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DNA damage signaling in response to double-strand breaks during mitosis

The signaling cascade initiated in response to DNA double-strand breaks (DSBs) has been extensively investigated in interphase cells. Here, we show that mitotic cells treated with DSB-inducing agents activate a “primary” DNA damage response (DDR) comprised of early signaling events, including activa...

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Detalles Bibliográficos
Autores principales: Giunta, Simona, Belotserkovskaya, Rimma, Jackson, Stephen P.
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2930281/
https://www.ncbi.nlm.nih.gov/pubmed/20660628
http://dx.doi.org/10.1083/jcb.200911156
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author Giunta, Simona
Belotserkovskaya, Rimma
Jackson, Stephen P.
author_facet Giunta, Simona
Belotserkovskaya, Rimma
Jackson, Stephen P.
author_sort Giunta, Simona
collection PubMed
description The signaling cascade initiated in response to DNA double-strand breaks (DSBs) has been extensively investigated in interphase cells. Here, we show that mitotic cells treated with DSB-inducing agents activate a “primary” DNA damage response (DDR) comprised of early signaling events, including activation of the protein kinases ataxia telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PK), histone H2AX phosphorylation together with recruitment of mediator of DNA damage checkpoint 1 (MDC1), and the Mre11–Rad50–Nbs1 (MRN) complex to damage sites. However, mitotic cells display no detectable recruitment of the E3 ubiquitin ligases RNF8 and RNF168, or accumulation of 53BP1 and BRCA1, at DSB sites. Accordingly, we found that DNA-damage signaling is attenuated in mitotic cells, with full DDR activation only ensuing when a DSB-containing mitotic cell enters G1. Finally, we present data suggesting that induction of a primary DDR in mitosis is important because transient inactivation of ATM and DNA-PK renders mitotic cells hypersensitive to DSB-inducing agents.
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spelling pubmed-29302812011-01-26 DNA damage signaling in response to double-strand breaks during mitosis Giunta, Simona Belotserkovskaya, Rimma Jackson, Stephen P. J Cell Biol Research Articles The signaling cascade initiated in response to DNA double-strand breaks (DSBs) has been extensively investigated in interphase cells. Here, we show that mitotic cells treated with DSB-inducing agents activate a “primary” DNA damage response (DDR) comprised of early signaling events, including activation of the protein kinases ataxia telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PK), histone H2AX phosphorylation together with recruitment of mediator of DNA damage checkpoint 1 (MDC1), and the Mre11–Rad50–Nbs1 (MRN) complex to damage sites. However, mitotic cells display no detectable recruitment of the E3 ubiquitin ligases RNF8 and RNF168, or accumulation of 53BP1 and BRCA1, at DSB sites. Accordingly, we found that DNA-damage signaling is attenuated in mitotic cells, with full DDR activation only ensuing when a DSB-containing mitotic cell enters G1. Finally, we present data suggesting that induction of a primary DDR in mitosis is important because transient inactivation of ATM and DNA-PK renders mitotic cells hypersensitive to DSB-inducing agents. The Rockefeller University Press 2010-07-26 /pmc/articles/PMC2930281/ /pubmed/20660628 http://dx.doi.org/10.1083/jcb.200911156 Text en © 2009 Giunta 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
Giunta, Simona
Belotserkovskaya, Rimma
Jackson, Stephen P.
DNA damage signaling in response to double-strand breaks during mitosis
title DNA damage signaling in response to double-strand breaks during mitosis
title_full DNA damage signaling in response to double-strand breaks during mitosis
title_fullStr DNA damage signaling in response to double-strand breaks during mitosis
title_full_unstemmed DNA damage signaling in response to double-strand breaks during mitosis
title_short DNA damage signaling in response to double-strand breaks during mitosis
title_sort dna damage signaling in response to double-strand breaks during mitosis
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2930281/
https://www.ncbi.nlm.nih.gov/pubmed/20660628
http://dx.doi.org/10.1083/jcb.200911156
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