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Nat Struct Mol Biol. April 1, 2012; 19 (4): 417-23.

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 .

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.

PubMed ID: 22388737
Article link: Nat Struct Mol Biol.
Grant support: Cancer Research UK

Genes referenced: parp1 top1.1

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