohesins holding the sister chromatids of each chromosome are cleaved by enzymes. Then the chromatids separated, and they move towards the opposite ends of the cell. The region of overlap is reduced as motor proteins attached to the microtubules move away from one another, using ATP. As the microtubules push apart from each other, their spindle poles are pushed apart, elongating the cell. As the duplicate groups of chromosomes arrive at the opposite ends of the elongated parent cell, the telophase begins; during telophase nuclei reforms and cytokinesis begins.
* G$_2$ of Interphase:During G$_2$ phase, a bombclear envelope bounds the nucleus, and two centrosomes forms by replication of a single centrosome. In animal cells, each centrosome contains two centrioles. The chromosomes are duplicated during S phase but cannot be seen since they are not condensed yet.
* Prophase: the chromatin fibers coils and dense into chromosomes and the nucleoli disappear. Each duplicated chromosome has tow identical sister chromatids joined at their centromeres along with their arms by cohesins, then the mitotic spindle form. The asters are the radial arrays of shorter microtubules that extend from the centrosomes. Propelled by the lengthening microtubules, the centrosomes move away from each other.
* Prometaphase: As the nuclear envelope fragments, the microtubules extending from each centrosome invade the nuclear area. the chromosome become more condensed as each of the two chromatids of each chromosome has a kinetochore. Some of the microtubules attach to the kinetochores ("kinetochore microtubules" and other nonkinetochore microtubules interact with each from fromt he opposite pole of the spindle.
* Metaphase: Metaphse is the longest stage of mitosis. The centrosomes are placed at the opposite poles of the cell. The chromosomes' centromeres lie ont he metaphse plate as the chromosome convene on the metaphase plate. Each kinetochores of the sister chromatids are attacged to kinetochore microtubules coming from opposite poles.
* Anaphase: Anaphase is the shortest stage of mitosis, and begins when the cohesin proteins are cleaved, allowing the two sister chromatids of each pair to part suddenly. The two liberated daughter chromosomes moves towards oppostie ends of the cell as the kinetochore microtubules shorten. The cell starts to elongate and nonkinetochore microtubules lengthen. By the end of anaphase, the two ends of the cell have equivalent collections of chromosome.
* Telophase: Two daughter nuclei form in the cell, and nuclear envelopes arise from the fragments of the parent cell's nuclear envelope. As nucleoli reappear, the chromosome become less condensed, and completes the division of the one nucleus into two genetically identical nuclei.
* Cytokinesis: In animal cells, cytokinesis involves formation of cleavage furrow; in plante cell the cleavage furrow does not exist. The formation of cell wall in the middle of cell (cell plate) divides the cell into two daughter cells.

## Cytokinesis

The cytokinesis process begins with cleavage. Cleavage furrow, a shallow groove in the cell surface near the old metaphase plate, is the first sign of cleavage. As it process, contractile ring of actin microfilaments form on the cytoplasmic side. The actin microfilaments interact with the myosin molecules, and cause the ring to contract. As the cleavage furrow deepens, the cell is separated into two with its own nucleus. For plant cells, there is no cleavage furrow because they have the cell walls. Instead of forming cleavages, vesicles derived from the Golgi apparatus move along microtubules to the middle of the cells, and forms cell plate. As the cell plate enlarges, and surrounding membrane fuses with the plasma membrane along the perimeter of the cell and from two daughter cells.

## Binary Fission

Binary fission is a method of asexual reproduction by "division in half". In prokaryotes, binary fission does not involve mitosis, but in single celled eukaryotes that undergo binary fission. In bacteria, motst genes are carried on a single bacterial chromosome that consists of a circular DNA molecule and associated proteins. The chromosome of the bacterium Escherichia coli, is 500 times as long as the cell when it is sctreched out. At the origin of replication, DNA of the bacterial chromosome begins to replicate. As the chromosome continues to replicate, one origin moves rapidly toward the opposite end of the cell, and the cell elongates. When the replication is complete the bacterium is about twice its initial size, and its plasma membrane grows inward, dividing the parent E. coli cell into two daughter cells. Bacteria don’t have mitotic spindles; the two origins of replication end up at opposite ends of the cell or in some other very specific location.

