DNA Damage Checkpoints

DNA is damaged thousands of times a day. Checkpoints pause the cycle so repair can happen. Two master kinases sense trouble: ATM responds mainly to double-strand breaks, while ATR responds to single-stranded DNA and stalled replication forks.

They phosphorylate the effector kinases Chk2 (from ATM) and Chk1 (from ATR), which in turn inactivate Cdc25 phosphatases — so CDKs stay inhibited and the cycle halts.

ATM and Chk2 also phosphorylate p53, stabilizing it. Normally p53 is kept low by MDM2, an E3 ubiquitin ligase that tags it for destruction. Damage-induced phosphorylation blocks MDM2 binding, so p53 accumulates.

p53 is a transcription factor. It turns on p21 (cell-cycle arrest), DNA-repair genes, and — if damage is too severe — pro-apoptotic genes like PUMA, NOXA and BAX. It decides between 'pause and fix' and 'self-destruct'.

TP53 is mutated in roughly half of all human cancers. Without p53, damaged cells keep dividing, accumulating more mutations — a vicious cycle called genomic instability.

Inherited mutation of one TP53 copy causes Li-Fraumeni syndrome, with high risk of many cancers early in life. Inherited ATM loss causes ataxia-telangiectasia with radiation sensitivity and cancer predisposition.