Figure 7.1 A sea urchin begins life as a single cell that (a) divides to form two cells, visible by scanning electron microscopy. After four rounds of cell division, (b) there are 16 cells, as seen in this SEM image. After many rounds of cell division, the individual develops into a complex, multicellular organism, as seen in this (c) mature sea urchin. (credit a: modification of work by Evelyn Spiegel, Louisa Howard; credit b: modification of work by Evelyn Spiegel, Louisa Howard; credit c:modification of work by Marco Busdraghi; scale-bar data from Matt Russell)

Introduction

A human, as well as every sexually reproducing organism, begins life as a fertilized egg (embryo) or zygote. Trillions of cell divisions subsequently occur in a controlled manner to produce a complex, multicellular human. In other words, that original single cell is the ancestor of every other cell in the body. Once a being 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 the maintenance and repair of cells and tissues. Cell division is tightly regulated, and the occasional failure of regulation can have life-threatening consequences. Single-celled organisms use cell division as their method of reproduction.

The ability to reproduce in kind is a basic characteristic of all living things. In kind means that the offspring of any organism closely resemble their parent or parents. Hippopotamuses give birth to hippopotamus calves, Joshua trees produce seeds from which Joshua tree seedlings emerge, and adult flamingos lay eggs that hatch into flamingo chicks. In kind does not generally mean exactly the same. Whereas many unicellular organisms and a few multicellular organisms can produce genetically identical clones of themselves through cell division, many single-celled organisms and most multicellular organisms reproduce regularly using another method. Sexual reproduction is the production by parents of two haploid cells and the fusion of two haploid cells to form a single, unique diploid cell. In most plants and animals, through tens of rounds of mitotic cell division, this diploid cell will develop into an adult organism. Haploid cells that are part of the sexual reproductive cycle are produced by a type of cell division called meiosis. Sexual reproduction, specifically meiosis and fertilization, introduces variation into offspring that may account for the evolutionary success of sexual reproduction. The vast majority of eukaryotic organisms, both multicellular and unicellular, can or must employ some form of meiosis and fertilization to reproduce.

7.1 | Cell Division

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 that describes the stages of a cell’s life from the division of a single parent cell to the production of two new daughter cells. The mechanisms involved in the cell cycle are highly regulated.

Genomic DNA

Before discussing the steps a cell must undertake to replicate, a deeper understanding of the structure and function of a cell’s genetic information is necessary. A cell’s DNA, packaged as a double-stranded DNA molecule, is called its genome. In prokaryotes, the genome is composed of a single, double stranded DNA molecule in the form of a loop or circle (Figure 7.2). 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. Bacteria can exchange these plasmids with other bacteria, sometimes receiving beneficial new genes that the recipient can add to their chromosomal DNA. Antibiotic resistance is one trait that often spreads through a bacterial colony through plasmid exchange.

Figure 7.2 Prokaryotes, including bacteria and archaea, have a single, circular chromosome located in a central region called the nucleoid.

In eukaryotes, the genome consists of several double-stranded linear DNA molecules (Figure 7.3). Each species of eukaryotes has a characteristic number of chromosomes in the nuclei of its cells. Human body cells have 46 chromosomes, while human gametes (sperm or eggs) have 23 chromosomes each. A typical body cell, or 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 chromosomes are called gametes, or sex cells; these are eggs and sperm, and are designated 1n, or haploid.

Figure 7.3 There are 23 pairs of homologous chromosomes in a female human somatic cell. The condensed chromosomes are viewed within the nucleus (top), removed from a cell in mitosis and spread out on a slide (right), and artificially arranged according to length (left); an arrangement like this is called a karyotype. In this image, the chromosomes were exposed to fluorescent stains for differentiation of the different chromosomes. A method of staining called “chromosome painting” employs fluorescent dyes that highlight chromosomes in different colors. (credit: National Human Genome Project/NIH)

Matched pairs of chromosomes in a diploid organism are called homologous (“same knowledge”) 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. Traits are the variations of those characteristics. For example, hair color is a characteristic with traits that are blonde, brown, or black.

Each copy of a homologous pair of chromosomes originates from a different parent; therefore, the genes themselves are not identical. The variation of individuals within a species is due to the specific combination of the genes inherited from both parents. Even a slightly altered sequence of nucleotides within a gene can result in an alternative trait. 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 on both homologous chromosomes, with one on each (for example,AA, BB, or OO), or two different sequences, such as AB.Minor variations of traits, such as blood type, eye color, and handedness, contribute to the natural variation found within a species. However, if the entire DNA sequence from any pair of human homologous chromosomes is compared, the difference is less than one percent. The sex chromosomes, X and Y, are the single exception to the rule of homologous chromosome uniformity: Other than a small amount of homology that is necessary to accurately produce gametes, the genes found on the X and Y chromosomes are different.

Eukaryotic Chromosomal Structure and Compaction

If the DNA from all 46 chromosomes in a human cell nucleus was laid out end to end, it would measure approximately two meters; however, its diameter would be only 2 nm. Considering that the size of a typical human cell is about 10 µm (100,000 cells lined up to equal one meter), DNA must be tightly packaged to fit in the cell’s nucleus. At the same time, it must also be readily accessible for the genes to be expressed. During some stages of the cell cycle, the long strands of DNA are condensed into compact chromosomes. There are a number of ways that chromosomes are compacted.

