How is the Cell Cycle Controlled in Normal Cells

In normal cells, the control of cell cycle events occurs mainly in two ways: the cell cycle checkpoints and the cell cycle regulators. Cell cycle checkpoints are the stages of the eukaryotic cell cycle that examine both internal and external cues to determine the progression of the cell cycle to the next stage. Cell cycle regulators allow the occurrence of the cell cycle in a sequential manner. 

Cell cycle is the series of events that occur during the life cycle of a cell. The three sequential events of the cell cycle are interphase, mitotic phase, and cytokinesis. During interphase, the organelles, proteins, and other molecules which are required for DNA replication double in their amounts. During mitotic phase, the division of the nucleus occurs. During cytokinesis, the division of the cytoplasm surrounding the two daughter nuclei causes the formation of two daughter cells. All the events of the cell cycle have to be tightly controlled in order to ensure a proper cell division. Therefore, a cell has to pass through several checkpoints cycle in order to move into the next stage. These checkpoints are described in this article.

Key Areas Covered

1. What is Cell Cycle
     – Definition, Stages, Function
2. How is the Cell Cycle Controlled in Normal Cells
    – Cell Cycle Control through Checkpoints

Key Terms: Cell Cycle, Checkpoints, Cyclins, Cytokinesis, Interphase, Mitotic Phase

What is Cell Cycle

Cell cycle is the series of events the take place within the cell, leading to the division of the cell into two identical daughter cells. The three stages of the cell cycle are interphase, mitotic phase, and cytokinesis. Generally, mitosis is the type of cell division that occurs during the cell cycle. Mitosis results in two daughter cells that are identical to the parent cell. Daughter cells consist of the same amount of genetic material, organelles, and other molecules to that of the parent cell. The stages of the cell cycle are shown in figure 1.

Figure 1: Cell Cycle

Interphase

The first phase of the cell cycle is the interphase. The cell prepares for the upcoming nuclear division during interphase. The three phases of the interphase are G₁ phase, S phase, and G₂ phase. G₀ phase is the resting phase of the cell, existing prior to the entering to the cell cycle. A cell in the G₀ phase enters the G₁ phase.

1. G₁ phase – During G₁ phase, protein synthesis occurs in the cell.
2. S phase – During S phase, DNA replication and the synthesis of histone proteins occur.
3. G₂ phase – During G₂phase, organelles divide.

Mitotic (M) Phase

The second phase of the cell cycle is the mitotic phase in which the division of the nucleus occurs. The four phases of mitotic phase are prophase, metaphase, anaphase, and telophase.

1. Prophase – During prophase, chromatids are condensed into chromosomes and they are aligned in the equatorial plate. The formation of the spindle apparatus is started at the prophase and microtubules are attached to the centromere.
2. Metaphase – The microtubules attached to the centromere are contracted to align homologous chromosomes on the cell equator.
3. Anaphase – Further contraction of microtubules leads to the separation of homologous chromosomes from each other.
4. Telophase – During telophase, the individual chromosomes move into the opposite poles of the cell. New nuclear membranes are formed surrounding the two daughter nuclei.

Cytokinesis

The third or the final stage of the cell cycle is the cytokinesis. During cytokinesis, the cytoplasm along with the organelles is divided into two in an approximately equal manner.

How is the Cell Cycle Controlled in Normal Cells

The events of the cell cycle have to be controlled in order to ensure the proper division of the parent cell, producing two identical daughter cells. The control of cell cycle events occurs mainly in two ways: cell cycle checkpoints and cell cycle regulators.

Cell Cycle Checkpoints

Cell cycle checkpoints are the stages of the eukaryotic cell cycle that examine both internal and external cues to determine the progression of the cell cycle to the next stage. Internal cues can be signal molecules and external cues can be signals of DNA damage. G₁ checkpoint, the G₂ checkpoint, and spindle assembly checkpoint are the three most important cell cycle checkpoints.

1. G₁ checkpoint – G₁ checkpoint occurs at the transition of G₁/S. The presence of sufficient raw materials for the DNA replication is checked at the G₁ It is the rate-limiting step of the cell cycle known as the restriction point. Therefore, the G₁ checkpoint serves as the main decision point of the progression of cell cycle.
2. G₂ checkpoint – G₂ checkpoint occurs at the transition of G₂/M. In G₂ checkpoint, the integrity of DNA and the DNA replication is checked.
3. Spindle assembly checkpoint – Spindle assemble checkpoint is also known as the mitotic checkpoint; here, the correct attachment of spindle microtubules to the chromosomes is checked. The spindle assembly checkpoint occurs at the mitotic phase.

Regulation of cell cycle by with checkpoints and cyclins is shown in figure 2.

Figure 2: Checkpoints and Cyclins

Cell Cycle Regulators

Cyclins and cyclin-dependent kinases (CDKs) are the two types of regulatory molecules that allow the occurrence of the cell cycle in a sequential manner. Both cyclins and CDKs work in an interactive manner. Cyclins are proteins that produce regulatory subunits while CDKs are the enzymes that produce catalytic subunits. The G₁ cyclin-CDK complex prepares the G₁ phase cell for S phase by promoting the expression of transcription factors that promote the S cyclins. G₁ cyclin-CDK complex also degrades the S phase inhibitors. Cyclins expressed during each stage of cell cycle is shown in figure 3.

Figure 3: Expression Cycle of Cyclins

The cyclin D-CDK4/6 regulates the timing of the G₁ phase. It is activated by G₁ cyclin-CDK complex. The cyclin E-CDK2 complex pushes the cell from G₁ to S phase (G₁/S transition). Cyclin A-CDK2 inhibits the DNA replication of the S phase by disassembling the replication complex. A large pool of cyclin A-CDK2 activates the G₂ phase. Cyclin B-CDK2 pushes G₂ phase to the M phase (G₂/M transition). 

Conclusion

Cell cycle is a series of events that occur during the life cycle of a cell. The three stages of the cell cycle are interphase, mitotic phase, and cytokinesis. Each stage of the cell cycle has to be controlled in order to ensure the proper division of the cell. Therefore, each stage is controlled through three checkpoints and various cyclin-CDK complexes.

Reference:

1. “Cell Cycle Checkpoints.” Khan Academy, Available here.
2. “Cell Cycle Regulators.” Khan Academy, Available here.

Image Courtesy:

1. “Animal cell cycle-en” By Kelvinsong – Own work (CC0) via Commons Wikimedia
2. “0332 Cell Cycle With Cyclins and Checkpoints” By OpenStax –  (CC BY 4.0) via Commons Wikimedia
3. “Figure 10 03 02” By CNX OpenStax – (CC BY 4.0) via Commons Wikimedia