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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Bibliographic Details
Published in:	Nature structural & molecular biology Vol. 19; no. 4; pp. 417 - 423
Main Authors:	Ray Chaudhuri, Arnab, Hashimoto, Yoshitami, Herrador, Raquel, Neelsen, Kai J, Fachinetti, Daniele, Bermejo, Rodrigo, Cocito, Andrea, Costanzo, Vincenzo, Lopes, Massimo
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01.04.2012 Nature Publishing Group
Subjects:	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
Online Access:	Get full text
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Abstract	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.
AbstractList	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. 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. 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. [PUBLICATION 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.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.
Audience	Academic
Author	Costanzo, Vincenzo Hashimoto, Yoshitami Bermejo, Rodrigo Lopes, Massimo Neelsen, Kai J Cocito, Andrea Ray Chaudhuri, Arnab Fachinetti, Daniele Herrador, Raquel
Author_xml	– sequence: 1 givenname: Arnab surname: Ray Chaudhuri fullname: Ray Chaudhuri, Arnab organization: Institute of Molecular Cancer Research, University of Zurich – sequence: 2 givenname: Yoshitami surname: Hashimoto fullname: Hashimoto, Yoshitami organization: London Research Institute, Clare Hall Laboratories – sequence: 3 givenname: Raquel surname: Herrador fullname: Herrador, Raquel organization: Institute of Molecular Cancer Research, University of Zurich – sequence: 4 givenname: Kai J surname: Neelsen fullname: Neelsen, Kai J organization: Institute of Molecular Cancer Research, University of Zurich – sequence: 5 givenname: Daniele surname: Fachinetti fullname: Fachinetti, Daniele organization: IFOM, Istituto FIRC di Oncologia Molecolare (IFOM-IEO Campus), Present addresses: Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, California, USA (D.F.); Instituto de Biología Funcional y Genómica, Consejo Superior de Investigaciones Científicas, Universidad de Salamanca, Spain (R.B.) – sequence: 6 givenname: Rodrigo surname: Bermejo fullname: Bermejo, Rodrigo organization: IFOM, Istituto FIRC di Oncologia Molecolare (IFOM-IEO Campus), Present addresses: Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, California, USA (D.F.); Instituto de Biología Funcional y Genómica, Consejo Superior de Investigaciones Científicas, Universidad de Salamanca, Spain (R.B.) – sequence: 7 givenname: Andrea surname: Cocito fullname: Cocito, Andrea organization: IFOM, Istituto FIRC di Oncologia Molecolare (IFOM-IEO Campus) – sequence: 8 givenname: Vincenzo surname: Costanzo fullname: Costanzo, Vincenzo organization: London Research Institute, Clare Hall Laboratories – sequence: 9 givenname: Massimo surname: Lopes fullname: Lopes, Massimo email: lopes@imcr.uzh.ch organization: Institute of Molecular Cancer Research, University of Zurich
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/22388737$$D View this record in MEDLINE/PubMed
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Snippet	Topoisomerase 1 (Top1) inhibition is believed to mediate cellular toxicity by trapping Top1 on nicked DNA, leading to double-strand break formation during... Topoisomerase I (Top1) releases torsional stress during DNA replication and transcription and is inhibited by camptothecin and camptothecin-derived cancer...
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SubjectTerms	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
Title	Topoisomerase I poisoning results in PARP-mediated replication fork reversal
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