Positional replication fork instability drives PARP inhibitor cytotoxicity.

Loss of ESCO2, a replication-coupled cohesin acetyltransferase, is linked to PARP inhibitor hypersensitivity by promoting G-quadruplex accumulation at fragile pericentromeric replication sites.

• Why it matters: PARPi hypersensitivity extends beyond homologous recombination deficiency, but the specific replication-fork DNA lesions that trigger cytotoxicity are not well defined.
• What they did: CRISPR screens identified ESCO2 loss as conferring PARPi hypersensitivity independently of homologous recombination deficiency, and single-molecule imaging showed increased G4 DNA at replication-associated sites with PARP1 activation and TIMELESS engagement.
• The result: PARP inhibition disrupts PARP1-dependent engagement of TIMELESS and DDX11, leading to G4 accumulation, DNA damage, and chromosomal instability, defining a G4–PARP1–TIMELESS–DDX11 safeguard axis.

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