In our last post, we explored how the cell cycle is essential for every living organism. The cell cycle allows cells to divide, which is crucial for both growth and repair. However, not all cells divide at the same rate. For example, cells in the human intestine divide more than twice a day, while mature nerve cells may never divide again.

These differences mean that the cell cycle must be carefully regulated, and scientists have spent many years studying how this regulation happens. In this post, we’ll explore one of the most important ways the cell cycle is controlled: through checkpoints.

What Are Cell Cycle Checkpoints?

Cell cycle checkpoints are control mechanisms that ensure each stage of the cell cycle is completed accurately before the cell moves on to the next stage. There are three main checkpoints:

G1 Checkpoint
G2 Checkpoint
Metaphase Checkpoint

Each checkpoint verifies that specific conditions are met before allowing the cell to proceed to the next phase of the cycle. Let’s take a closer look at each one.

Download a Vocabulary Organizer

Alt Text: A diagram illustrating the cell cycle checkpoints. The phases of the cell cycle are represented in a circle starting at G1, S, G2, and a smaller shaded region for mitosis. There is a yellow and black X at the G1/S boundary for the G1 checkpoint. A yellow X at the G2/Mitosis boundary for the G2 checkpoint and another yellow X in the mitosis region for the Metaphase Checkpoint.

G1 Checkpoint

The G1 checkpoint occurs at the end of the G1 phase, just before the cell enters the S phase (where DNA is replicated). If the cell passes the G1 checkpoint, it will move into the S phase. To pass this checkpoint, the cell must meet the following conditions:

Adequate size: The cell needs to be large enough to divide.
Nutrient availability: The cell must have access to the nutrients it needs to grow and divide.
Social signals: In multicellular organisms, the cell needs signals from other cells to proceed.
Undamaged DNA: If the cell’s DNA is damaged, a protein called p53 can stop the cell cycle so the DNA can be repaired. If the damage is too severe, the cell will undergo programmed cell death, called apoptosis. This prevents the division of cells with harmful mutations. Because of this, p53 is known as a tumor suppressor, as it helps prevent the development of cancer.

In addition, different cyclin-Cdk complexes play an important role at the G1 checkpoint. For example, cyclin D and cyclin E bind to their respective Cdks and help regulate the cell’s progression into the S phase.

Note: Cdk stands for cyclin dependent kinase. Throughout the cell cycle, cyclin and cdk’s play an important role in regulation. Both of these are proteins and there are many different versions of these proteins (i.e. cyclin B and E). In this post, we will look at some of the cyclin-Cdk complexes that help with cell regulation and explain more about what these are later in this post.

If the cell meets all these conditions, it will move on to the S phase and begin replicating its DNA. If not, the cell will enter a resting state called the G0 phase, where it may stay until conditions improve, or it may remain indefinitely.

G2 Checkpoint

The G2 checkpoint occurs between the G2 phase and the start of mitosis (M phase). This checkpoint ensures that the cell is ready to divide by checking:

Successful DNA replication: The cell’s chromosomes must have been copied correctly.
Undamaged DNA: Any damage from the replication process must be repaired.
Mitosis Promoting Factors (MPF): These proteins must be active for mitosis to begin.

Note: Mitosis Promoting Factors can also be referred to as Maturation Promoting Factors. Both will have the acronym MPF.

If any of these conditions are not met, the cell cycle will be halted to prevent faulty cell division. DNA damage at this point activates proteins, which detect the damage and stop the cell cycle so repair mechanisms can fix the problem.

Metaphase Checkpoint (Spindle Assembly Checkpoint)

The final checkpoint occurs during metaphase in mitosis and is often referred to as the Mitosis Checkpoint or Spindle Assembly Checkpoint (SAC). At this stage, the cell must ensure that:

Chromosomes are properly attached to spindle fibers: This is crucial because the spindle fibers pull the chromosomes apart during cell division. If they are not properly attached, the chromosomes may be unevenly distributed between the two new cells, leading to an abnormal number of chromosomes.

Proteins are involved in making sure this attachment is correct. If the chromosomes are not properly attached, these proteins prevent the cell from progressing into anaphase.

Alt Text: A diagram illustrating the mitosis checkpoint. There is a cell with two chromosomes in the middle and spindles as dotted lines, connecting to the chromosomes and either sides of the cell. Each chromosome has an orange dot to represent the kinetochores. There is a box to the right of the diagram explaining that correct attachment to kinetochores allows the cell to properly divide the chromosomes.

What Are Mitosis/Maturation Promoting Factors (MPF)?

You may have noticed that the G2 checkpoint checks for the presence of Mitosis/Maturation Promoting Factors (MPF). But what exactly are they?

MPF is a protein complex that triggers the onset of mitosis. It is made up of two parts:

Protein Kinase: This enzyme starts the process of mitosis but only works if it is bound to another protein called cyclin. When the kinase is dependent on cyclin, it is referred to as cyclin-dependent kinase (Cdk).
Cyclin: This protein’s concentration levels change throughout the cell cycle. Cyclin levels rise during interphase, peak during mitosis, and then drop again during anaphase. When cyclin levels are high, Cdk binds to it and activates MPF, which triggers mitosis. As cyclin levels decrease, MPF becomes inactive, helping to stop the cell division process.

This regulation is an example of negative feedback, where a product (in this case, MPF) slows down or stops its own production. This feedback loop helps keep cell division under control.

Alt Text: A diagram illustrating the role of Mitosis Promoting Factors (MPF) in the cell cycle. The image shows that Cyclin binds to cyclin-dependent kinase (Cdk) to form the MPF complex. This MPF complex then activates through phosphorylation, initiating cell division by phosphorylating target proteins. Cyclin degrades during M phase, leading to the inactivation of MPF, and its concentration rebuilds as the cell cycle progresses. The cycle of activation and degradation repeats as Cyclin levels fluctuate throughout the cell cycle.

Alt Text: A simple graph illustrating Cyclin concentrations in the cell cycle. At the top of the graph the cell cycle is represented as G1, S, G2, and mitosis. A yellow horizontal line is shown below to represent cdk with text that reads “concentrations remain consistent, but cdk is not always active. A green line representing cyclin concentration is low during G1, and starts to increase in S, peaking in mitosis and then dropping back down to the low concentrations. Two cell cycles are shown.

What Happens If Cell Division Isn’t Regulated?

If cell division is not properly regulated, uncontrolled growth can occur, leading to the formation of tumors and cancer. Proteins like p53 (a tumor suppressor) and checkpoint proteins play crucial roles in preventing this. However, mutations in tumor suppressor genes like p53 can cause the cell to bypass these checkpoints, leading to unregulated cell growth.

In cancer, mutations that affect these checkpoints are common, which is why studying them is so important. By understanding how the cell cycle is controlled and what happens when this control is lost, scientists can develop new treatments for cancer.

External Signals and Cell Cycle Regulation

The cell cycle is not only controlled internally but also influenced by external signals. For example:

Growth factors: These signals stimulate cell division. If growth factors are present, the cell is more likely to pass the G1 checkpoint.
Contact inhibition: When cells become too crowded and touch one another, they stop dividing. This is a way to prevent unnecessary cell growth. In cancer, cells often lose this ability, leading to uncontrolled division and tumor formation.

Conclusion

In our next post, we’ll look at the case of Henrietta Lacks, whose cells have contributed to many medical discoveries. Her story also raises important ethical questions about medical research and consent, which we’ll discuss in detail.

The Cell Cycle: Checkpoints and Cancer