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Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002.

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Molecular Biology of the Cell. 4th edition.

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An Overview of M Phase

The central problem for a mitotic cell in M phase is how to accurately separate and distribute (segregate) its chromosomes, which were replicated in the preceding S phase, so that each new daughter cell receives an identical copy of the genome (see Figure 18-1). With minor variations, all eucaryotes solve this problem in a similar way: they assemble specialized cytoskeletal machines—first to pull the duplicated chromosome sets apart and then to split the cytoplasm into two halves. Before the duplicated chromosomes can be separated and distributed equally to the two daughter cells during mitosis, however, they must be appropriately configured, and this process begins in S phase.

Cohesins and Condensins Help Configure Replicated Chromosomes for Segregation

When the chromosomes are duplicated in S phase, the two copies of each replicated chromosome remain tightly bound together as identical sister chromatids. The sister chromatids are glued together by multisubunit protein complexes called cohesins, which are deposited along the length of each sister chromatid as the DNA is replicated. This cohesion between sister chromatids is crucial to the chromosome segregation process and is broken only late in mitosis (at the start of anaphase) to allow the sisters to be pulled apart.

The first readily visible sign that a cell is about to enter M phase is the progressive compaction of the replicated chromosomes, which become visible as threadlike structures—a process called chromosome condensation. In humans, for example, each interphase chromosome becomes compacted after replication into a mitotic chromosome that is about 50 times shorter (Figure 18-2). As discussed in Chapter 4, proteins called condensins do the work of chromosome condensation. Activated M-Cdk phosphorylates some of the condensin subunits, triggering the assembly of condensin complexes on DNA and, thereby, the progressive condensation of the chromosomes. The condensins can use the energy of ATP hydrolysis to promote DNA coiling in a test tube, and they are thought to do the same in cells during chromosome condensation. By a mechanism that is still poorly understood, they eventually produce fully condensed mitotic chromosomes, with each of the two sister chromatids organized around a linear central axis, where the condensin complexes are concentrated (see Figure 18-2).

Figure 18-2. Human mitotic chromosomes stained to reveal a scaffold-like structure along the chromosome axis.

Figure 18-2

Human mitotic chromosomes stained to reveal a scaffold-like structure along the chromosome axis. In these confocal fluorescence micrographs, the DNA has been stained with a blue dye, and the axis has been stained red with a fluorescent antibody against (more...)

The cohesins and condensins are structurally related, and they work together to configure the replicated chromosomes in preparation for mitosis. Genetic studies show that, if chromatid cohesion is not established properly in S phase, full condensation cannot occur in M phase and chromosomes are abnormally segregated at anaphase. A model for how cohesins can glue two DNA molecules together, while the closely related condensins can bind to a single DNA molecule and induce its supercoiling and condensation, is illustrated in Figure 18-3.

Figure 18-3. The related structure and function of cohesins and condensins.

Figure 18-3

The related structure and function of cohesins and condensins. (A) Both proteins have two identical DNA- and ATP-binding domains at one end and a hinge region at the other, joined by two, long, coiled-coil regions. This flexible structure is well suited (more...)

In budding yeast, the sudden degradation and release of the cohesin complexes allows sister chromatids to separate at anaphase. In vertebrate cells, by contrast, most of the cohesin is released from the chromosomes at the start of mitosis, when condensins bind to drive condensation. The small amount of cohesin that remains, however, is enough to hold sister chromatids together until anaphase, when the residual cohesins are degraded, allowing the chromatids to separate, as we discuss later.

Cytoskeletal Machines Perform Both Mitosis and Cytokinesis

After the chromosomes have condensed, two distinct cytoskeletal machines are assembled in sequence to perform the mechanical processes of mitosis and cytokinesis. Both machines disassemble rapidly after they have completed their tasks.

To produce two genetically identical daughter cells, the cell has to separate its replicated chromosomes and allocate one copy to each daughter cell. In all eucaryotic cells, this task is performed during mitosis by a bipolar mitotic spindle, which is composed of microtubules and various proteins that interact with them, including microtubule-dependent motor proteins (discussed in Chapter 16).

Different cytoskeletal structures are responsible for cytokinesis. In animal cells and many unicellular eucaryotes, it is the contractile ring; in most plant cells, it is the phragmoplast. The contractile ring contains both actin and myosin filaments and forms around the equator of the cell, just under the plasma membrane; as the ring contracts, it pulls the membrane inward, thereby dividing the cell in two (Figure 18-4). Plant cells, which have a cell wall to contend with, divide their cytoplasm by a very different mechanism. As we discuss later, instead of using a contractile process that acts on the plasma membrane, the phragmoplast constructs a new cell wall from within the cell, between the two sets of replicated chromosomes.

