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Replication fork stalling in WRN-deficient cells is overcome by prompt activation of a MUS81-dependent pathway

Failure to stabilize and properly process stalled replication forks results in chromosome instability, which is a hallmark of cancer cells and several human genetic conditions that are characterized by cancer predisposition. Loss of WRN, a RecQ-like enzyme mutated in the cancer-prone disease Werner...

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Autores principales: Franchitto, Annapaola, Pirzio, Livia Maria, Prosperi, Ennio, Sapora, Orazio, Bignami, Margherita, Pichierri, Pietro
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2568021/
https://www.ncbi.nlm.nih.gov/pubmed/18852298
http://dx.doi.org/10.1083/jcb.200803173
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author Franchitto, Annapaola
Pirzio, Livia Maria
Prosperi, Ennio
Sapora, Orazio
Bignami, Margherita
Pichierri, Pietro
author_facet Franchitto, Annapaola
Pirzio, Livia Maria
Prosperi, Ennio
Sapora, Orazio
Bignami, Margherita
Pichierri, Pietro
author_sort Franchitto, Annapaola
collection PubMed
description Failure to stabilize and properly process stalled replication forks results in chromosome instability, which is a hallmark of cancer cells and several human genetic conditions that are characterized by cancer predisposition. Loss of WRN, a RecQ-like enzyme mutated in the cancer-prone disease Werner syndrome (WS), leads to rapid accumulation of double-strand breaks (DSBs) and proliferating cell nuclear antigen removal from chromatin upon DNA replication arrest. Knockdown of the MUS81 endonuclease in WRN-deficient cells completely prevents the accumulation of DSBs after fork stalling. Also, MUS81 knockdown in WS cells results in reduced chromatin recruitment of recombination enzymes, decreased yield of sister chromatid exchanges, and reduced survival after replication arrest. Thus, we provide novel evidence that WRN is required to avoid accumulation of DSBs and fork collapse after replication perturbation, and that prompt MUS81-dependent generation of DSBs is instrumental for recovery from hydroxyurea-mediated replication arrest under such pathological conditions.
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spelling pubmed-25680212009-04-20 Replication fork stalling in WRN-deficient cells is overcome by prompt activation of a MUS81-dependent pathway Franchitto, Annapaola Pirzio, Livia Maria Prosperi, Ennio Sapora, Orazio Bignami, Margherita Pichierri, Pietro J Cell Biol Research Articles Failure to stabilize and properly process stalled replication forks results in chromosome instability, which is a hallmark of cancer cells and several human genetic conditions that are characterized by cancer predisposition. Loss of WRN, a RecQ-like enzyme mutated in the cancer-prone disease Werner syndrome (WS), leads to rapid accumulation of double-strand breaks (DSBs) and proliferating cell nuclear antigen removal from chromatin upon DNA replication arrest. Knockdown of the MUS81 endonuclease in WRN-deficient cells completely prevents the accumulation of DSBs after fork stalling. Also, MUS81 knockdown in WS cells results in reduced chromatin recruitment of recombination enzymes, decreased yield of sister chromatid exchanges, and reduced survival after replication arrest. Thus, we provide novel evidence that WRN is required to avoid accumulation of DSBs and fork collapse after replication perturbation, and that prompt MUS81-dependent generation of DSBs is instrumental for recovery from hydroxyurea-mediated replication arrest under such pathological conditions. The Rockefeller University Press 2008-10-20 /pmc/articles/PMC2568021/ /pubmed/18852298 http://dx.doi.org/10.1083/jcb.200803173 Text en © 2008 Franchitto et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Franchitto, Annapaola
Pirzio, Livia Maria
Prosperi, Ennio
Sapora, Orazio
Bignami, Margherita
Pichierri, Pietro
Replication fork stalling in WRN-deficient cells is overcome by prompt activation of a MUS81-dependent pathway
title Replication fork stalling in WRN-deficient cells is overcome by prompt activation of a MUS81-dependent pathway
title_full Replication fork stalling in WRN-deficient cells is overcome by prompt activation of a MUS81-dependent pathway
title_fullStr Replication fork stalling in WRN-deficient cells is overcome by prompt activation of a MUS81-dependent pathway
title_full_unstemmed Replication fork stalling in WRN-deficient cells is overcome by prompt activation of a MUS81-dependent pathway
title_short Replication fork stalling in WRN-deficient cells is overcome by prompt activation of a MUS81-dependent pathway
title_sort replication fork stalling in wrn-deficient cells is overcome by prompt activation of a mus81-dependent pathway
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2568021/
https://www.ncbi.nlm.nih.gov/pubmed/18852298
http://dx.doi.org/10.1083/jcb.200803173
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