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Phosphorylation of p65(RelA) on Ser(547) by ATM Represses NF-κB-Dependent Transcription of Specific Genes after Genotoxic Stress
The NF-κB pathway is involved in immune and inflammation responses, proliferation, differentiation and cell death or survival. It is activated by many external stimuli including genotoxic stress. DNA double-strand breaks activate NF-κB in an ATM-dependent manner. In this manuscript, a direct interac...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3371017/ https://www.ncbi.nlm.nih.gov/pubmed/22715377 http://dx.doi.org/10.1371/journal.pone.0038246 |
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author | Sabatel, Hélène Di Valentin, Emmanuel Gloire, Geoffrey Dequiedt, Franck Piette, Jacques Habraken, Yvette |
author_facet | Sabatel, Hélène Di Valentin, Emmanuel Gloire, Geoffrey Dequiedt, Franck Piette, Jacques Habraken, Yvette |
author_sort | Sabatel, Hélène |
collection | PubMed |
description | The NF-κB pathway is involved in immune and inflammation responses, proliferation, differentiation and cell death or survival. It is activated by many external stimuli including genotoxic stress. DNA double-strand breaks activate NF-κB in an ATM-dependent manner. In this manuscript, a direct interaction between p65(RelA) and the N-terminal extremity of ATM is reported. We also report that only one of the five potential ATM-(S/T)Q target sites present in p65, namely Ser(547), is specifically phosphorylated by ATM in vitro. A comparative transcriptomic analysis performed in HEK-293 cells expressing either wild-type HA-p65 or a non-phosphorylatable mutant HA-p65(S547A) identified several differentially transcribed genes after an etoposide treatment (e.g. IL8, A20, SELE). The transcription of these genes is increased in cells expressing the mutant. Substitution of Ser(547) to alanine does not affect p65 binding abilities on the κB site of the IL8 promoter but reduces p65 interaction with HDAC1. Cells expressing p65(S547A) have a higher level of histone H3 acetylated on Lys(9) at the IL8 promoter, which is in agreement with the higher gene induction observed. These results indicate that ATM regulates a sub-set of NF-κB dependent genes after a genotoxic stress by direct phosphorylation of p65. |
format | Online Article Text |
id | pubmed-3371017 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-33710172012-06-19 Phosphorylation of p65(RelA) on Ser(547) by ATM Represses NF-κB-Dependent Transcription of Specific Genes after Genotoxic Stress Sabatel, Hélène Di Valentin, Emmanuel Gloire, Geoffrey Dequiedt, Franck Piette, Jacques Habraken, Yvette PLoS One Research Article The NF-κB pathway is involved in immune and inflammation responses, proliferation, differentiation and cell death or survival. It is activated by many external stimuli including genotoxic stress. DNA double-strand breaks activate NF-κB in an ATM-dependent manner. In this manuscript, a direct interaction between p65(RelA) and the N-terminal extremity of ATM is reported. We also report that only one of the five potential ATM-(S/T)Q target sites present in p65, namely Ser(547), is specifically phosphorylated by ATM in vitro. A comparative transcriptomic analysis performed in HEK-293 cells expressing either wild-type HA-p65 or a non-phosphorylatable mutant HA-p65(S547A) identified several differentially transcribed genes after an etoposide treatment (e.g. IL8, A20, SELE). The transcription of these genes is increased in cells expressing the mutant. Substitution of Ser(547) to alanine does not affect p65 binding abilities on the κB site of the IL8 promoter but reduces p65 interaction with HDAC1. Cells expressing p65(S547A) have a higher level of histone H3 acetylated on Lys(9) at the IL8 promoter, which is in agreement with the higher gene induction observed. These results indicate that ATM regulates a sub-set of NF-κB dependent genes after a genotoxic stress by direct phosphorylation of p65. Public Library of Science 2012-06-08 /pmc/articles/PMC3371017/ /pubmed/22715377 http://dx.doi.org/10.1371/journal.pone.0038246 Text en Sabatel et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Sabatel, Hélène Di Valentin, Emmanuel Gloire, Geoffrey Dequiedt, Franck Piette, Jacques Habraken, Yvette Phosphorylation of p65(RelA) on Ser(547) by ATM Represses NF-κB-Dependent Transcription of Specific Genes after Genotoxic Stress |
title | Phosphorylation of p65(RelA) on Ser(547) by ATM Represses NF-κB-Dependent Transcription of Specific Genes after Genotoxic Stress |
title_full | Phosphorylation of p65(RelA) on Ser(547) by ATM Represses NF-κB-Dependent Transcription of Specific Genes after Genotoxic Stress |
title_fullStr | Phosphorylation of p65(RelA) on Ser(547) by ATM Represses NF-κB-Dependent Transcription of Specific Genes after Genotoxic Stress |
title_full_unstemmed | Phosphorylation of p65(RelA) on Ser(547) by ATM Represses NF-κB-Dependent Transcription of Specific Genes after Genotoxic Stress |
title_short | Phosphorylation of p65(RelA) on Ser(547) by ATM Represses NF-κB-Dependent Transcription of Specific Genes after Genotoxic Stress |
title_sort | phosphorylation of p65(rela) on ser(547) by atm represses nf-κb-dependent transcription of specific genes after genotoxic stress |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3371017/ https://www.ncbi.nlm.nih.gov/pubmed/22715377 http://dx.doi.org/10.1371/journal.pone.0038246 |
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