ATM safeguards DNA replication by restraining pathological repriming at endogenous base lesions.

ATM prevents pathological repriming at oxidative DNA lesions, and its absence leads to DNA gaps that cause PARPi sensitivity in mammalian cells.

• Why it matters: Understanding how ATM deficiency causes cell death is crucial because it reveals vulnerabilities in cancer and genetic disorders like ataxia telangiectasia, where genome stability is compromised.
• What they did: The study examined ATM-deficient cells using molecular techniques, demonstrating that unrestrained PRIMPOL-dependent repriming at oxidative lesions creates DNA gaps that activate PARP, leading to cell death.
• The result: Inhibiting repriming, repair pathways, or oxidative stress reduces DNA damage and cell death, highlighting a new paradigm of post-replicative repair addiction and linking oxidative damage to genome instability.