In other words, the genome is being replicated during this phase; thus at the end of S phase, the cell has twice the normal amount of DNA. After S phase, the cell proceeds into G 2 , which provides an opportunity for the cell to perform a self-assessment and make final preparations such as more cell growth, repairs of DNA as necessary before it finally heads into mitosis.
Prokaryotes replicate their DNA continuously throughout their relatively short cell cycle whereas eukaryotic cells replicate DNA only in the S-phase of the cell cycle discussed in detail in Section 1. This mini-review will specifically discuss the intricacies of the eukaryotic cell cycle with special focus on DNA replication, cell cycle control, and key biomarkers of cell division.
The highly regulated cell cycle is divided into phases, referred to as interphase G1, S, and G2 and the mitotic M phase Figure 1. In the gap 1 G1 phase, the cell grows and acquires the energy needed for division. Cellular components, except for chromosomes, are duplicated at this stage. In the synthesis S phase, DNA replication occurs to duplicate the genetic material, with each chromosome now consisting of two sister chromatids.
In the gap 2 G2 phase, the cell prepares to divide by inducing metabolic changes that assemble the cytoplasmic components necessary for mitosis. During the M phase, nuclear division occurs, and the cell finally divides to create two identical daughter cells. At the end of cytokinesis each new cell consists of a full complement of DNA from the parent cell Kapinas et al. Another specialized cell division process known as meiosis is required to produce egg and sperm cells for reproduction.
This process is split into meiosis I and meiosis II, in which meiosis I is unique to germ cells and meiosis II is similar to mitosis.
However, in contrast to mitosis, the molecular and regulatory mechanisms involved in meiosis are less understood Ohkura Under certain conditions, a cell can exit the cell cycle and enter a state of quiescence referred to as the gap 0 G0 phase.
This phase is however reversible and G0 cells can return to the G1 phase and resume growth and division if appropriately stimulated. Overview of the eukaryotic cell cycle. During cell division, cells pass through a series of stages collectively referred to as the cell cycle. To ensure that healthy cells are produced after each round of cell division, the cell cycle consists of three major checkpoints with distinct functions: G1, G2, and Spindle M checkpoints.
These checkpoints are surveillance mechanisms whose function is to ensure that the generated daughter cells are duplicates of the parent cell complete with the accurate number of chromosomes and are mutation free Figure 1.
During the G1 checkpoint, cellular conditions necessary for progression through the cell cycle are evaluated. A cell generally passes the G1 checkpoint if it is an appropriate size, possesses adequate energy, and does not have damaged DNA. The main function of the G2 checkpoint is to ensure that replication of all chromosomes is complete and without introductions of mutations or unrepaired DNA damage.
In addition, appropriate cell size and protein reserves are also assessed during this checkpoint. These checkpoints halt cell cycle progression if the cell has not met each of the requirements being evaluated. This is necessary to allow the identified unfavorable conditions to be addressed.
Since it plays such an important role in preventing the continued cell cycle progression of cells with mutated DNA, p53 is considered a tumor suppressor Zilfou and Lowe Consequently, it has been reported to be commonly mutated or absent in several types of cancer Hussain and Harris The master regulators of the cell cycle in eukaryotes are however heterodimeric enzyme complexes, which consist of cyclins and cyclin-dependent kinases Cdks Murray The expression of cyclins increases or decreases in distinct phases of the cell cycle, and they are divided into groups based on the cell cycle phase that they regulate Figure 2 Murray However, in most cases, the concentration of Cdks remains relatively constant.
Each Cdk subunit can associate with different cyclins, and the associated cyclin determines which protein substrates are phosphorylated by the Cdk-cyclin complex Lodish et al. Moreover, Cdks have no kinase activity unless cyclin bound.
In addition to the binding of cyclins, activation of the complex also requires phosphorylation of key residues in the activation loop of the Cdk subunit Harper and Elledge , Hochegger et al. Several mechanisms have been identified for inhibiting activated cyclin-Cdk complexes. These include inhibitory phosphorylation of important residues such as tyrosine 15 and threonine 14 in Cdk1, degradation of the cyclin subunits by specific ubiquitin-mediated proteolysis, or association of the complex with a highly specific inhibitor protein such as p16 in the case of the cyclin D-Cdk4 complex Hochegger et al.
Expression of cyclins throughout the cell cycle phases Lodish et al. Cyclins are differentially expressed at various phases of the cell cycle and play distinct roles in cell cycle control.
The figure demonstrates the stages in the cell cycle in which each cyclin is expressed. The grey shaded areas represent the peak expression of the respective cyclin. The classical model of cell cycle control indicates that D-type cyclins and Cdk4 or Cdk6 regulate events in the early G1 phase Nurse The cyclin B-Cdk1 complex is subsequently responsible for mitosis Table 1. During the mitotic phase, the replicated DNA and cytoplasmic contents are separated, and the cell divides.