In the first level of compaction, short stretches of the DNA double helix wrap around a core of eight histone proteins at regular intervals along the entire length of the chromosome (Figure 7.4). The DNA histone complex is called chromatin. The beadlike, histone DNA complex is called a nucleosome, and DNA connecting the nucleosomes is called linker DNA. A DNA molecule in this form is about seven times shorter than the double helix without the histones, and the beads are about 10 nm in diameter, in contrast with the 2-nm diameter of a DNA double helix. The next level of compaction occurs as the nucleosomes and the linker DNA between them are coiled into a 30-nm chromatin fiber. This coiling further shortens the chromosome so that it is now about 50 times shorter than the extended form. In the third level of packing, a variety of fibrous proteins is used to pack the chromatin. These fibrous proteins also ensure that each chromosome in a non-dividing cell occupies a particular area of the nucleus that does not overlap with that of any other chromosome (see the top image in Figure 7.3).

Figure 7.4 Double-stranded DNA wraps around histone proteins to form nucleosomes that have the appearance of “beads on a string.” The nucleosomes are coiled into a 30-nm chromatin fiber. When a cell undergoes mitosis, the chromosomes condense even further.DNA replicates in the S phase of interphase. After replication, the chromosomes are composed of two linked sister chromatids. When fully compact, the pairs of identically packed chromosomes are bound to each other by cohesin proteins. The connection between the sister chromatids is closest in a region called the centromere. The conjoined sister chromatids, with a diameter of about 1 µm, are visible under a light microscope. The centromeric region is highly condensed and thus will appear as a constricted area.

This animation (http://openstaxcollege.org/l/Packaged_DNA) illustrates the different levels of chromosome packing.

7.2 | 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 produces two identical (clone) cells. The cell cycle has two major phases: interphase and the mitotic phase (Figure 7.5). 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 7.5 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.

Interphase

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 G1, S, and G2.

G1 Phase (First Gap)

The first stage of interphase is called the G1 phase (first gap) because, from a microscopic aspect, 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 sufficient energy reserves to complete the task of replicating each chromosome in the nucleus.

S Phase (Synthesis of DNA)

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.

G2 Phase (Second Gap)

In the G2 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 G2. 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

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.

Revisit the stages of mitosis at this site (http://openstaxcollege.org/l/Cell_cycle_mito) .

Karyokinesis (Mitosis)

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 10.6). Karyokinesis is also called mitosis.

During prophase, the “first phase,” the nuclear envelope starts to dissociate into small vesicles, and the membranous organelles (such as the Golgi complex or Golgi apparatus, and endoplasmic reticulum), fragment and disperse toward the periphery of the cell. 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.During prometaphase, the “first change phase,” many processes that were begun in prophase continue to advance. The remnants of the nuclear envelope fragment. 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 discrete. Each sister chromatid develops a protein structure called a kinetochore in the centromeric region (Figure 7.7). The proteins of the kinetochore attract and bind mitotic spindle microtubules. As the spindle microtubules extend from the centrosomes, some of these microtubules come into contact with and firmly bind to the kinetochores. Once a mitotic fiber attaches to a chromosome, the chromosome will be oriented until the kinetochores of sister chromatids face the opposite poles. Eventually, all the sister chromatids will be attached via their kinetochores to microtubules from opposing poles. Spindle microtubules that do not engage the chromosomes are called polar microtubules. These microtubules overlap each other midway between the two poles and contribute to cell elongation. Astral microtubules are located near the poles, aid in spindle orientation, and are required for the regulation of mitosis.

Figure 7.7 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.

 

During metaphase, the “change phase,” all 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 by cohesin proteins. At this time, the chromosomes are maximally condensed.

During anaphase, the “upward phase,” the cohesin proteins degrade, and the sister chromatids separate at the centromere. Each chromatid, now called a chromosome, is pulled rapidly toward the centrosome to which its microtubule is attached. The cell becomes visibly elongated (oval shaped) as the polar microtubules slide against each other at the metaphase plate where they overlap.

During telophase, the “distance phase,” the chromosomes reach the opposite poles and begin to decondense (unravel), relaxing into a chromatin configuration. The mitotic spindles are depolymerized into tubulin monomers that will be used to assemble cytoskeletal components for each daughter cell. Nuclear envelopes form around the chromosomes, and nucleosomes appear within the nuclear area.

Cytokinesis

Cytokinesis, or “cell motion,” is the second main stage of the mitotic phase during which cell division is completed via the physical separation of the cytoplasmic components into two daughter cells. Division is not complete until the cell components have been apportioned and completely separated into the 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 follows 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 is cleaved in two (Figure 7.8).

In plant cells, 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 into vesicles and dispersing throughout the dividing cell. During telophase, these Golgi vesicles are transported on microtubules to form a phragmoplast (a vesicular structure) at the metaphase plate. There, the vesicles fuse and coalesce 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 walls at the periphery of the cell. Enzymes use the glucose that has accumulated between the membrane layers to build a new cell wall. The Golgi membranes become parts of the plasma membrane on either side of the new cell wall

(Figure 7.8).

Figure 7.8 During cytokinesis in animal cells, a ring of actin filaments forms at the metaphase plate. The ring contracts, forming a cleavage furrow, which divides the cell in two. In plant cells, Golgi vesicles coalesce at the former metaphase plate, forming a phragmoplast. A cell plate formed by the fusion of the vesicles of the phragmoplast grows from the center toward the cell walls, and the membranes of the vesicles fuse to form a plasma membrane that divides the cell in two.

