The individual sexually reproducing organism – including humans – begins life as a fertilized egg, or zygote. Trillions of cell divisions subsequently occur in a controlled manner to produce a complex, multicellular organism like, for instance, the human organism. Hence, that original single cell is the ancestor of every other cell in the body. Once a human individual is fully grown, cell reproduction is still necessary to repair or regenerate tissues. For example, new blood and skin cells are constantly being produced. All multicellular organisms use cell division for growth, and in most cases, the maintenance and repair of cells and tissues. Single-celled organisms use cell division as their method of reproduction.
The continuity of life from one cell to another has its foundation in the reproduction of cells by way of the cell cycle. The cell cycle is an orderly sequence of events in the life of a cell from the division of a single parent cell to produce two new daughter cells, to the subsequent division of those daughter cells. The mechanisms involved in the cell cycle are highly conserved across eukaryotes. Organisms as diverse as protists, plants, and animals employ similar steps.
The genome
The complete complement of DNA of a cell is called its genome. Genome is a fancy word for all the DNA of a living organism. Each genome contains the information needed to build and maintain that organism throughout its life.
The human genome represents virtually all of the genetic information stored in nuclear and mitochondrial DNA. The human genome is identical in all individuals of the human population in proportion of 99.9%. It differs by about 1.23% from the chimpanzee genome, with very small variations, around 2%, between the human genome and the genome of apes.
In prokaryotes, the genome is composed of a single, double-stranded DNA molecule in the form of a loop or circle. The region in the cell containing this genetic material is called a nucleoid. Some prokaryotes also have smaller loops of DNA called plasmids that are not essential for normal growth.
In eukaryotes, the genome comprises several double-stranded, linear DNA molecules (Figure 4.1) bound with proteins to form complexes called chromosomes. Each species of eukaryote has a characteristic number of chromosomes in the nuclei of its cells. Human body cells (somatic cells) have 46 chromosomes. A somatic cell contains two matched sets of chromosomes, a configuration known as diploid. The letter n is used to represent a single set of chromosomes; therefore a diploid organism is designated 2n. Human cells that contain one set of 23 chromosomes are called gametes or sex cells; these eggs and sperm are designated n or haploid.
The matched pairs of chromosomes in a diploid organism are called homologous chromosomes. Homologous chromosomes are the same length and have specific nucleotide segments called genes in exactly the same location, or locus. Genes, the functional units of chromosomes, determine specific characteristics by coding for specific proteins. More precisely, each gene synthesizes a specific protein. Traits are the different forms of a characteristic. For example, the shape of earlobes is a characteristic with traits of free or attached.
Each copy of the homologous pair of chromosomes originates from a different parent; therefore, the copies of each of the genes themselves may not be identical. The variation of individuals within a species is caused by the specific combination of the genes inherited from both parents. For example, there are three possible gene sequences on the human chromosome that code for blood type: sequence A, sequence B, and sequence O. Because all diploid human cells have two copies of the chromosome that determines blood type, the blood type (the trait) is determined by which two versions of the marker gene are inherited. It is possible to have two copies of the same gene sequence, one on each homologous chromosome, such as AA, BB, or OO, or two different sequences, such as AB.
Minor variations in traits such as those for blood type, eye color, and height contribute to the natural variation found within a species. The sex chromosomes, X and Y, are the single exception to the rule of homologous chromosomes; other than a small amount of homology that is necessary to reliably produce gametes, the genes found on the X and Y chromosomes are not the same.
For cases in which one gene controls a single characteristic, a diploid organism has two genetic copies that may or may not encode the same version of that characteristic. For example, one individual may carry a gene that determines white flower color and a gene that determines violet flower color. Gene variants that arise by mutation and exist at the same relative locations on homologous chromosomes are called alleles.
Two alleles for a given gene in a diploid organism are expressed and interact to produce physical characteristics. The observable traits expressed by an organism are referred to as its phenotype. An organism’s underlying genetic makeup, consisting of both the physically visible and the non-expressed alleles, is called its genotype.