Figure 18-4. Two cytoskeletal machines that operate in M phase.

Figure 18-4

Two cytoskeletal machines that operate in M phase. The mitotic spindle assembles first and segregates the chromosomes. The contractile ring assembles later and divides the cell in two. Plant cells use a very different mechanism to divide the cytoplasm, (more...)

Two Mechanisms Help Ensure That Mitosis Always Precedes Cytokinesis

In most animal cells, M phase takes only about an hour—a small fraction of the total cell-cycle time, which often lasts 12–24 hours. The rest of the cycle is occupied by interphase. Under the microscope, interphase appears as a deceptively uneventful interlude, in which the cell simply continues to grow in size. Other techniques, however, reveal that interphase is actually a busy time for a proliferating cell, during which elaborate preparations for cell division are occurring in a tightly ordered sequence. Two critical preparatory events that are completed during interphase are DNA replication and duplication of the centrosome.

As discussed in Chapter 17, cyclical oscillations in the activities of the Cdks and of proteolytic complexes drive the cell cycle forward. Cdks trigger various steps of the cycle either by directly phosphorylating structural or regulatory proteins or by activating other protein kinases to do so. The proteolytic complexes activate specific steps in the cycle by degrading key cell-cycle proteins such as cyclins and Cdk inhibitor proteins. Like throwing switches, the activation of Cdks and proteolytic complexes triggers cell-cycle transitions that are normally points of no return. Thus, a green light from M-Cdk to enter M phase results in chromosome condensation, nuclear envelope breakdown, and a dramatic change in microtubule dynamics, all triggered by the phosphorylation of regulatory proteins that control these processes.

It is crucial that the two major events of M phase—nuclear division (mitosis) and cytoplasmic division (cytokinesis)—occur in the correct sequence (see Figure 18-1). It would be catastrophic if cytokinesis occurred before all of the chromosomes had segregated during mitosis. At least two mechanisms seem to prevent this catastrophe. First, the cell-cycle control system that activates proteins required for mitosis is thought to inactivate some of the proteins required for cytokinesis; presumably for this reason, cytokinesis cannot occur until M-Cdk is inactivated at the end of mitosis. Second, after the mitotic spindle has segregated the two sets of chromosomes to opposite poles of the cell, the residual central region of the spindle is required to maintain a functional contractile ring (see Figure 18-4); thus, until the spindle has separated the chromosomes and formed a central spindle, the ring cannot divide the cytoplasm in two.

M Phase in Animal Cells Depends on Centrosome Duplication in the Preceding Interphase

Two critical events must be completed in interphase before M phase begins—replication of the DNA and, in animal cells, duplication of the centrosome. DNA is duplicated so that each new daughter cell inherits an identical copy of the genome, while the centrosome is duplicated to help initiate the formation of the two poles of the mitotic spindle and to supply each daughter cell with its own centrosome. As we discuss later, after the chromosomes have been segregated in late mitosis, the microtubules that emanate from the two centrosomes signal to the cell cortex to help establish the plane of cytoplasmic division. This ensures that the division occurs exactly midway between the two separated groups of chromosomes (see Figure 18-4).

The centrosome is the principal microtubule-organizing center in animal cells (discussed in Chapter 16). It consists of a cloud of amorphous material (called the centrosome matrix or pericentriolar material) that surrounds a pair of centrioles (see Figure 16-24). During interphase, the centrosome matrix nucleates a cytoplasmic array of microtubules, with their fast-growing plus ends projecting outward toward the cell perimeter and their minus ends associated with the centrosome. The matrix contains a great variety of proteins, including microtubule-dependent motor proteins, coiled-coil proteins that are thought to link the motors to the centrosome, structural proteins, and components of the cell-cycle control system. Most important, it contains the γ–tubulin ring complex, which is the component mainly responsible for nucleating microtubules (see Figure 16-22).

The process of centrosome duplication and separation is known as the centrosome cycle. During interphase of each animal cell cycle, the centrioles and other components of the centrosome are duplicated (by an unknown mechanism) but remain together as a single complex on one side of the nucleus (Figure 18-5). As mitosis begins, this complex splits in two, and each centriole pair becomes part of a separate microtubule organizing center that nucleates a radial array of microtubules called an aster (Figure 18-6). The two asters move to opposite sides of the nucleus to initiate the formation of the two poles of the mitotic spindle. When the nuclear envelope breaks down (at prometaphase), the spindle captures the chromosomes; it will separate them toward the end of mitosis (Figure 18-7). As mitosis ends and the nuclear envelope re-forms around the separated chromosomes, each daughter cell receives a centrosome in association with its chromosomes.

