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13.3Checkpoint mechanisms in the cell cycle

Both accurate replication and even distribution of genetic information (genome) to the 2 daughter cells are critically important events in the cell cycle. If these are not ensured, the consequences would be catastrophic. For instance, if cells were to enter the M phase without sufficiently completing the replication of genetic information, the daughter cells would not carry the same amount of genetic information as the mother cell. In another example, if chromosomes were to be pulled toward the spindle poles during the prometaphase stage of the M phase without being attached to the spindle microtubules, it would mean that the chromosomes would not be segregated evenly. In order to minimize such accidents, cells have checkpoints that function to monitor the progression of the cell cycle. The following paragraphs list some of the representative checkpoint mechanisms (Figure 13-7).

Figure 13-7 Molecular mechanism of DNA damage checkpoint

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13.3.1

DNA damage checkpoint

Our DNA is subject to various damages every day. If DNA synthesis starts before any cell damage is repaired, the cell would not replicate correctly, leading to high possibility of mutations or cell death. To prevent this, cells have a mechanism to check whether the DNA bases and their sequences are correct. If the DNA is found to be damaged, ATM/R phosphorylate and activate the p53 protein during the G1, S, and G2 phases (Column Figure 13-3), whereas unphosphorylated p53 is broken down by Mdm2. The phosphorylated p53 protein activates numerous genes (some genes are inactivated). One role of the p53 protein is to activate the genes of the p21 protein, a type of CKI, to create large amounts of p21 protein, and to inhibit the actions of cyclin-CDK. As a result, cells cannot move onto the next step until the DNA damage is repaired. Once the repair is completed, the p53 protein is inactivated, and the p21 protein is broken down, allowing the cells to transition to the next step.

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Checkpoints at different phases of the cell cycle

Other than the DNA damage checkpoint, various other cell cycle checkpoints are known (Column Figure 13-3).

* DNA replication checkpoint
This checkpoint allows the cell cycle to transition to nuclear division after DNA has been adequately replicated. If any part of the DNA has not been replicated, the checkpoint identifies such parts and inhibits the activity of the G2-phase cyclin-CDK, the protein that instructs entry into the M phase. First, the ATR protein kinase binds to the replication fork to activate its kinase activity, and then phosphorylates and activates another protein kinase Chk-1. The phosphorylated Chk-1 then phosphorylates and inactivates the Cdc25 phosphatase. With the Cdc25 phosphatase kept inactive, CDK dephosphorylation is prevented from occurring. As a result, the G2-phase cyclin-CDK complex remains inactivated, which prevents complete phosphorylation of the target protein of the G2-phase cyclin-CDK complex required for entry into the M phase. The ATR continues to activate the Chk-1 protein kinase until all replication forks complete DNA replication and the replication forks are broken down.

* Spindle assembly checkpoint
Incorrect spindle assembly prevents the advancement into anaphase. The mechanism responsible for ensuring appropriate spindle assembly is called the spindle assembly checkpoint. If any one kinetochore of either sister chromatid does not appropriately attach to a spindle microtubule, then transition to anaphase is inhibited. It has been recently understood that the protein Mad2 is involved in this process. Mad2 attaches to the kinetochores that have failed to attach to microtubules and becomes activated. It interacts with the protein Cdc20 to inhibit Cdc20 activity. Because Cdc20 is an activator of APC/C that is required to initiate anaphase, transition to anaphase will not occur as long as activated Mad2 is present. The production of activated Mad2 will stop only when all kinetochores are properly attached to the microtubules. Thus, the spindle assembly checkpoint ensures that cell division does not progress any further until all chromosomes are properly attached to microtubules so that the genome of the parent cell can be accurately segregated to the 2 daughter cells.

* Chromosome segregation checkpoint
Once the chromosomes have segregated properly, telophase starts. The G2/M cyclin-CDK complex needs to be inactivated to allow transition to telophase and for the subsequent cytokinesis events. This checkpoint monitors the positions of the segregating daughter chromosomes. After proper chromosome segregation is confirmed, the regulatory factor Cdc14 inactivates the G2/M cyclin-CDK complex, allowing cells to transition to telophase and then to cytokinesis.

Column Figure 13-3 Control of checkpoints in cell cycle

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