A mutation is an alteration in the genetic material (the genome) of a cell of a living organism or of a virus that is more or less permanent and that can be transmitted to the cell’s or the virus’s descendants. In the broadest sense, genetic mutations are changes that occur in genes, chromosomes or other cellular constituents that carry heredity. In a concrete sense, genetic mutations are changes in genotype. Depending on the substrate it affects, mutations can be divided into: gene, chromosomal, genomic, and plastid mutations.
Mutation in the DNA of a body cell of a multicellular organism (somatic mutation) may be transmitted to descendant cells by DNA replication and hence result in a sector or patch of cells having abnormal function, an example being cancer. Mutations in egg or sperm cells (germinal mutations) may result in an individual offspring all of whose cells carry the mutation, which often confers some serious malfunction, as in the case of a human genetic disease such as cystic fibrosis. Mutations result either from accidents during the normal chemical transactions of DNA, often during replication, or from exposure to high-energy electromagnetic radiation (e.g., ultraviolet light or X-rays) or particle radiation or to highly reactive chemicals in the environment.
Figure 4.1: There are 23 pairs of homologous chromosomes in a female human somatic cell. These chromosomes are viewed within the nucleus (top), removed from a cell in mitosis (right), and arranged according to length (left) in an arrangement called a karyotype. In this image, the chromosomes were exposed to fluorescent stains to distinguish them (credit: “718 Bot” / Wikimedia Commons, National Human Genome Research).
The cell cycle
The cell cycle is an ordered series of events involving cell growth and cell division that produces two new daughter cells. Cells on the path to cell division proceed through a series of precisely timed and carefully regulated stages of growth, DNA replication, and division that produce two genetically identical cells. The cell cycle has two major phases: interphase and the mitotic phase (Figure 4.2). During interphase, the cell grows and DNA is replicated. During the mitotic phase, the replicated DNA and cytoplasmic contents are separated and the cell divides.
Figure 4.2: A cell moves through a series of phases in an orderly manner. During interphase, G1 involves cell growth and protein synthesis, the S phase involves DNA replication and the replication of the centrosome, and G2 involves further growth and protein synthesis. The mitotic phase follows interphase. Mitosis is nuclear division during which duplicated chromosomes are segregated and distributed into daughter nuclei. Usually the cell will divide after mitosis in a process called cytokinesis in which the cytoplasm is divided and two daughter cells are formed.
Interphase
During interphase, the cell undergoes normal processes while also preparing for cell division. For a cell to move from interphase to the mitotic phase, many internal and external conditions must be met. The three stages of interphase are called G1, S, and G2.
G1 Phase
The first stage of interphase is called the G1 phase, or first gap, because little change is visible. However, during the G1 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 enough energy reserves to complete the task of replicating each chromosome in the nucleus.
S Phase
Throughout interphase, nuclear DNA remains in a semi-condensed chromatin configuration. In the S phase (synthesis phase), DNA replication results in the formation of two identical copies of each chromosome – sister chromatids – that are firmly attached at the centromere region. At this stage, each chromosome is made of two sister chromatids and is a duplicated chromosome. 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. The centrosome consists of a pair of rod-like centrioles at right angles to each other. Centrioles help organize cell division. Centrioles are not present in the centrosomes of many eukaryotic species, such as plants and most fungi.
G2 Phase
In the G2 phase, or second gap, the cell replenishes its energy stores and synthesizes the proteins necessary for chromosome manipulation. Some cell organelles are duplicated, and the cytoskeleton is dismantled to provide resources for the mitotic spindle. There may be additional cell growth during G2. The final preparations for the mitotic phase must be completed before the cell is able to enter the first stage of mitosis.
Mitotic phase
To make two daughter cells, the contents of the nucleus and the cytoplasm must be divided. The mitotic phase is a multi-step process during which the duplicated chromosomes are aligned, separated, and moved to opposite poles of the cell, and then the cell is divided into two new identical daughter cells. The first portion of the mitotic phase, mitosis, is composed of five stages, which accomplish nuclear division. The second portion of the mitotic phase, called cytokinesis, is the physical separation of the cytoplasmic components into two daughter cells.