Figure 1. The cell cycle consists of interphase and the mitotic phase. During interphase, the cell grows and the nuclear DNA is duplicated. Interphase is followed by the mitotic phase. During the mitotic phase, the duplicated chromosomes are segregated and distributed into daughter nuclei. The cytoplasm is usually divided as well, resulting in two daughter cells. During interphase, the cell undergoes normal growth processes while also preparing for cell division.
In order for a cell to move from interphase into the mitotic phase, many internal and external conditions must be met. The three stages of interphase are called G 1 , S, and G 2. The first stage of interphase is called the G 1 phase first gap because, from a microscopic aspect, little change is visible.
However, during the G 1 stage, the cell is quite active at the biochemical level. The cell is accumulating the building blocks of chromosomal DNA and the associated proteins as well as accumulating sufficient energy reserves to complete the task of replicating each chromosome in the nucleus.
Throughout interphase, nuclear DNA remains in a semi-condensed chromatin configuration. In the S phase, DNA replication can proceed through the mechanisms that result in the formation of identical pairs of DNA molecules—sister chromatids—that are firmly attached to the centromeric region. The centrosome is duplicated during the S phase.
The two centrosomes will give rise to the mitotic spindle, the apparatus that orchestrates the movement of chromosomes during mitosis. At the center of each animal cell, the centrosomes of animal cells are associated with a pair of rod-like objects, the centrioles, which are at right angles to each other. Centrioles help organize cell division. Centrioles are not present in the centrosomes of other eukaryotic species, such as plants and most fungi. In the G 2 phase, the cell replenishes its energy stores and synthesizes proteins necessary for chromosome manipulation.
Some cell organelles are duplicated, and the cytoskeleton is dismantled to provide resources for the mitotic phase. There may be additional cell growth during G 2. The final preparations for the mitotic phase must be completed before the cell is able to enter the first stage of mitosis. The mitotic phase is a multistep process during which the duplicated chromosomes are aligned, separated, and move into two new, identical daughter cells.
The first portion of the mitotic phase is called karyokinesis, or nuclear division. The second portion of the mitotic phase, called cytokinesis, is the physical separation of the cytoplasmic components into the two daughter cells. Karyokinesis, also known as mitosis, is divided into a series of phases—prophase, prometaphase, metaphase, anaphase, and telophase—that result in the division of the cell nucleus Figure 2. Karyokinesis is also called mitosis. Figure 2. Karyokinesis or mitosis is divided into five stages—prophase, prometaphase, metaphase, anaphase, and telophase.
The pictures at the bottom were taken by fluorescence microscopy hence, the black background of cells artificially stained by fluorescent dyes: blue fluorescence indicates DNA chromosomes and green fluorescence indicates microtubules spindle apparatus. The nucleolus disappears disperses. The centrosomes begin to move to opposite poles of the cell. Microtubules that will form the mitotic spindle extend between the centrosomes, pushing them farther apart as the microtubule fibers lengthen.
The sister chromatids begin to coil more tightly with the aid of condensin proteins and become visible under a light microscope. Figure 3. During prometaphase, mitotic spindle microtubules from opposite poles attach to each sister chromatid at the kinetochore. In anaphase, the connection between the sister chromatids breaks down, and the microtubules pull the chromosomes toward opposite poles.
The remnants of the nuclear envelope fragment. The cellular life cycle, also called the cell cycle , includes many processes necessary for successful self-replication. Beyond carrying out the tasks of routine metabolism, the cell must duplicate its components — most importantly, its genome — so that it can physically split into two complete daughter cells. The cell must also pass through a series of checkpoints that ensure conditions are favorable for division. In eukaryotes, the cell cycle consists of four discrete phases: G 1 , S, G 2 , and M.
The S or synthesis phase is when DNA replication occurs, and the M or mitosis phase is when the cell actually divides. The other two phases — G 1 and G 2 , the so-called gap phases — are less dramatic but equally important. During G 1 , the cell conducts a series of checks before entering the S phase. Later, during G 2 , the cell similarly checks its readiness to proceed to mitosis.
Together, the G 1 , S, and G 2 phases make up the period known as interphase. Cells typically spend far more time in interphase than they do in mitosis. Of the four phases, G 1 is most variable in terms of duration, although it is often the longest portion of the cell cycle Figure 1.
Figure Detail. In order to move from one phase of its life cycle to the next, a cell must pass through numerous checkpoints. At each checkpoint, specialized proteins determine whether the necessary conditions exist.
If so, the cell is free to enter the next phase. If not, progression through the cell cycle is halted. Errors in these checkpoints can have catastrophic consequences, including cell death or the unrestrained growth that is cancer.
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