Theme 6: What Causes Cancer?
6.1 The Cell Cycle
By the end of this section, you will be able to:
- Describe how the cell cycle functions normally, including what happens during each of the three stages of interphase (G1, S, G2) as well as M
- In general terms, discuss what happens during M phase. How do the daughter cells compare to the original cell? How does the cell ensure that each daughter cell gets a complete set of genetic information? (IMPORTANT: You do NOT need to memorize the steps of mitosis!)
- Define the quiescent G0 phase. When does a cell go into G0?
- Explain how the three internal control checkpoints occur at the end of G1, at the G2–M transition, and during metaphase
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 1). 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. Watch this video about the cell cycle: https://www.youtube.com/watch?v=Wy3N5NCZBHQ
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.
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.
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.
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.
The Mitotic Phase
To make two daughter cells, the contents of the nucleus and the cytoplasm must be divided. The mitotic phase is a multistep 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 is divided into a series of phases—prophase, prometaphase, metaphase, anaphase, and telophase—that result in the division of the cell nucleus (Figure 2).
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 3).
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).
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.
Concept in Action
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. Mitosis and cytokinesis are the steps during which the cell divides into two daughter cells.
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.
- the stage of mitosis during which sister chromatids are separated from each other
- cell cycle
- the ordered sequence of events that a cell passes through between one cell division and the next
- cell cycle checkpoints
- mechanisms that monitor the preparedness of a eukaryotic cell to advance through the various cell cycle stages
- the division of the cytoplasm following mitosis to form two daughter cells
- G0 phase
- a cell-cycle phase distinct from the G1 phase of interphase; a cell in G0 is not preparing to divide
- G1 phase
- (also, first gap) a cell-cycle phase; first phase of interphase centered on cell growth during mitosis
- G2 phase
- (also, second gap) a cell-cycle phase; third phase of interphase where the cell undergoes the final preparations for mitosis
- the period of the cell cycle leading up to mitosis; includes G1, S, and G2 phases; the interim between two consecutive cell divisions
- the stage of mitosis during which chromosomes are lined up at the metaphase plate
- the period of the cell cycle at which the duplicated chromosomes are separated into identical nuclei; includes prophase, prometaphase, metaphase, anaphase, and telophase
- mitotic phase
- the period of the cell cycle when duplicated chromosomes are distributed into two nuclei and the cytoplasmic contents are divided; includes mitosis and cytokinesis
- mitotic spindle
- the microtubule apparatus that orchestrates the movement of chromosomes during mitosis
- the stage of mitosis during which chromosomes condense and the mitotic spindle begins to form
- describes a cell that is performing normal cell functions and has not initiated preparations for cell division
- S phase
- the second, or synthesis phase, of interphase during which DNA replication occurs
- the stage of mitosis during which chromosomes arrive at opposite poles, decondense, and are surrounded by new nuclear envelopes