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CtIP-dependent DNA resection is required for DNA damage checkpoint maintenance but not initiation

To prevent accumulation of mutations, cells respond to DNA lesions by blocking cell cycle progression and initiating DNA repair. Homology-directed repair of DNA breaks requires CtIP-dependent resection of the DNA ends, which is thought to play a key role in activation of ATR (ataxia telangiectasia m...

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Autores principales: Kousholt, Arne Nedergaard, Fugger, Kasper, Hoffmann, Saskia, Larsen, Brian D., Menzel, Tobias, Sartori, Alessandro A., Sørensen, Claus Storgaard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3384414/
https://www.ncbi.nlm.nih.gov/pubmed/22733999
http://dx.doi.org/10.1083/jcb.201111065
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author Kousholt, Arne Nedergaard
Fugger, Kasper
Hoffmann, Saskia
Larsen, Brian D.
Menzel, Tobias
Sartori, Alessandro A.
Sørensen, Claus Storgaard
author_facet Kousholt, Arne Nedergaard
Fugger, Kasper
Hoffmann, Saskia
Larsen, Brian D.
Menzel, Tobias
Sartori, Alessandro A.
Sørensen, Claus Storgaard
author_sort Kousholt, Arne Nedergaard
collection PubMed
description To prevent accumulation of mutations, cells respond to DNA lesions by blocking cell cycle progression and initiating DNA repair. Homology-directed repair of DNA breaks requires CtIP-dependent resection of the DNA ends, which is thought to play a key role in activation of ATR (ataxia telangiectasia mutated and Rad3 related) and CHK1 kinases to induce the cell cycle checkpoint. In this paper, we show that CHK1 was rapidly and robustly activated before detectable end resection. Moreover, we show that the key resection factor CtIP was dispensable for initial ATR–CHK1 activation after DNA damage by camptothecin and ionizing radiation. In contrast, we find that DNA end resection was critically required for sustained ATR–CHK1 checkpoint signaling and for maintaining both the intra–S- and G2-phase checkpoints. Consequently, resection-deficient cells entered mitosis with persistent DNA damage. In conclusion, we have uncovered a temporal program of checkpoint activation, where CtIP-dependent DNA end resection is required for sustained checkpoint signaling.
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spelling pubmed-33844142012-12-25 CtIP-dependent DNA resection is required for DNA damage checkpoint maintenance but not initiation Kousholt, Arne Nedergaard Fugger, Kasper Hoffmann, Saskia Larsen, Brian D. Menzel, Tobias Sartori, Alessandro A. Sørensen, Claus Storgaard J Cell Biol Research Articles To prevent accumulation of mutations, cells respond to DNA lesions by blocking cell cycle progression and initiating DNA repair. Homology-directed repair of DNA breaks requires CtIP-dependent resection of the DNA ends, which is thought to play a key role in activation of ATR (ataxia telangiectasia mutated and Rad3 related) and CHK1 kinases to induce the cell cycle checkpoint. In this paper, we show that CHK1 was rapidly and robustly activated before detectable end resection. Moreover, we show that the key resection factor CtIP was dispensable for initial ATR–CHK1 activation after DNA damage by camptothecin and ionizing radiation. In contrast, we find that DNA end resection was critically required for sustained ATR–CHK1 checkpoint signaling and for maintaining both the intra–S- and G2-phase checkpoints. Consequently, resection-deficient cells entered mitosis with persistent DNA damage. In conclusion, we have uncovered a temporal program of checkpoint activation, where CtIP-dependent DNA end resection is required for sustained checkpoint signaling. The Rockefeller University Press 2012-06-25 /pmc/articles/PMC3384414/ /pubmed/22733999 http://dx.doi.org/10.1083/jcb.201111065 Text en © 2012 Kousholt 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.rupress.org/terms). 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
Kousholt, Arne Nedergaard
Fugger, Kasper
Hoffmann, Saskia
Larsen, Brian D.
Menzel, Tobias
Sartori, Alessandro A.
Sørensen, Claus Storgaard
CtIP-dependent DNA resection is required for DNA damage checkpoint maintenance but not initiation
title CtIP-dependent DNA resection is required for DNA damage checkpoint maintenance but not initiation
title_full CtIP-dependent DNA resection is required for DNA damage checkpoint maintenance but not initiation
title_fullStr CtIP-dependent DNA resection is required for DNA damage checkpoint maintenance but not initiation
title_full_unstemmed CtIP-dependent DNA resection is required for DNA damage checkpoint maintenance but not initiation
title_short CtIP-dependent DNA resection is required for DNA damage checkpoint maintenance but not initiation
title_sort ctip-dependent dna resection is required for dna damage checkpoint maintenance but not initiation
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3384414/
https://www.ncbi.nlm.nih.gov/pubmed/22733999
http://dx.doi.org/10.1083/jcb.201111065
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