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- Title
Topoisomerase I poisoning results in PARP-mediated replication fork reversal.
- Authors
Ray Chaudhuri, Arnab; Hashimoto, Yoshitami; Herrador, Raquel; Neelsen, Kai J; Fachinetti, Daniele; Bermejo, Rodrigo; Cocito, Andrea; Costanzo, Vincenzo; Lopes, Massimo
- Abstract
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.
- Subjects
DNA topoisomerase I; DNA replication; CAMPTOTHECIN; CANCER chemotherapy; MAMMALIAN cell cycle; CELL lines
- Publication
Nature Structural & Molecular Biology, 2012, Vol 19, Issue 4, p417
- ISSN
1545-9993
- Publication type
Article
- DOI
10.1038/nsmb.2258