G0 Phase

Not all cells adhere to the classic cell cycle pattern in which a newly formed daughter cell immediately enters the preparatory phases of interphase, closely followed by the mitotic phase. Cells in G0 phase are not actively preparing to divide. The cell is in a quiescent (inactive) stage that occurs when cells exit 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.

7.3 | Control of the Cell Cycle

The length of the cell cycle is highly variable, even within the cells of a single 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, and 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 about 24 hours. In rapidly dividing human cells with a 24-hour cell cycle, the G1 phase lasts approximately nine hours, the S phase lasts 10 hours, the G2 phase lasts about four and one-half hours, and the M phase lasts approximately one-half hour. In early embryos of fruit flies, the cell cycle is completed in about eight minutes. The timing of events in the cell cycle is controlled by mechanisms that are both internal and external to the cell.

Regulation of the Cell Cycle by External Events

Both the initiation and inhibition of cell division are triggered by events external to the cell when it is about to begin the replication process. An event may be as simple as the death of a nearby cell or as sweeping as the release of growth-promoting hormones, such as human growth hormone (HGH). A lack of HGH can inhibit cell division, resulting in dwarfism, whereas too much HGH can result in gigantism. Crowding of cells can also inhibit cell division. Another factor that can initiate cell division is the size of the cell; as a cell grows, it becomes inefficient due to its decreasing surface-to-volume ratio. The solution to this problem is to divide.

Whatever the source of the message, the cell receives the signal, and a series of events within the cell allows it to proceed into interphase. Moving forward from this initiation point, every parameter required during each cell cycle phase must be met or the cycle cannot progress.

Regulation at Internal Checkpoints

It is essential that the daughter cells produced 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 an abnormal cell. To prevent a compromised cell from continuing to divide, there are internal control mechanisms that operate at three main cell cycle checkpoints. A checkpoint is one of several points in the eukaryotic cell cycle at which the progression of a cell to the next stage in the cycle can be halted until conditions are favorable. These checkpoints occur near the end of G1, at the G2/M transition, and during metaphase (Figure 7.10).

Figure 7.10 The cell cycle is controlled at three checkpoints. The 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 (in yeast), is a point at which the cell irreversibly commits to the cell division process. External influences, such as growth factors, play a large role in carrying the cell past the G1 checkpoint. In addition to adequate reserves and cell size, there is a check for genomic DNA damage at the G1 checkpoint. A cell that does not meet all the requirements will not be allowed to progress into the S phase. The cell can halt the cycle and attempt to remedy the problematic condition, or the cell can advance into G0 and await further signals when conditions improve.

The G2 Checkpoint

The G2 checkpoint bars entry into the mitotic phase if certain conditions are not met. As at 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. If the checkpoint mechanisms detect problems with the DNA, the cell cycle is halted, and the cell attempts to either complete DNA replication or repair the damaged DNA.

The M Checkpoint

The M checkpoint occurs near the end of the metaphase stage of karyokinesis. The M checkpoint is also known as the spindle checkpoint, because it determines whether 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 at least two spindle fibers arising from opposite poles of the cell.

Watch what occurs at the G1, G2, and M check points by visiting this website(http://openstaxcollege.org/l/cell_checkpnts)  to see an animation of the cell cycle.

Regulator Molecules of the Cell Cycle

In addition to the internally controlled checkpoints, there are two groups of intracellular molecules that regulate the cell cycle. These regulatory molecules either promote progress of the cell to the next phase (positive regulation) or halt the cycle (negative regulation). Regulator molecules may act individually, or they can influence the activity or production of other regulatory proteins. Therefore, the failure of a single regulator may have almost no effect on the cell cycle, especially if more than one mechanism controls the same event. Conversely, the effect of a deficient or non-functioning regulator can be wide ranging and possibly fatal to the cell if multiple processes are affected.

Positive Regulation of the Cell Cycle

Two groups of proteins, called cyclins and cyclin-dependent kinases (Cdks), are responsible for the progress of the cell through the various checkpoints. The levels of the four cyclin proteins fluctuate throughout the cell cycle in a predictable pattern (Figure 10.11). Increases in the concentration of cyclin proteins are triggered by both external and internal signals. After the cell moves to the next stage of the cell cycle, the cyclins that were active in the previous stage are degraded.

Figure 7.11 The concentrations of cyclin proteins change throughout the cell cycle. There is a direct correlation between cyclin accumulation and the three major cell cycle checkpoints. Also note the sharp decline of cyclin levels following each checkpoint (the transition between phases of the cell cycle), as cyclin is degraded by cytoplasmic enzymes. (credit: modification of work by “WikiMiMa”/Wikimedia Commons)Cyclins regulate the cell cycle only when they are tightly bound to Cdks. To be fully active, the Cdk/cyclin complex must also be phosphorylated in specific locations. Like all kinases, Cdks are enzymes (kinases) that phosphorylate other proteins. Phosphorylation activates the protein by changing its shape. The proteins phosphorylated by Cdks are involved in advancing the cell to the next phase. (Figure 7.12). The levels of Cdk proteins are relatively stable throughout the cell cycle; however, the concentrations of cyclin fluctuate and determine when Cdk/cyclin complexes form. The different cyclins and Cdks bind at specific points in the cell cycle and thus regulate different checkpoints.

Figure 7.12 Cyclin-dependent kinases (Cdks) are protein kinases that, when fully activated, can phosphorylate and thus activate other proteins that advance the cell cycle past a checkpoint. To become fully activated, a Cdk must bind to a cyclin protein and then be phosphorylated by another kinase.