Mitosis
Mitosis is divided into a series of phases – prophase, prometaphase, metaphase, anaphase, and telophase – that result in the division of the cell nucleus (Figure 4.3).
Figure 4.3: Animal cell mitosis is divided into five stages – prophase, prometaphase, metaphase, anaphase, and telophase – visualized here by light microscopy with fluorescence. Mitosis is usually accompanied by cytokinesis, shown here by a transmission electron microscope (credit “diagrams”: modification of work by Mariana Ruiz Villareal; credit “mitosis micrographs”: modification of work by Roy van Heesbeen; credit “cytokinesis micrograph”: modification of work by the Wadsworth Center, NY State Department of Health; donated to the Wikimedia foundation; scale-bar data from Matt Russell).
During prophase, the “first phase,” several events must occur to provide access to the chromosomes in the nucleus. The nuclear envelope starts to break into small vesicles, and the Golgi apparatus and endoplasmic reticulum fragment and disperse to the periphery of the cell. The nucleolus disappears. The centrosomes begin to move to opposite poles of the cell. The microtubules that form the basis of the mitotic spindle extend between the centrosomes, pushing them farther apart as the microtubule fibers lengthen. The sister chromatids begin to coil more tightly and become visible under a light microscope.
During prometaphase, many processes that were begun in prophase continue to advance and culminate in the formation of a connection between the chromosomes and cytoskeleton. The remnants of the nuclear envelope disappear. The mitotic spindle continues to develop as more microtubules assemble and stretch across the length of the former nuclear area. Chromosomes become more condensed and visually discrete. Each sister chromatid attaches to spindle microtubules at the centromere via a protein complex called the kinetochore.
During metaphase, all of the chromosomes are aligned in a plane called the metaphase plate, or the equatorial plane, midway between the two poles of the cell. The sister chromatids are still tightly attached to each other. At this time, the chromosomes are maximally condensed.
During anaphase, the sister chromatids at the equatorial plane are split apart at the centromere. Each chromatid, now called a chromosome, is pulled rapidly toward the centrosome to which its microtubule was attached. The cell becomes visibly elongated as the non-kinetochore microtubules slide against each other at the metaphase plate where they overlap.
During telophase, all of the events that set up the duplicated chromosomes for mitosis during the first three phases are reversed. The chromosomes reach the opposite poles and begin to decondense (unravel). The mitotic spindles are broken down into monomers that will be used to assemble cytoskeleton components for each daughter cell. Nuclear envelopes form around chromosomes.
Cytokinesis
Cytokinesis is the second part of the mitotic phase during which cell division is completed by the physical separation of the cytoplasmic components into two daughter cells.
Although the stages of mitosis are similar for most eukaryotes, the process of cytokinesis is quite different for eukaryotes that have cell walls, such as plant cells. In cells such as animal cells that lack cell walls, cytokinesis begins following the onset of anaphase. A contractile ring composed of actin filaments forms just inside the plasma membrane at the former metaphase plate. The actin filaments pull the equator of the cell inward, forming a fissure. This fissure, or “crack,” is called the cleavage furrow. The furrow deepens as the actin ring contracts, and eventually the membrane and cell are cleaved in two (Figure 4.4a). In plant cells, a cleavage furrow is not possible because of the rigid cell walls surrounding the plasma membrane. A new cell wall must form between the daughter cells. During interphase, the Golgi apparatus accumulates enzymes, structural proteins, and glucose molecules prior to breaking up into vesicles and dispersing throughout the dividing cell. During telophase, these Golgi vesicles move on microtubules to collect at the metaphase plate. There, the vesicles fuse from the center toward the cell walls; this structure is called a cell plate. As more vesicles fuse, the cell plate enlarges until it merges with the cell wall at the periphery of the cell. Enzymes use the glucose that has accumulated between the membrane layers to build a new cell wall of cellulose. The Golgi membranes become the plasma membrane on either side of the new cell wall (Figure 4.4b).