Figure 18-5. Centrioles.

Figure 18-5

Centrioles. (A) Electron micrograph of an S-phase mammalian cell in culture, showing a duplicated centrosome. Each centrosome contains a pair of centrioles; although the centrioles have duplicated, they remain together in a single complex, as shown in (more...)

Figure 18-6. Centriole replication.

Figure 18-6

Centriole replication. The centrosome consists of a centriole pair and associated matrix (green). At a certain point in G1, the two centrioles of the pair separate by a few micrometers. During S phase, a daughter centriole begins to grow near the base (more...)

Figure 18-7. The centrosome cycle.

Figure 18-7

The centrosome cycle. The centrosome in a proliferating animal cell duplicates in interphase in preparation for mitosis. In most animal cells, a centriole pair (shown here as a pair of dark green bars) is associated with the centrosome matrix (light green) (more...)

In early embryonic cell cycles, the centrosome cycle can operate even if the nucleus is physically removed or nuclear DNA replication is blocked by a drug that inhibits DNA synthesis. Cycles of centrosome duplication and separation proceed almost normally, first yielding two centrosomes, then four, and then eight, and so on. Egg cell extracts from the frog Xenopus (see Figure 17-9) support multiple rounds of centrosome duplication in a test tube. This system has been used to test the individual protein components of the cell-cycle control system for their ability to stimulate centrosome duplication. Such experiments show that the G1/S-Cdk (a complex of cyclin E and Cdk2) that initiates DNA replication in S phase (discussed in Chapter 17) also stimulates centrosome duplication, presumably explaining why centrosome duplication begins at the start of S phase.

M Phase Is Traditionally Divided into Six Stages

The first five stages of M phase constitute mitosis, which was originally defined as the period in which the chromosomes are visibly condensed. Cytokinesis occurs in the sixth stage, which overlaps with the end of mitosis. These six stages form a dynamic sequence, in which many independent cycles, involving the chromosomes, cytoskeleton, and centrosomes, have to be coordinated in order to produce two genetically identical daughter cells. The stages that occur during M phase are summarized in Panel 18-1. The complexity and beauty of M phase, however, are hard to appreciate from written descriptions or from a set of static pictures.

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Panel 18-1

The Principal Stages of M Phase (Mitosis and Cytokinesis) in an Animal Cell.

The five stages of mitosisprophase, prometaphase, metaphase, anaphase, and telophase—occur in strict sequential order, while cytokinesis begins in anaphase and continues through telophase. Light micrographs of cell division in a typical animal cell and a typical plant cell are shown in Figures 18-8 and 18-9, respectively. During prophase, the replicated chromosomes condense in step with the reorganization of the cytoskeleton. In metaphase, the chromosomes are aligned at the equator of the mitotic spindle, and in anaphase they are segregated to the two poles of the spindle. Cytoplasmic division is complete by the end of telophase, and the nucleus and cytoplasm of each of the daughter cells then return to interphase, signaling the end of M phase.

Figure 18-8. The course of mitosis in a typical animal cell.

Figure 18-8

The course of mitosis in a typical animal cell. In these micrographs of cultured newt lung cells, the microtubules (green) have been visualized by immunofluorescence, while the chromatin is stained with a blue fluorescent dye. During interphase, the centrosome (more...)

Figure 18-9. The course of mitosis in a plant cell.

Figure 18-9

The course of mitosis in a plant cell. These light micrographs of a living Haemanthus (lily) cell were taken at the times indicated, using differential-interference-contrast microscopy. The cell has unusually large chromosomes that are easy to see. (A) (more...)


Cell division occurs during M phase, which consists of nuclear division (mitosis) followed by cytoplasmic division (cytokinesis). The DNA is replicated in the preceding S phase; the two copies of each replicated chromosome (called sister chromatids) remain glued together by cohesins. At the start of M phase, cohesin-related proteins called condensins bind to the replicated chromosomes and progressively condense them. A microtubule-based mitotic spindle is responsible for chromosome segregation in all eucaryotic cells. The mitotic spindle in animal cells develops from the microtubule asters that form around each of the two centrosomes produced when the centrosome duplicates, beginning in S phase; at the onset of M phase, the duplicated centrosomes separate and move to opposite sides of the nucleus to initiate the formation of the two poles of the spindle. An actin and myosin-based contractile ring is responsible for cytoplasmic division in animal cells and in many unicellular eucaryotes, but not in plant cells.

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By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2002, Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, and Peter Walter; Copyright © 1983, 1989, 1994, Bruce Alberts, Dennis Bray, Julian Lewis, Martin Raff, Keith Roberts, and James D. Watson .
Bookshelf ID: NBK26931