## The Evolution of Mitosis

Since the prokaryotes were on Earth more than a billion years than eukaryotes that mitosis had its origins in simpler prokaryotic mechanism of the cell reproduction can be assumed. Some of the proteins involved in bacterial binary fission are related to eukaryotic proteins that function in mitosis. Possible hypothesis of evolution of mitosis is that prokaryotic cell's reproduction gave rise to mitosis.

## The Cell Cycle Control System

Based from mammalian cell grow experiment, possible hypothesis was supported: the cell cycle is driven by specific signaling molecules present in the cytoplasm. In this experiment two cells in different phase of the cell cycle were fused to form a single cell with two nuclei. One cell was in the S phase and the other was in G$_1$, and G$_1$ nucleus immediately entered the S phase, as though stimulated by chemicals present in the cytoplasm of the first cell. Therefore, if a cell undergoing mitosis (M phase) was fused with another cell in any stage of its cell cycle, the second nucleus enteres mitosis. Other experiments on animal cells and yeasts demonstrates the sequential events of the cell cycle control system; the cell cycle control system operates set of molecules in the cell that both triggers and coordinates key events in the cell cycles. The cell cycle control system proceeds on its own, but it is regulated at certain checkpoints by internal and external signals. Animal cells have built-in stop signals that halt the cell cycle at checkpoints until they get go-ahead signals. The signals report whether crucial cellular processes that should have occurred by that point have in fact been completed correctly and thus whether or not the cell cycle should proceed. The three check points are in G$_1$, G$_2$, and M phase. For mammalian cells, G$_1$ check points are the most important. When a cell receives a go-ahead signal at the G$_1$ checkpoint, the cell complete the G$_1$, S, G$_2$ and M phases and divide; however when a cell does not get a go-ahead signal, it will exit the cycle and enter non dividing state, G$_0$ phase. Most of human cells are in G$_0$ phase, such as mature nerve cells and muscle cells. However the liver cells can re-enter the cycle by external signals such as growth factor released during injury. Rhythmic fluctuations in the abundance and activity of cell cycle control molecules pase the sequential events of the cell cycle. The regulatory molecules are portins of two types: protein kinases and cyclins. Portin kinases are enzymes that activate or inactivate other proteins by phosphorylating. The protein kinases give the go-ahead signals at the G$_1$ and G$_2$ checkpoints. The kinases that drive the cell cycle are present at a constant concentration in the growing cell, but they are in an inactive form. In order to activate them, kinase must be attached to a cyclin, a protein that cyclically fluctuating concentration in the cell. Because of such requirement, these are called cyclin-dependent kinases or Cdks. The activity of cdks rises and falls with changes in the concentration of its cyclin partner. The cylclin level rises during the S and G$_2$ phases and then falls rapidly during M phase. MPF, the maturation -promoting factor, or M-phase -promoting factor, activity corresponds to the peaks of cyclin concentration. MPF triggers the cell's passage past the G$_2$ checkpoint into M phase. MPF acts both directly as a kinase and indirectly by activating other kinases. During anaphase, MPF hels switch itself off by initiating a process that leads to the destruction of its own cyclin. The Cdk, noncyclin part of MPF, persists in the cell in inactive form until it associates with new cyclin molecules synthesized during the S and G$_2$ phase of the next round of the cycle. Density-dependent inhibition is a phenomenon in which crowded cells stop dividing. It is caused by external physical factor. Also most animal cells exhibit anchorage dependence; in order to divide, the cells must be attached to a substratum; like a cell density, anchorage is signaled to the cell cycle control system via pathways involving plasma membrane proteins and elements of cytoskeleton linked to them. The loss of cell cycle controls leads to cancer cells, which exhibit neither density-dependent inhibition nor anchorage dependence.

## Reference

Berg, Jeremy M., John L. Tymoczko, and Lubert Stryer. Biochemistry. 7th ed. New York: W.H. Freeman, 2012. Print.
Reece, Campbell, Lisa A. Urry, Michael L. Cain, Steven A. Wasserman, Peter V. Minosky, and Robert B. Jackson. Biology. 8th ed. San Francisco: Cummings, 2010. Print.