Since the cyclic fluctuations of cyclin levels are based on the timing of the cell cycle and not on specific events, regulation of the cell cycle usually occurs by either the Cdk molecules alone or the Cdk/cyclin complexes. Without a specific concentration of fully activated cyclin/Cdk complexes, the cell cycle cannot proceed through the checkpoints.

Although the cyclins are the main regulatory molecules that determine the forward momentum of the cell cycle, there are several other mechanisms that fine-tune the progress of the cycle with negative, rather than positive, effects. These mechanisms essentially block the progression of the cell cycle until problematic conditions are resolved. Molecules that prevent the full activation of Cdks are called Cdk inhibitors. Many of these inhibitor molecules directly or indirectly monitor a particular cell cycle event. The block placed on Cdks by inhibitor molecules will not be removed until the specific event that the inhibitor monitors is completed.

Negative Regulation of the Cell Cycle

The second group of cell cycle regulatory molecules are negative regulators. Negative regulators halt the cell cycle. Remember that in positive regulation, active molecules cause the cycle to progress.

The best understood negative regulatory molecules are retinoblastoma protein (Rb), p53, and p21. Retinoblastoma proteins are a group of tumor-suppressor proteins common in many cells. The 53 and 21 designations refer to the functional molecular masses of the proteins (p) in kilodaltons. Much of what is known about cell cycle regulation comes from research conducted with cells that have lost regulatory control. All three of these regulatory proteins were discovered to be damaged or non-functional in cells that had begun to replicate uncontrollably (became cancerous). In each case, the main cause of the unchecked progress through the cell cycle was a faulty copy of the regulatory protein.

Rb, p53, and p21 act primarily at the G1 checkpoint. p53 is a multi-functional protein that has a major impact on the commitment of a cell to division because it acts when there is damaged DNA in cells that are undergoing the preparatory processes during G1. If damaged DNA is detected, p53 halts the cell cycle and recruits enzymes to repair the DNA. If the DNA cannot be repaired, p53 can trigger apoptosis, or cell suicide, to prevent the duplication of damaged chromosomes. As p53 levels rise, the production of p21 is triggered. p21 enforces the halt in the cycle dictated by p53 by binding to and inhibiting the activity of the Cdk/cyclin complexes. As a cell is exposed to more stress, higher levels of p53 and p21 accumulate, making it less likely that the cell will move into the S phase.

Rb exerts its regulatory influence on other positive regulator proteins. Chiefly, Rb monitors cell size. In the active, dephosphorylated state, Rb binds to proteins called transcription factors, most commonly, E2F (Figure 7.13). Transcription factors “turn on” specific genes, allowing the production of proteins encoded by that gene. When Rb is bound to E2F, production of proteins necessary for the G1/S transition is blocked. As the cell increases in size, Rb is slowly phosphorylated until it becomes inactivated. Rb releases E2F, which can now turn on the gene that produces the transition protein, and this particular block is removed. For the cell to move past each of the checkpoints, all positive regulators must be “turned on,” and all negative regulators must be “turned off.”

7.4 | Cancer and the Cell Cycle

Cancer comprises many different diseases caused by a common mechanism: uncontrolled cell growth. Despite the redundancy and overlapping levels of cell cycle control, errors do occur. One of the critical processes monitored by the cell cycle checkpoint surveillance mechanism is the proper replication of DNA during the S phase. Even when all of the cell cycle controls are fully functional, a small percentage of replication errors (mutations) will be passed on to the daughter cells. If changes to the DNA nucleotide sequence occur within a coding portion of a gene and are not corrected, a gene mutation results. All cancers start when a gene mutation gives rise to a faulty protein that plays a key role in cell reproduction. The change in the cell that results from the malformed protein may be minor: perhaps a slight delay in the binding of Cdk to cyclin or an Rb protein that detaches from its target DNA while still phosphorylated. Even minor mistakes, however, may allow subsequent mistakes to occur more readily. Over and over, small uncorrected errors are passed from the parent cell to the daughter cells and amplified as each generation produces more non-functional proteins from uncorrected DNA damage. Eventually, the pace of the cell cycle speeds up as the effectiveness of the control and repair mechanisms decreases. Uncontrolled growth of the mutated cells outpaces the growth of normal cells in the area, and a tumor (“-oma”) can result.

Proto-oncogenes

The genes that code for the positive cell cycle regulators are called proto-oncogenes. Proto-oncogenes are normal genes that, when mutated in certain ways, become oncogenes, genes that cause a cell to become cancerous. Consider what might happen to the cell cycle in a cell with a recently acquired oncogene. In most instances, the alteration of the DNA sequence will result in a less functional (or nonfunctional) protein. The result is detrimental to the cell and will likely prevent the cell from completing the cell cycle; however, the organism is not harmed because the mutation will not be carried forward. If a cell cannot reproduce, the mutation is not propagated and the damage is minimal. Occasionally, however, a gene mutation causes a change that increases the activity of a positive regulator. For example, a mutation that allows Cdk to be activated without being partnered with cyclin could push the cell cycle past a checkpoint before all of the required conditions are met. If the resulting daughter cells are too damaged to undergo further cell divisions, the mutation would not be propagated and no harm would come to the organism. However, if the atypical daughter cells are able to undergo further cell divisions, subsequent generations of cells will probably accumulate even more mutations, some possibly in additional genes that regulate the cell cycle.

