Topoisomerase I poisoning results in PARP-mediated replication fork reversal

Topoisomerase 1 (Top1) inhibition is believed to mediate cellular toxicity by trapping Top1 on nicked DNA, leading to double-strand break formation during replication. New studies show that clinically relevant doses of Top1 poisons lead instead to extensive replication-fork reversal that is mediated by Poly(ADP-ribose) polymerases, limiting double-strand break formation.