Definition:
Types
DNA damage checkpoints
- G1/S checkpoint
- G2/M checkpoint
- intra-S checkpoint
spindle checkpoint (metaphase checkpoint)
DNA damage checkpoints
DNA damage checkpoints ensure the fidelity of genetic information both by arresting cell cycle progression and facilitating DNA repair pathways.
DNA damage checkpoints are control mechanisms that ensure the fidelity of DNA replication during cell division in eukaryotic cells. These checkpoints verify whether the processes at each phase of the cell cycle have been accurately completed before progression into the next phase. Multiple checkpoints have been identified, but some of them are less well understood than others. There is a network of proteins that form the DNA damage checkpoints.
After DNA damage, cell cycle checkpoints are activated. Checkpoint activation pauses the cell cycle and gives the cell time to repair the damage before continuing to divide.
DNA damage checkpoints occur at the G1/S (G1/S checkpoint) and G2/M boundaries (G2/M checkpoint). An intra-S checkpoint also exists.
Checkpoint activation is controlled by two master kinases, ATM and ATR. ATM responds to DNA double-strand breaks and disruptions in chromatin structure, whereas ATR primarily responds to stalled replication forks. These kinases phosphorylate downstream targets in a signal transduction cascade, eventually leading to cell cycle arrest.
A class of checkpoint mediator proteins including BRCA1, MDC1, and 53BP1 has also been identified. These proteins seem to be required for transmitting the checkpoint activation signal to downstream proteins.
p53 is an important downstream target of ATM and ATR, as it is required for inducing apoptosis following DNA damage. At the G1/S checkpoint, p53 functions by deactivating the CDK2/cyclin E complex. Similarly, p21 mediates the G2/M checkpoint by deactivating the CDK1/cyclin B complex.
- mitotic spindle checkpoint
The mitotic spindle checkpoint occurs at the point in metaphase where all the chromosomes have/should have aligned at the mitotic plate and be under bipolar tension. The tension created by this bipolar attachment is what is sensed and this is what initiates the anaphase entry.
This sensing mechanism allows the degradation of cyclin B which harbours a D-box (destruction box).
Degradation of cyclin B ensures it no longer inhibits the anaphase promoting complex, which in turn is now free to breakdown securin. The latter is a protein whose function is to inhibit separase, the protein composite which is responsible for the separation of sister chromatids.
Once this inhibitory protein is degraded via ubiquitination and subsequent proteolysis, separin then causes sister chromatid separation. After the cell has split into its two daughter cells (M phase; mitosis), the cell enters the G1 phase of cell cycle.
See also
DNA damage
DNA lesions
DNA repair