Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Nat Struct Mol Biol
2012 Mar 04;194:417-23. doi: 10.1038/nsmb.2258.
Show Gene links
Show Anatomy links
Topoisomerase I poisoning results in PARP-mediated replication fork reversal.
Ray Chaudhuri A
,
Hashimoto Y
,
Herrador R
,
Neelsen KJ
,
Fachinetti D
,
Bermejo R
,
Cocito A
,
Costanzo V
,
Lopes M
.
???displayArticle.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.
Atkinson,
Replication fork reversal and the maintenance of genome stability.
2009, Pubmed
Atkinson,
Replication fork reversal and the maintenance of genome stability.
2009,
Pubmed
Bermejo,
The replication checkpoint protects fork stability by releasing transcribed genes from nuclear pores.
2011,
Pubmed
Bermejo,
Top1- and Top2-mediated topological transitions at replication forks ensure fork progression and stability and prevent DNA damage checkpoint activation.
2007,
Pubmed
Bermejo,
Genome-organizing factors Top2 and Hmo1 prevent chromosome fragility at sites of S phase transcription.
2009,
Pubmed
Bryant,
Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.
2005,
Pubmed
Curtin,
PARP inhibitors for cancer therapy.
2005,
Pubmed
de Feraudy,
A minority of foci or pan-nuclear apoptotic staining of gammaH2AX in the S phase after UV damage contain DNA double-strand breaks.
2010,
Pubmed
Doksani,
Replicon dynamics, dormant origin firing, and terminal fork integrity after double-strand break formation.
2009,
Pubmed
Durkacz,
The effect of inhibition of (ADP-ribose)n biosynthesis on DNA repair assayed by the nucleoid technique.
1981,
Pubmed
Fachinetti,
Replication termination at eukaryotic chromosomes is mediated by Top2 and occurs at genomic loci containing pausing elements.
2010,
Pubmed
Ge,
Chk1 inhibits replication factory activation but allows dormant origin firing in existing factories.
2010,
Pubmed
Greenfeder,
Replication forks pause at yeast centromeres.
1992,
Pubmed
Hanada,
The structure-specific endonuclease Mus81 contributes to replication restart by generating double-strand DNA breaks.
2007,
Pubmed
Hashimoto,
Rad51 protects nascent DNA from Mre11-dependent degradation and promotes continuous DNA synthesis.
2010,
Pubmed
,
Xenbase
Hassa,
The diverse biological roles of mammalian PARPS, a small but powerful family of poly-ADP-ribose polymerases.
2008,
Pubmed
Higgins,
A model for replication repair in mammalian cells.
1976,
Pubmed
Hsiang,
Arrest of replication forks by drug-stabilized topoisomerase I-DNA cleavable complexes as a mechanism of cell killing by camptothecin.
1989,
Pubmed
Jackson,
Replicon clusters are stable units of chromosome structure: evidence that nuclear organization contributes to the efficient activation and propagation of S phase in human cells.
1998,
Pubmed
Katou,
S-phase checkpoint proteins Tof1 and Mrc1 form a stable replication-pausing complex.
2003,
Pubmed
Koster,
Antitumour drugs impede DNA uncoiling by topoisomerase I.
2007,
Pubmed
Koster,
Cellular strategies for regulating DNA supercoiling: a single-molecule perspective.
2010,
Pubmed
Kummar,
Phase I study of PARP inhibitor ABT-888 in combination with topotecan in adults with refractory solid tumors and lymphomas.
2011,
Pubmed
Lopes,
Electron microscopy methods for studying in vivo DNA replication intermediates.
2009,
Pubmed
Lord,
The DNA damage response and cancer therapy.
2012,
Pubmed
O'Connell,
A genome-wide camptothecin sensitivity screen identifies a mammalian MMS22L-NFKBIL2 complex required for genomic stability.
2010,
Pubmed
Pellicioli,
Activation of Rad53 kinase in response to DNA damage and its effect in modulating phosphorylation of the lagging strand DNA polymerase.
1999,
Pubmed
Petermann,
Chk1 requirement for high global rates of replication fork progression during normal vertebrate S phase.
2006,
Pubmed
Pommier,
Topoisomerase I inhibitors: camptothecins and beyond.
2006,
Pubmed
Postow,
Positive torsional strain causes the formation of a four-way junction at replication forks.
2001,
Pubmed
Räschle,
Mechanism of replication-coupled DNA interstrand crosslink repair.
2008,
Pubmed
,
Xenbase
Reid,
Yeast as a model organism for studying the actions of DNA topoisomerase-targeted drugs.
1998,
Pubmed
Rouleau,
PARP inhibition: PARP1 and beyond.
2010,
Pubmed
Sartori,
Human CtIP promotes DNA end resection.
2007,
Pubmed
Sogo,
Fork reversal and ssDNA accumulation at stalled replication forks owing to checkpoint defects.
2002,
Pubmed
Stojic,
Mismatch repair-dependent G2 checkpoint induced by low doses of SN1 type methylating agents requires the ATR kinase.
2004,
Pubmed
Sugimura,
PARP-1 ensures regulation of replication fork progression by homologous recombination on damaged DNA.
2008,
Pubmed
Teicher,
Next generation topoisomerase I inhibitors: Rationale and biomarker strategies.
2008,
Pubmed
Tentori,
Inhibition of poly(ADP-ribose) polymerase prevents irinotecan-induced intestinal damage and enhances irinotecan/temozolomide efficacy against colon carcinoma.
2006,
Pubmed
Wang,
Mice lacking ADPRT and poly(ADP-ribosyl)ation develop normally but are susceptible to skin disease.
1995,
Pubmed
Zhang,
Poly(ADP-ribose) polymerase and XPF-ERCC1 participate in distinct pathways for the repair of topoisomerase I-induced DNA damage in mammalian cells.
2011,
Pubmed
Zierhut,
Break dosage, cell cycle stage and DNA replication influence DNA double strand break response.
2008,
Pubmed
