DNA Damage Can Stall the Cell Cycle

Damaged DNA stalls the replication fork, causing it to become unstable and the helicase and polymerase to uncouple from the DNA. To prevent the damaged single-stranded DNA from reannealing, replication protein A (RPA) coats the single-stranded DNA at the stalled replication fork, which is then detected by the ATR protein.

ATR detects single-stranded DNA breaks at stalled replication forks, while ATM responds to double-strand breaks detected by the MRN protein complex. Both ATM and ATR are kinases that phosphorylate downstream kinases Chk1 and Chk2, respectively, initiating a cascade that halts cell cycle progression.

Phosphorylated p53 acts as a transcription factor that directly binds to DNA and stimulates production of p21, a CDK inhibitor. p21 prevents the cell from progressing to the next stage of cell division by inhibiting cyclin-CDK complexes, making p53 critical to the G1/S checkpoint mechanism.

CDC25 is a phosphatase required for CDK activation. When ATR and ATM phosphorylate Chk1 and Chk2, these kinases phosphorylate CDC25, preventing it from accepting further phosphates from CDK1. This inactivates CDK1, the regulator of the cell cycle, stopping progression to the S phase.

In cells where p53 is mutated or absent, cell division can no longer be regulated properly. This uncontrolled cell division results in malignant tumors, as cells lose the ability to arrest the cell cycle in response to DNA damage or activate appropriate repair mechanisms.

Cells pause at critical checkpoints during the cell cycle where multiple enzymes probe DNA for damage. Only intact, undamaged DNA is allowed to pass through. If damage is detected, the cell cycle pauses until repair is complete, preventing damaged DNA from being passed to the next generation.

Replication stress caused by damaged DNA initiates a choreographed pathway of proteins that respond to specific damage types with appropriate repair mechanisms. For example, ionizing radiation causing double-strand breaks activates ATM, which sets in motion molecular interactions involving repair pathways such as nonhomologous end joining and homologous recombination.