The Cdk gene in the above example is only one of many genes that are considered proto-oncogenes. In addition to the cell cycle regulatory proteins, any protein that influences the cycle can be altered in such a way as to override cell cycle checkpoints. An oncogene is any gene that, when altered, leads to an increase in the rate of cell cycle progression.

Tumor Suppressor Genes

Like proto-oncogenes, many of the negative cell cycle regulatory proteins were discovered in cells that had become cancerous. Tumor suppressor genes are segments of DNA that code for negative regulator proteins, the type of regulators that, when activated, can prevent the cell from undergoing uncontrolled division. The collective function of the best-understood tumor suppressor gene proteins, Rb, p53, and p21, is to put up a roadblock to cell cycle progression until certain events are completed. A cell that carries a mutated form of a negative regulator might not be able to halt the cell cycle if there is a problem. Tumor suppressors are similar to brakes in a vehicle: Malfunctioning brakes can contribute to a car crash.

Mutated p53 genes have been identified in more than one-half of all human tumor cells. This discovery is not surprising in light of the multiple roles that the p53 protein plays at the G1 checkpoint. A cell with a faulty p53 may fail to detect errors present in the genomic DNA (Figure 7.14). Even if a partially functional p53 does identify the mutations, it may no longer be able to signal the necessary DNA repair enzymes. Either way, damaged DNA will remain uncorrected. At this point, a functional p53 will deem the cell unsalvageable and trigger programmed cell death (apoptosis). The damaged version of p53 found in cancer cells, however, cannot trigger apoptosis.

The loss of p53 function has other repercussions for the cell cycle. Mutated p53 might lose its ability to trigger p21 production. Without adequate levels of p21, there is no effective block on Cdk activation. Essentially, without a fully functional p53, the G1 checkpoint is severely compromised and the cell proceeds directly from G1 to S regardless of internal and external conditions. At the completion of this shortened cell cycle, two daughter cells are produced that have inherited the mutated p53 gene. Given the non-optimal conditions under which the parent cell reproduced, it is likely that the daughter cells will have acquired other mutations in addition to the faulty tumor suppressor gene. Cells such as these daughter cells quickly accumulate both oncogenes and non-functional tumor suppressor genes. Again, the result is tumor growth.

Go to this website (http://openstaxcollege.org/l/cancer) to watch an animation of how cancer results from errors in the cell cycle.

7.5 | Prokaryotic Cell Division

Prokaryotes, such as bacteria, propagate by binary fission. For unicellular organisms, cell division is the only method to produce new individuals. In both prokaryotic and eukaryotic cells, the outcome of cell reproduction is a pair of daughter cells that are genetically identical to the parent cell. In unicellular organisms, daughter cells are individuals.

To achieve the outcome of cloned offspring, certain steps are essential. The genomic DNA must be replicated and then allocated into the daughter cells; the cytoplasmic contents must also be divided to give both new cells the machinery to sustain life. In bacterial cells, the genome consists of a single, circular DNA chromosome; therefore, the process of cell division is simplified. Karyokinesis is unnecessary because there is no nucleus and thus no need to direct one copy of the multiple chromosomes into each daughter cell. This type of cell division is called binary (prokaryotic) fission.

Binary Fission

Due to the relative simplicity of the prokaryotes, the cell division process, called binary fission, is a less complicated and much more rapid process than cell division in eukaryotes. The single, circular DNA chromosome of bacteria is not enclosed in a nucleus, but instead occupies a specific location, the nucleoid, within the cell (Figure 7.2). Although the DNA of the nucleoid is associated with proteins that aid in packaging the molecule into a compact size, there are no histone proteins and thus no nucleosomes in prokaryotes. The packing proteins of bacteria are, however, related to the cohesin and condensin proteins involved in the chromosome compaction of eukaryotes.

The bacterial chromosome is attached to the plasma membrane at about the midpoint of the cell. The starting point of replication, the origin, is close to the binding site of the chromosome to the plasma membrane (Figure 7.15). Replication of the DNA is bidirectional, moving away from the origin on both strands of the loop simultaneously. As the new double strands are formed, each origin point moves away from the cell wall attachment toward the opposite ends of the cell. As the cell elongates, the growing membrane aids in the transport of the chromosomes. After the chromosomes have cleared the midpoint of the elongated cell, cytoplasmic separation begins. The formation of a ring composed of repeating units of a protein called FtsZ directs the partition between the nucleoids. Formation of the FtsZ ring triggers the accumulation of other proteins that work together to recruit new membrane and cell wall materials to the site. A septum is formed between the nucleoids, extending gradually from the periphery toward the center of the cell. When the new cell walls are in place, the daughter cells separate.

