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...

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Vydáno v:Nature structural & molecular biology Ročník 19; číslo 4; s. 417 - 423
Hlavní autoři: Ray Chaudhuri, Arnab, Hashimoto, Yoshitami, Herrador, Raquel, Neelsen, Kai J, Fachinetti, Daniele, Bermejo, Rodrigo, Cocito, Andrea, Costanzo, Vincenzo, Lopes, Massimo
Médium: Journal Article
Jazyk:angličtina
Vydáno: New York Nature Publishing Group US 01.04.2012
Nature Publishing Group
Témata:
631/337/1427
631/337/151
631/67/1059/99
Adenosine diphosphate
Animals
Biochemistry
Biological Microscopy
Biomedical and Life Sciences
Camptothecin - pharmacology
Cancer
Cell Line
Cellular biology
Chemotherapy
Chromosomes
Cytotoxicity
Deoxyribonucleic acid
DNA
DNA - chemistry
DNA - metabolism
DNA Repair - drug effects
DNA replication
DNA Replication - drug effects
DNA Topoisomerases, Type I - metabolism
Enzymes
Genetic aspects
Humans
Life Sciences
Mammals
Membrane Biology
Nucleic Acid Conformation - drug effects
Physiological aspects
Poisons
Poly(ADP-ribose) Polymerases - metabolism
Protein Structure
Saccharomyces cerevisiae - cytology
Saccharomyces cerevisiae - drug effects
Topoisomerase I Inhibitors - pharmacology
Topoisomerases
Toxicity
Xenopus laevis
Xenopus laevis - metabolism
Yeast
Yeasts
United States
ISSN:1545-9993, 1545-9985, 1545-9985
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Shrnutí: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. 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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ISSN:1545-9993
1545-9985
1545-9985
DOI:10.1038/nsmb.2258