Figure 4.4: In part (a), a cleavage furrow forms at the former metaphase plate in the animal cell. The plasma membrane is drawn in by a ring of actin fibers contracting just inside the membrane. The cleavage furrow deepens until the cells are pinched in two. In part (b), Golgi vesicles coalesce at the former metaphase plate in a plant cell. The vesicles fuse and form the cell plate. The cell plate grows from the center toward the cell walls. New cell walls are made from the vesicle contents.
The G0 Phase
Not all cells adhere to the classic cell-cycle pattern in which a newly formed daughter cell immediately enters interphase, closely followed by the mitotic phase. Cells in the G0 phase are not actively preparing to divide. The cell is in a quiescent (inactive) stage, having exited the cell cycle. Some cells enter G0 temporarily until an external signal triggers the onset of G1. Other cells that never or rarely divide, such as mature cardiac muscle and nerve cells, remain in G0 permanently (Figure 4.5).
Figure 4.5: Cells that are not actively preparing to divide enter an alternate phase called G0. In some cases, this is a temporary condition until triggered to enter G1. In other cases, the cell will remain in G0 permanently.
The control of the cell cycle
The length of the cell cycle is highly variable even within the cells of an individual organism. In humans, the frequency of cell turnover ranges from a few hours in early embryonic development to an average of two to five days for epithelial cells, or to an entire human lifetime spent in G0 by specialized cells such as cortical neurons or cardiac muscle cells. There is also variation in the time that a cell spends in each phase of the cell cycle. When fast-dividing mammalian cells are grown in culture (outside the body under optimal growing conditions), the length of the cycle is approximately 24 hours. In rapidly dividing human cells with a 24-hour cell cycle, the G1 phase lasts approximately 11 hours. The timing of events in the cell cycle is controlled by mechanisms that are both internal and external to the cell.
Regulation at internal checkpoints
It is essential that daughter cells be exact duplicates of the parent cell. Mistakes in the duplication or distribution of the chromosomes lead to mutations that may be passed forward to every new cell produced from the abnormal cell. To prevent a compromised cell from continuing to divide, there are internal control mechanisms that operate at three main cell cycle checkpoints at which the cell cycle can be stopped until conditions are favorable. These checkpoints occur near the end of G1, at the G2 – M transition, and during metaphase (Figure 4.6).
Figure 4.6: The cell cycle is controlled at three checkpoints. Integrity of the DNA is assessed at the G1 checkpoint. Proper chromosome duplication is assessed at the G2 checkpoint. Attachment of each kinetochore to a spindle fiber is assessed at the M checkpoint.
The G1 Checkpoint
The G1 checkpoint determines whether all conditions are favorable for cell division to proceed. The G1 checkpoint, also called the restriction point, is the point at which the cell irreversibly commits to the cell-division process. In addition to adequate reserves and cell size, there is a check for damage to the genomic DNA at the G1 checkpoint. A cell that does not meet all the requirements will not be released into the S phase.
The G2 Checkpoint
The G2 checkpoint bars the entry to the mitotic phase if certain conditions are not met. As in the G1 checkpoint, cell size and protein reserves are assessed. However, the most important role of the G2 checkpoint is to ensure that all of the chromosomes have been replicated and that the replicated DNA is not damaged.
The M Checkpoint
The M checkpoint occurs near the end of the metaphase stage of mitosis. The M checkpoint is also known as the spindle checkpoint because it determines if all the sister chromatids are correctly attached to the spindle microtubules. Because the separation of the sister chromatids during anaphase is an irreversible step, the cycle will not proceed until the kinetochores of each pair of sister chromatids are firmly anchored to spindle fibers arising from opposite poles of the cell.
References:
- Fowler, Samantha, et al. Concepts of Biology. OpenStax College, Rice University, 2013. Download for free at: https://openstax.org/details/books/concepts-biology.