Figure 7.15 These images show the steps of binary fission in prokaryotes. (credit: modification of work by “Mcstrother”/Wikimedia Commons)

KEY TERMS

anaphase stage of mitosis during which sister chromatids are separated from each other

binary fission prokaryotic cell division process

cell cycle ordered sequence of events that a cell passes through between one cell division and the next

cell cycle ordered series of events involving cell growth and cell division that produces two new daughter cells

cell cycle checkpoint mechanism that monitors the preparedness of a eukaryotic cell to advance through the various cell cycle stages

cell plate structure formed during plant cell cytokinesis by Golgi vesicles, forming a temporary structure (phragmoplast) and fusing at the metaphase plate; ultimately leads to the formation of cell walls that separate the two daughter cells

centriole rod-like structure constructed of microtubules at the center of each animal cell centrosome

centromere region at which sister chromatids are bound together; a constricted area in condensed chromosomes

chromatid single DNA molecule of two strands of duplicated DNA and associated proteins held together at the centromere

cleavage furrow constriction formed by an actin ring during cytokinesis in animal cells that leads to cytoplasmic division

condensin proteins that help sister chromatids coil during prophase

cyclin one of a group of proteins that act in conjunction with cyclin-dependent kinases to help regulate the cell cycle by phosphorylating key proteins; the concentrations of cyclins fluctuate throughout the cell cycle

cyclin-dependent kinase one of a group of protein kinases that helps to regulate the cell cycle when bound to cyclin; it functions to phosphorylate other proteins that are either activated or inactivated by phosphorylation

cytokinesis division of the cytoplasm following mitosis that forms two daughter cells.

diploid cell, nucleus, or organism containing two sets of chromosomes (2n)

G0 phase distinct from the G1 phase of interphase; a cell in G0 is not preparing to divide

G1 phase (also, first gap) first phase of interphase centered on cell growth during mitosis

G2 phase (also, second gap) third phase of interphase during which the cell undergoes final preparations for mitosis

gamete haploid reproductive cell or sex cell (sperm, pollen grain, or egg)

gene physical and functional unit of heredity, a sequence of DNA that codes for a protein.

genome total genetic information of a cell or organism

haploid cell, nucleus, or organism containing one set of chromosomes (n)

histone one of several similar, highly conserved, low molecular weight, basic proteins found in the chromatin of all eukaryotic cells; associates with DNA to form nucleosomes

homologous chromosomes chromosomes of the same morphology with genes in the same location; diploid organisms have pairs of homologous chromosomes (homologs), with each homolog derived from a different parent

interphase period of the cell cycle leading up to mitosis; includes G1, S, and G2 phases (the interim period between two consecutive cell divisions

karyokinesis mitotic nuclear division

kinetochore protein structure associated with the centromere of each sister chromatid that attracts and binds spindle microtubules during prometaphase

locus position of a gene on a chromosome

metaphase stage of mitosis during which chromosomes are aligned at the metaphase plate

metaphase plate equatorial plane midway between the two poles of a cell where the chromosomes align during metaphase

mitosis (also, karyokinesis) period of the cell cycle during which the duplicated chromosomes are separated into identical nuclei; includes prophase, prometaphase, metaphase, anaphase, and telophase

mitotic phase period of the cell cycle during which duplicated chromosomes are distributed into two nuclei and cytoplasmic contents are divided; includes karyokinesis (mitosis) and cytokinesis

mitotic spindle apparatus composed of microtubules that orchestrates the movement of chromosomes during mitosis

nucleosome subunit of chromatin composed of a short length of DNA wrapped around a core of histone proteins

oncogene mutated version of a normal gene involved in the positive regulation of the cell cycle

origin (also, ORI) region of the prokaryotic chromosome where replication begins (origin of replication)

p21 cell cycle regulatory protein that inhibits the cell cycle; its levels are controlled by p53

p53 cell cycle regulatory protein that regulates cell growth and monitors DNA damage; it halts the progression of the cell cycle in cases of DNA damage and may induce apoptosis

prometaphase stage of mitosis during which the nuclear membrane breaks down and mitotic spindle fibers attach to kinetochores

prophase stage of mitosis during which chromosomes condense and the mitotic spindle begins to form proto-oncogene normal gene that when mutated becomes an oncogene

quiescent refers to a cell that is performing normal cell functions and has not initiated preparations for cell division

retinoblastoma protein (Rb) regulatory molecule that exhibits negative effects on the cell cycle by interacting with a transcription factor (E2F)

S phase second, or synthesis, stage of interphase during which DNA replication occurs

septum structure formed in a bacterial cell as a precursor to the separation of the cell into two daughter cells

telophase stage of mitosis during which chromosomes arrive at opposite poles, decondense, and are surrounded by a new nuclear envelope

tumor suppressor gene segment of DNA that codes for regulator proteins that prevent the cell from undergoing uncontrolled division

chiasmata (singular, chiasma) the structure that forms at the crossover points after genetic material is exchanged

cohesin proteins that form a complex that seals sister chromatids together at their centromeres until anaphase II of meiosis

crossover exchange of genetic material between non-sister chromatids resulting in chromosomes that incorporate genes from both parents of the organism

diploid-dominant life-cycle type in which the multicellular diploid stage is prevalent

fertilization union of two haploid cells from two individual organisms

gametophyte a multicellular haploid life-cycle stage that produces gametes germ cells specialized cell line that produces gametes, such as eggs or sperm

haploid-dominant life-cycle type in which the multicellular haploid stage is prevalent

interkinesis (also, interphase II) brief period of rest between meiosis I and meiosis II

life cycle the sequence of events in the development of an organism and the production of cells that produce offspring

meiosis a nuclear division process that results in four haploid cells

meiosis I first round of meiotic cell division; referred to as reduction division because the ploidy level is reduced from diploid to haploid

meiosis II second round of meiotic cell division following meiosis I; sister chromatids are separated into individual chromosomes, and the result is four unique haploid cells

recombination nodules protein assemblies formed on the synaptonemal complex that mark the points of crossover events and mediate the multistep process of genetic recombination between non-sister chromatids

reduction division nuclear division that produces daughter nuclei each having one-half as many chromosome sets as the parental nucleus; meiosis I is a reduction division

somatic cell all the cells of a multicellular organism except the gametes or reproductive cells

spore haploid cell that can produce a haploid multicellular organism or can fuse with another spore to form a diploid cell

sporophyte a multicellular diploid life-cycle stage that produces haploid spores by meiosis

synapsis formation of a close association between homologous chromosomes during prophase I

synaptonemal complex protein lattice that forms between homologous chromosomes during prophase I, supporting crossover

tetrad two duplicated homologous chromosomes (four chromatids) bound together by chiasmata during prophase I

