Phases of the Cell Cycle: Non-cycling (Arrested) Cells

The various phases of the growth and reproduction of cells constitute what is called the cell cycle (Fig. 2-9), a complete cycle taking place in one generation time.

The principal signposts of the cell cycle are the repli­cation of the nuclear DNA and its distribution among the progeny cells.

The replication of the nuclear DNA occurs in that portion of the cell cycle known as the interphase. This was definitively shown for the first time in the classic experiments of A. Howard and S. Pelc in 1953.

Using the technique of autoradiography, Howard and Pelc found that the in­corporation of radioactive phosphorous into newly synthesized DNA occurred only during a short time interval within the interphase.

The distribution of the replicated DNA and the physical division of the parent cell into two daughter cells occur in the “period of di­vision” referred to as the M phase. The symbol M stands for “mitosis,” the process of nuclear division familiar to even the beginning biology student and consisting of the prophase, metaphase, anaphase, and telophase.

The duration of the cell cycle varies ac­cording to cell type and whether the cells are growing in vivo or in vitro. The in vivo cell cycle of most higher animals and plants is about 10 to 25 hours, of which only about one hour is spent in the M phase. In mammalian cell cultures, the range is somewhat broader (i.e., about 8 to 30 hours).

The cell cycles of prokaryotic cells, which lack a nucleus and whose DNA is usually considerably smaller in content and is differently organized, are generally much shorter. For example, in Benekea natriegens, the cell cycle is com­pleted in 10 minutes.

In eukaryotic cells, the replication of nuclear DNA occurs in a specific portion of the interphase called the S phase (S for “synthesis”); this phase typically lasts six to eight hours. Usually several hours elapse be­tween the conclusion of the M phase of the parent cell and the onset of the S phase in the two daughter cells. This interval is known as the G₁ phase (G for “gap”).

Usually, completion of the S phase is not immediately followed by the M phase. The gap between the end of the S phase and the onset of the M phase is called the G₂ phase and also lasts several hours. The G₁ phase of the cell cycle is characterized by the synthesis and ac­cumulation of RNA and protein in the cytoplasm and is accompanied by considerable cell growth.

Much of the protein synthesis during the S phase is histone synthesis; these histones enter the cell nucleus, where they become closely associated with the newly synthe­sized DNA. By the end of the S phase, the cell nucleus contains two full complements of genetic material; the cell then enters the G₂ phase, in which some cytoplas­mic growth resumes and preparations are made for nuclear division.

The lengths of the G₁, S, G₂, and M phases vary among different types of cells, but variations between cells of the same type are usually very small. The greatest variation is seen in the G₁ phase. When the cell cycle is very long, most of the prolongation can be accounted for by a lengthened G, phase. In contrast, in egg cells, where the cell cycle is very short, the G₁ phase is very brief (or even nonexistent). The cells of animal embryos undergo a rapid sequence of divisions with very little intervening cell growth.

The cell cycle may last only an hour with no G₁ phase and with some DNA synthesis occurring during mitosis or soon after mitosis is completed. Thus, the overall length of the cell cycle depends primarily on the length of the G₁ phase. The four areas under the solid curve of Figure 2-7 show for a random population the numbers of cells in each of the four phases of the cell cycle.

During the M phase, the nuclear contents undergo a series of changes and rearrangements. Prior to the onset of mitosis, the DNA is dispersed throughout the nucleus, but as the prophase of mitosis commences, the nuclear material condenses to form the clearly vis­ible chromosomes.

The dramatic nature of this con­densation process can be appreciated when one con­siders that in a human cell, the DNA, Which is 10-15 feet long in its dispersed state, condenses to form 46 duplicated chromosomes whose combined length is less that 1/25 of an inch. In the remaining phases of mi­tosis, the duplicated chromosomes are distributed to the daughter cells, leading to cell division or cytokinesis itself.

These events are clearly depicted in the excellent interference optics photomicrographs of A. S. Bajer, reproduced.

Non-cycling (Arrested) Cells:

The cells of some tissues (e.g., liver tissue cells) may exist in a non-growing, non-dividing state for a long pe­riod of time. Such cells are said to have been arrested in the G, phase or to have withdrawn from the normal cell cycle and entered a separate phase called G₀ (Fig. 2-9). If a separate G₀ phase exists, it is entered from the G, phase. Non-cycling or arrested cells may ulti­mately be “recruited” from the G₀ phase into the G, phase and then continue through the cell cycle, dupli­cating their DNA, carrying out mitosis, and dividing.

For example, the surgical removal of a portion of the liver is followed by renewed growth and division of the remaining liver tissue, quickly replacing the tissue that had been excised. Prior to removal of some of the liver tissue, the cells were in a G₀ state; after excision of some of the liver tissue, cells were recruited from the G₀ state into the G, phase.

It has been suggested that a restriction point (called R) or control mechanism of some sort exists in the G₁ phase. If a G₁ phase cell passes through the re­striction point, it continues through the cell cycle. The restriction point or control mechanism is responsive to the cell’s environment, acting to arrest the cell cy­cle or permit continued cycling according to signals received from outside the cell.

Arrested cells enter the G₀ phase for what may be an extended period of time. Some cells may not return to the cell cycle after leav­ing the G₁ phase. Indeed, the differentiation of certain cells such as muscle and nerve permanently removes them from the cell cycle (see Fig. 2-9).

Finally, it should be noted that in considering the various phases of the cell cycle, it is important to bear in mind that the stages are a part of a continuous pro­cess and that the cycle’s subdivision into the G₁, S, and G₂ phases of interphase and the prophase, metaphase, anaphase, and telophase of mitosis is a matter of de­scriptive convenience only.