Topoisomerase I Poisoning Results in PARP-mediated Replication Fork Reversal

Overview

Journal Nat Struct Mol Biol

Specialties Cell Biology
Molecular Biology

Date 2012 Mar 6

PMID 22388737

Citations 294

Authors

Arnab Ray Chaudhuri

Yoshitami Hashimoto

Raquel Herrador

Kai J Neelsen

Daniele Fachinetti

Rodrigo Bermejo

Andrea Cocito

Vincenzo Costanzo

Massimo Lopes

Affiliations

Soon will be listed here.

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.

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