CHAPTER SUMMARY

7.1 Cell Division

Prokaryotes have a single circular chromosome composed of double-stranded DNA, whereas eukaryotes have multiple, linear chromosomes composed of chromatin surrounded by a nuclear membrane. The 46 chromosomes of human somatic cells are composed of 22 pairs of autosomes (matched pairs) and a pair of sex chromosomes, which may or may not be matched. This is the 2n or diploid state. Human gametes have 23 chromosomes or one complete set of chromosomes; a set of chromosomes is complete with either one of the sex chromosomes. This is the n or haploid state. Genes are segments of DNA that code for a specific protein. An organism’s traits are determined by the genes inherited from each parent. Duplicated chromosomes are composed of two sister chromatids. Chromosomes are compacted using a variety of mechanisms during certain stages of the cell cycle. Several classes of protein are involved in the organization and packing of the chromosomal DNA into a highly condensed structure. The condensing complex compacts chromosomes, and the resulting condensed structure is necessary for chromosomal segregation during mitosis.

7.2 The Cell Cycle

The cell cycle is an orderly sequence of events. Cells on the path to cell division proceed through a series of precisely timed and carefully regulated stages. In eukaryotes, the cell cycle consists of a long preparatory period, called interphase. Interphase is divided into G1, S, and G2 phases. The mitotic phase begins with karyokinesis (mitosis), which consists of five stages: prophase, prometaphase, metaphase, anaphase, and telophase. The final stage of the mitotic phase is cytokinesis, during which the cytoplasmic components of the daughter cells are separated either by an actin ring (animal cells) or by cell plate formation (plant cells).

7.3 Control of the Cell Cycle

Each step of the cell cycle is monitored by internal controls called checkpoints. There are three major checkpoints in the cell cycle: one near the end of G1, a second at the G2/M transition, and the third during metaphase. Positive regulator molecules allow the cell cycle to advance to the next stage. Negative regulator molecules monitor cellular conditions and can halt the cycle until specific requirements are met.

7.4 Cancer and the Cell Cycle

Cancer is the result of unchecked cell division caused by a breakdown of the mechanisms that regulate the cell cycle. The loss of control begins with a change in the DNA sequence of a gene that codes for one of the regulatory molecules. Faulty instructions lead to a protein that does not function as it should.

Any disruption of the monitoring system can allow other mistakes to be passed on to the daughter cells. Each successive cell division will give rise to daughter cells with even more accumulated damage. Eventually, all checkpoints become nonfunctional, and rapidly reproducing cells crowd out normal cells, resulting in a tumor or leukemia (blood cancer).

7.5 Prokaryotic Cell Division

In both prokaryotic and eukaryotic cell division, the genomic DNA is replicated and then each copy is allocated into a daughter cell. In addition, the cytoplasmic contents are divided evenly and distributed to the new cells. However, there are many differences between prokaryotic and eukaryotic cell division. Bacteria have a single, circular DNA chromosome but no nucleus. Therefore, mitosis is not necessary in bacterial cell division. Bacterial cytokinesis is directed by a ring composed of a protein called FtsZ. Ingrowth of membrane and cell wall material from the periphery of the cells results in the formation of a septum that eventually constructs the separate cell walls of the daughter cells.

REVIEW QUESTIONS

A diploid cell has_______ the number of chromosomes as a haploid cell.

one-fourth

half

twice

four times

An organism’s traits are determined by the specific combination of inherited _____.

cells.

genes.

proteins.

chromatids.

The first level of DNA organization in a eukaryotic cell is maintained by which molecule?

cohesin

condensin

chromatin

histone

Identical copies of chromatin held together by cohesin at the centromere are called _____.

histones.

nucleosomes.

chromatin.

sister chromatids.

Chromosomes are duplicated during what stage of the cell cycle?

G1 phase

S phase

prophase

prometaphase

Which of the following events does not occur during some stages of interphase?

DNA duplication

organelle duplication

increase in cell size

separation of sister chromatids

The mitotic spindles arise from which cell structure?

centromere

centrosome

kinetochore

cleavage furrow

Attachment of the mitotic spindle fibers to the kinetochores is a characteristic of which stage of mitosis?

prophase

prometaphase

metaphase

anaphase

Unpacking of chromosomes and the formation of a new nuclear envelope is a characteristic of which stage of mitosis?

prometaphase

metaphase

anaphase

telophase

Separation of the sister chromatids is a characteristic of which stage of mitosis?

prometaphase

metaphase

anaphase

telophase

The chromosomes become visible under a light microscope during which stage of mitosis?

prophase

prometaphase

metaphase

anaphase

The fusing of Golgi vesicles at the metaphase plate of dividing plant cells forms what structure?

cell plate

actin ring

cleavage furrow

mitotic spindle

At which of the cell cycle checkpoints do external forces have the greatest influence?

