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BRCA1 and Tip60 determine the cellular response to ultraviolet irradiation through distinct pathways

The histone acetyltransferase Tip60 regulates the apoptotic response to ultraviolet (UV) irradiation. A previously suggested mechanism for this regulation consists of the ability of Tip60 to coactivate transcription by the tumor suppressor p53. In this study, we show that Tip60 is required for the e...

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Detalles Bibliográficos
Autores principales: Kranz, Dominique, Dohmesen, Christoph, Dobbelstein, Matthias
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2447902/
https://www.ncbi.nlm.nih.gov/pubmed/18625847
http://dx.doi.org/10.1083/jcb.200712014
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author Kranz, Dominique
Dohmesen, Christoph
Dobbelstein, Matthias
author_facet Kranz, Dominique
Dohmesen, Christoph
Dobbelstein, Matthias
author_sort Kranz, Dominique
collection PubMed
description The histone acetyltransferase Tip60 regulates the apoptotic response to ultraviolet (UV) irradiation. A previously suggested mechanism for this regulation consists of the ability of Tip60 to coactivate transcription by the tumor suppressor p53. In this study, we show that Tip60 is required for the early DNA damage response (DDR) to UV, including the phosphorylation of histone 2AX, c-Jun N-terminal kinases (JNKs), and ataxia telangiectasia–related substrates. In contrast, p53 was not required for UV-induced DDR. Rather, p53 accumulation by either knockdown of Mdm2 or addition of an Mdm2 inhibitor, Nutlin-3, before irradiation strongly attenuated the UV-induced DDR and increased cell survival. This protective effect of preaccumulated p53 was mediated, at least in part, by the increased expression of CDKN1A/p21, subsequent down-regulation of BRCA1, and impaired JNK activation accompanied by decreased association of replication protein A with chromatin. We conclude that Tip60 enables UV-induced DDR signaling even in the absence of p53, whereas preaccumulated p53 suppresses UV-induced DDR by reducing the levels of BRCA1.
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spelling pubmed-24479022009-01-14 BRCA1 and Tip60 determine the cellular response to ultraviolet irradiation through distinct pathways Kranz, Dominique Dohmesen, Christoph Dobbelstein, Matthias J Cell Biol Research Articles The histone acetyltransferase Tip60 regulates the apoptotic response to ultraviolet (UV) irradiation. A previously suggested mechanism for this regulation consists of the ability of Tip60 to coactivate transcription by the tumor suppressor p53. In this study, we show that Tip60 is required for the early DNA damage response (DDR) to UV, including the phosphorylation of histone 2AX, c-Jun N-terminal kinases (JNKs), and ataxia telangiectasia–related substrates. In contrast, p53 was not required for UV-induced DDR. Rather, p53 accumulation by either knockdown of Mdm2 or addition of an Mdm2 inhibitor, Nutlin-3, before irradiation strongly attenuated the UV-induced DDR and increased cell survival. This protective effect of preaccumulated p53 was mediated, at least in part, by the increased expression of CDKN1A/p21, subsequent down-regulation of BRCA1, and impaired JNK activation accompanied by decreased association of replication protein A with chromatin. We conclude that Tip60 enables UV-induced DDR signaling even in the absence of p53, whereas preaccumulated p53 suppresses UV-induced DDR by reducing the levels of BRCA1. The Rockefeller University Press 2008-07-14 /pmc/articles/PMC2447902/ /pubmed/18625847 http://dx.doi.org/10.1083/jcb.200712014 Text en © 2008 Kranz 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
Kranz, Dominique
Dohmesen, Christoph
Dobbelstein, Matthias
BRCA1 and Tip60 determine the cellular response to ultraviolet irradiation through distinct pathways
title BRCA1 and Tip60 determine the cellular response to ultraviolet irradiation through distinct pathways
title_full BRCA1 and Tip60 determine the cellular response to ultraviolet irradiation through distinct pathways
title_fullStr BRCA1 and Tip60 determine the cellular response to ultraviolet irradiation through distinct pathways
title_full_unstemmed BRCA1 and Tip60 determine the cellular response to ultraviolet irradiation through distinct pathways
title_short BRCA1 and Tip60 determine the cellular response to ultraviolet irradiation through distinct pathways
title_sort brca1 and tip60 determine the cellular response to ultraviolet irradiation through distinct pathways
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2447902/
https://www.ncbi.nlm.nih.gov/pubmed/18625847
http://dx.doi.org/10.1083/jcb.200712014
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