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Nat Struct Mol Biol
2012 Mar 04;194:417-23. doi: 10.1038/nsmb.2258.
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Topoisomerase I poisoning results in PARP-mediated replication fork reversal.
Ray Chaudhuri A
,
Hashimoto Y
,
Herrador R
,
Neelsen KJ
,
Fachinetti D
,
Bermejo R
,
Cocito A
,
Costanzo V
,
Lopes M
.
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Topoisomerase I (Top1) releases torsional stress during DNA replication and transcription and is inhibited by camptothecin and camptothecin-derived cancer chemotherapeutics. Top1 inhibitor cytotoxicity is frequently linked to double-strand break (DSB) formation as a result of Top1 being trapped on a nicked DNA intermediate in replicating cells. Here we use yeast, mammalian cell lines and Xenopus laevis egg extracts to show that Top1 poisons rapidly induce replication-fork slowing and reversal, which can be uncoupled from DSB formation at sublethal inhibitor doses. Poly(ADP-ribose) polymerase activity, but not single-stranded break repair in general, is required for effective fork reversal and limits DSB formation. These data identify fork reversal as a means to prevent chromosome breakage upon exogenous replication stress and implicate proteins involved in fork reversal or restart as factors modulating the cytotoxicity of replication stress-inducing chemotherapeutics.
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