Cell Division and Cell Cycle

In eukaryotic cells, the cell cycle refers to the entire process of generating two daughter cells from one original cell, with chromosomal replication as one of the steps. The two parts of the cell cycle are called interphase and mitosis.

DNA synthesis occurs during interphase and consists of three stages: gap 1 (G1), synthesis (S), and gap 2 (G2) (Figure 1-4). Regulation of cell division depends on specific cell-cycle-dependent proteins known as cyclins and growth factors. Some of these factors cause the cycle to progress while others stop the cycle at certain stages. Checkpoints, or times when the cycle may be paused, exist at the G1/S and G2/mitosis interfaces and allow the cell time to repair any DNA damage that may be present in the cell before and after replication of the DNA, respectively.

Growth factors initiate the G1 phase via cell surface receptors. Several molecular events such as the dephospho-rylation of the retinoblastoma protein and cyclin binding to cyclin-dependent kinases (Cdk) transition the cell toward the G1/S checkpoint. The amount of cellular P53 protein determines whether the cell progresses beyond this checkpoint, with higher levels preventing cell cycle progression. Because various DNA-damaging events, such as ultraviolet light, radiation, carcinogens, and double-stranded DNA breaks, induce production of P53 protein, this molecule serves as a sentinel for mutated DNA. The functional failure of P53 removes this sentinel from the cell cycle process and results in the accumulation of genetic errors. Therefore, inactivation of P53 facilitates oncogenesis.

Once DNA repairs have taken place during G1 prior to replication of the DNA, the cell proceeds to S phase. DNA synthesis occurs in the S phase, followed by the G2 phase. Replication errors occurring during the S phase are corrected in the G2 phase, the G2/M checkpoint. This final checkpoint marks the end of interphase.

Mitosis, the process of physical division of the parent cell into two daughter cells, occurs during the mitosis or M phase of the cell cycle. During mitosis, the duplicated chromosomes are physically separated so that each daughter cell receives the correct number of chromosomes. Mitosis consists of five phases: prophase, prometaphase, metaphase, anaphase, and telophase. The duplicated chromosomes condense during prophase. A structural element known as the mitotic spindle originates from two structures called centri-oles,which move to opposite poles of the cell and the spindle forms between the centrioles. The nuclear membrance dissipates, proteins form kinetochores on the chromosmes, and microtubules attach to the kinetochores during prometaphase. The duplicated chromosome pairs attach at central points along the spindles. The arrangement of the highly condensed chromosome pairs along an equatorial cell plane denotes metaphase. As previously discussed, highly condensed chromosomes cannot bind proteins necessary for gene expression. As a result, the cell's internal machinery focuses solely on cell division during metaphase. The cen-triole-derived spindle guidelines pull the duplicate chromosomes apart and drag them toward each centriole during anaphase. With the separation of the daughter chromosomes (chromatids) into opposite poles of the cell and the reformation of nuclear membranes around the two daughter sets of chromosomes, telophase begins. Cytokinesis, or the division of the cytoplasm, is the last step in cell division. During cytokinesis, the mitochondria are randomly and potentially unevenly distributed in the daughter cells. The cell cycle can then be reinitiated by one or both of the daughter cells to generate additional cells. Alternatively, some cells become quiescent in a G0 phase (between telephase and G1) and either have a prolonged delay before initiating replication again or no longer divide.

Cell division to generate gametes is called meiosis and consists of two divisions, meiosis I and meiosis II. Like mitosis, this process begins with the duplication of chromosomes in prophase I. During metaphase I, the maternal and paternal homologous chromosomes pair (i.e.,pairing occurs between each of the pairs of the 22 autosomal chromosomes, the two X chromosomes in females, and the X and Y chromosomes in males). Each pair attaches to the spindle apparatus along the equatorial plane of the cell spindle. DNA may be exchanged between the paired chromosomes by either crossing-over or recombination mechanisms during this pairing stage of meiosis I. During anaphase I, homologous chromosomes separate into daughter cells, resulting in 23 duplicated chromosomes in each daughter cell. A second cell-division cycle, meiosis II, separates the duplicated chromosomes, resulting in haploid cells, egg or sperm, containing only one copy of each of the 22 chromosomes plus an X (egg or sperm) or Y (only sperm) chromosome.

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