Cell cycle progression requires successful passage through multiple checkpoints.

Cyclins and CDKs not only allow a cell to progress through the cell cycle, but also give the cell opportunities to halt the cell cycle should something go wrong. In other words, if the preparations for the next stage of the cell cycle are incomplete or if there is some kind of damage, there are mechanisms that block the cyclin–CDK activity required for the next step, pausing cell division until preparations are complete or the damage is repaired. Each of these mechanisms is called a checkpoint.

Cells have many cell cycle checkpoints. Three major checkpoints that have been well studied are illustrated in Fig. 11.17. The presence of damaged DNA arrests the cell at the end of G1 before DNA synthesis; the presence of unreplicated DNA arrests the cell at the end of G2 before the cell enters mitosis; and abnormalities in chromosome attachment to the spindle arrest the cell in early mitosis. By way of illustration, we focus on the key checkpoint that occurs at the end of G1 in response to the presence of damaged DNA.

image
FIG. 11.17 Cell cycle checkpoints. Cell cycle checkpoints monitor key steps in the cell cycle.

DNA can be damaged by environmental insults such as ultraviolet radiation or chemical agents. Typically, damage takes the form of double-stranded breaks in the DNA. If the cell progresses through mitosis with DNA damage, the damage might be inherited by the daughter cells, or the chromosomes might not segregate normally. Some checkpoints delay progression through the cell cycle until DNA damage is repaired. An important one occurs in late G1. This DNA damage checkpoint depends on several regulatory proteins, some of which recognize damaged DNA while others arrest cell cycle progression before S phase (Fig. 11.17).

When DNA is damaged by radiation, a specific protein kinase is activated that phosphorylates a protein called p53. Phosphorylated p53 binds to DNA, where it turns on the expression of several genes. One of these genes codes for a protein that binds to and blocks the activity of the G1/S cyclin–CDK complex (Fig. 11.18). In so doing, p53 arrests the cell at the G1/S transition, giving the cell time to repair the damaged DNA. The p53 protein therefore is a good example of protein involved in halting the cell cycle when the cell is not ready to divide. Because of its role in protecting the genome from accumulating DNA damage, p53 is sometimes called the “guardian of the genome.” Mutations in p53 are common in cancer, a topic we turn to next.

image
FIG. 11.18 DNA damage checkpoint controlled by p53.

236

Quick Check 7 Can you think of two ways in which the function of p53 can be disrupted?

Quick Check 7 Answer

The function of the p53 protein can be disrupted by a mutation in the p53 gene. Alternatively, certain viral proteins, such as the E6 protein of HPV discussed in Case 2: Cancer, can interfere with the function of the p53 protein.