R1.5.3: Cell Cycle Checkpoints

Checkpoints exist as barriers to stop unwanted or dangerous progression through the cell cycle. These checkpoints are frequently deranged in human tumours, allowing them to proliferate at an uncontrolled rate but also causing them to enter cellular division when conditions are not ideal.

For instance, heading into mitosis when your chromosomes have been chopped up by ionising radiation is usually not a good idea.

G1/S phase checkpoint

This checkpoint is controlled mainly by the p53 protein. As described above, p53 may become activated in a number of circumstances, such as DNA damage (via the ATM->CHK2 pathway) or oncogene activation (p19ARF pathway). In these scenarios, p53 will accumulate and begin exerting its effect. The ATR protein does not appear to have a role in activating the G1 checkpoint.
p53 results in the transcription of many other proteins, of which the most important is thought to be p21. This CDK inhibitor is a member of the CIP/KIP group, and prevents the function of cyclin E/CDK2 and cyclin-α/CDK2. Without this CDK function, the cell is unable to progress around the cell cycle, and in particular through the G1/S checkpoint.
The activation of CHK2 by DNA damage can also lead to cdc25 inactivation or destruction. This response is faster than that of p53 (which requires new proteins to be synthesised), but less permanent.

S phase 'checkpoint'

ATM and ATR are both important sensors of DNA damage in S phase, activating the CHK2/1 proteins which then phosphorylates p53 and the cdc molecules. These processes serve to lengthen the S phase while the cell attempts to repair the double strand breaks.
Importantly, double strand breaks occurring due to normal DNA replication are protected from recognition by the ATM/ATR system, and therefore they do not cause a response or delay in the S phase.

G2 checkpoint

This checkpoint, frequently deranged in malignancy, prevents cells from proceeding into mitosis if their DNA is damaged.

ATM and ATR, via the CHK1 and CHK2 proteins, also regulate the G2 checkpoint. This checkpoint is designed to stop the cell progressing into mitosis if there are double strand breaks present, as this is a fatal situation.
CHK1 and CHK2 function by phosphorylating cdc25C, which is then unable to dephosphorylate the cyclin β/CDK1 complex. This leaves the complex inactive and halts progression in G2 until the CHK1/2 function decreases.
The activation of p53 by ATM/ATR also has a role to play, by decreasing the transcription of CDK1 and cyclin β.

Mitosis (or Spindle) Checkpoint

A further checkpoint in the cell cycle exists, located within metaphase. Through incompletely understood mechanisms, several proteins (MAD1 & 2, Bub, and others) recognise incomplete or incorrect positioning of the chromosomes on the mitotic spindle. They inhibit the action of separase to prevent it from cleaving the daughter chromatids.