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 the mechanism of PARPi cytotoxicity in ATM-deficient cells is crucial because it reveals how genome instability arises and suggests potential therapeutic targets for ATM-related cancers.
• What they did: The study examined mammalian ATM-deficient cells and found that unrestrained PRIMPOL-dependent repriming at oxidative base lesions creates post-replicative DNA gaps, activating PARP and leading to synthetic lethality.
• The result: Suppressing repriming, base excision repair, or oxidative stress alleviates DNA repair defects, highlighting a link between oxidative DNA damage, replication dysregulation, and genome instability in ATM-deficient contexts.