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Título: | Topoisomerase I poisoning results in PARP-mediated replication fork reversal |
Autor: | Bermejo, Rodrigo CSIC ORCID CVN | Fecha de publicación: | 2012 | Editor: | Nature Publishing Group | Citación: | Nature Structural and Molecular Biology 19(4): 417-423 (2012) | Resumen: | 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. © 2012 Nature America, Inc. All rights reserved. | URI: | http://hdl.handle.net/10261/67538 | DOI: | 10.1038/nsmb.2258 | Identificadores: | doi: 10.1038/nsmb.2258 issn: 1545-9993 e-issn: 1545-9985 |
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