G1 checkpoint

G2 checkpoint

M checkpoint

G0 checkpoint

What is the main prerequisite for clearance at the G2 checkpoint?

cell has reached a sufficient size

an adequate stockpile of nucleotides

accurate and complete DNA replication

proper attachment of mitotic spindle fibers to kinetochores

If the M checkpoint is not cleared, what stage of mitosis will be blocked?

prophase

prometaphase

metaphase

anaphase

Which protein is a positive regulator that phosphorylates other proteins when activated?

p53

retinoblastoma protein (Rb)

cyclin

cyclin-dependent kinase (Cdk)

Many of the negative regulator proteins of the cell cycle were discovered in what type of cells?

gametes

cells in G0

cancer cells

stem cells

Which negative regulatory molecule can trigger cell suicide (apoptosis) if vital cell cycle events do not occur?

p53

p21

retinoblastoma protein (Rb)

cyclin-dependent kinase (Cdk)

___________ are changes to the order of nucleotides in a segment of DNA that codes for a protein.

Proto-oncogenes

Tumor suppressor genes

Gene mutations

Negative regulators

A gene that codes for a positive cell cycle regulator is called a(n) _____.

kinase inhibitor.

tumor suppressor gene.

proto-oncogene.

oncogene.

A mutated gene that codes for an altered version of Cdk that is active in the absence of cyclin is a(n) _____.

kinase inhibitor.

tumor suppressor gene.

proto-oncogene.

oncogene.

Which molecule is a Cdk inhibitor that is controlled by p53?

cyclin

anti-kinase

Rb

p21

Which eukaryotic cell cycle event is missing in binary fission?

cell growth

DNA duplication

karyokinesis

cytokinesis

Meiosis produces ________ daughter cells.

two haploid

two diploid

four haploid

four diploid

What structure is most important in forming the tetrads?

centromere

synaptonemal complex

chiasma

kinetochore

At which stage of meiosis are sister chromatids separated from each other?

prophase I

prophase II

anaphase I

anaphase II

At metaphase I, homologous chromosomes are connected only at what structures?

chiasmata

recombination nodules

microtubules

kinetochores

Which of the following is not true in regard to crossover?

Spindle microtubules guide the transfer of DNA across the synaptonemal complex.

Non-sister chromatids exchange genetic material.

Chiasmata are formed.

Recombination nodules mark the crossover point.

What phase of mitotic interphase is missing from meiotic interkinesis?

G0 phase

G1 phase

S phase

G2 phase

The part of meiosis that is similar to mitosis is ________.

meiosis I

anaphase I

meiosis II

interkinesis

If a muscle cell of a typical organism has 32 chromosomes, how many chromosomes will be in a gamete of that same organism?

8

16

32

64

What is a likely evolutionary advantage of sexual reproduction over asexual reproduction?

Sexual reproduction involves fewer steps.

There is a lower chance of using up the resources in a given environment.

Sexual reproduction results in variation

in the offspring.

Sexual reproduction is more cost effective.

Which type of life cycle has both a haploid and diploid multicellular stage?

asexual

diploid-dominant

haploid-dominant

alternation of generations

Fungi typically display which type of life cycle?

diploid-dominant

haploid-dominant

alternation of generations

asexual

A diploid, multicellular life-cycle stage that gives rise to haploid cells by meiosis is called a ________.

sporophyte

gametophyte

spore

gamete

Critical Thinking Questions

Compare and contrast a human somatic cell to a human gamete.

What is the relationship between a genome, chromosomes, and genes?

Eukaryotic chromosomes are thousands of times longer than a typical cell. Explain how chromosomes can fit inside a eukaryotic nucleus.

Briefly describe the events that occur in each phase of interphase.

Chemotherapy drugs such as vincristine and colchicine disrupt mitosis by binding to tubulin (the subunit of microtubules) and interfering with microtubule assembly and disassembly. Exactly what mitotic structure is targeted by these drugs and what effect would that have on cell division?

Describe the similarities and differences between the cytokinesis mechanisms found in animal cells versus those in plant cells.

List some reasons why a cell that has just completed cytokinesis might enter the G0 phase instead of the G1 phase.

What cell cycle events will be affected in a cell that produces mutated (non-functional) cohesin protein?

Describe the general conditions that must be met at each of the three main cell cycle checkpoints.

Explain the roles of the positive cell cycle regulators compared to the negative regulators.

What steps are necessary for Cdk to become fully active?

Rb is a negative regulator that blocks the cell cycle at the G1 checkpoint until the cell achieves a requisite size. What molecular mechanism does Rb employ to halt the cell cycle?

Outline the steps that lead to a cell becoming cancerous.

Explain the difference between a protooncogene and a tumor suppressor gene.

List the regulatory mechanisms that might be lost in a cell producing faulty p53.

p53 can trigger apoptosis if certain cell cycle events fail. How does this regulatory outcome benefit a multicellular organism?

Name the common components of eukaryotic cell division and binary fission.

Describe how the duplicated bacterial chromosomes are distributed into new daughter cells without the direction of the mitotic spindle.

Explain how the random alignment of homologous chromosomes during metaphase I contributes to the variation in gametes produced by meiosis.

What is the function of the fused kinetochore found on sister chromatids in prometaphase I?

In a comparison of the stages of meiosis to the stages of mitosis, which stages are unique to meiosis and which stages have the same events in both meiosis and mitosis?

List and briefly describe the three processes that lead to variation in offspring with the same parents.