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Cellular Depletion of BRD8 Causes p53-Dependent Apoptosis and Induces a DNA Damage Response in Non-Stressed Cells
Regulation of the chromatin state is crucial for biological processes such as the regulation of transcription, DNA replication, and DNA damage repair. Here we show that knockdown of the BRD8 bromodomain protein – a subunit of the p400/Tip60 complex - leads to p21 induction, and concomitant cell cycl...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6147888/ https://www.ncbi.nlm.nih.gov/pubmed/30237520 http://dx.doi.org/10.1038/s41598-018-32323-3 |
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author | Lashgari, Anahita Fauteux, Myriam Maréchal, Alexandre Gaudreau, Luc |
author_facet | Lashgari, Anahita Fauteux, Myriam Maréchal, Alexandre Gaudreau, Luc |
author_sort | Lashgari, Anahita |
collection | PubMed |
description | Regulation of the chromatin state is crucial for biological processes such as the regulation of transcription, DNA replication, and DNA damage repair. Here we show that knockdown of the BRD8 bromodomain protein – a subunit of the p400/Tip60 complex - leads to p21 induction, and concomitant cell cycle arrest in G1/S. We further demonstrate that the p53 transcriptional pathway is activated in BRD8-depleted cells, and this accounts for upregulation of not only p21 but also of pro-apoptotic genes, leading to subsequent apoptosis. Importantly, the DNA damage response (DDR) is induced upon BRD8 depletion, and DNA damage foci are detectable in BRD8-depleted cells under normal growth conditions. Consistently with an activated DDR, we find that in BRD8-depleted cells, the ATM-CHK2 DDR pathway is turned on but, CHK1 proteins levels are severely reduced and replication stress is detectable as enhanced replication protein A (RPA32) phosphorylation levels. Notably, acetylation of histone H4 at K16 (H4K16ac) is reduced in BRD8-depleted cells, suggesting that BRD8 may have a role in the recruitment and/or stabilization of the p400/Tip60 complex within chromatin, thereby facilitating DNA repair. Taken together, our results suggest that BRD8 is involved not only in p53-dependent gene suppression, but also in the maintenance of genome stability. |
format | Online Article Text |
id | pubmed-6147888 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-61478882019-02-12 Cellular Depletion of BRD8 Causes p53-Dependent Apoptosis and Induces a DNA Damage Response in Non-Stressed Cells Lashgari, Anahita Fauteux, Myriam Maréchal, Alexandre Gaudreau, Luc Sci Rep Article Regulation of the chromatin state is crucial for biological processes such as the regulation of transcription, DNA replication, and DNA damage repair. Here we show that knockdown of the BRD8 bromodomain protein – a subunit of the p400/Tip60 complex - leads to p21 induction, and concomitant cell cycle arrest in G1/S. We further demonstrate that the p53 transcriptional pathway is activated in BRD8-depleted cells, and this accounts for upregulation of not only p21 but also of pro-apoptotic genes, leading to subsequent apoptosis. Importantly, the DNA damage response (DDR) is induced upon BRD8 depletion, and DNA damage foci are detectable in BRD8-depleted cells under normal growth conditions. Consistently with an activated DDR, we find that in BRD8-depleted cells, the ATM-CHK2 DDR pathway is turned on but, CHK1 proteins levels are severely reduced and replication stress is detectable as enhanced replication protein A (RPA32) phosphorylation levels. Notably, acetylation of histone H4 at K16 (H4K16ac) is reduced in BRD8-depleted cells, suggesting that BRD8 may have a role in the recruitment and/or stabilization of the p400/Tip60 complex within chromatin, thereby facilitating DNA repair. Taken together, our results suggest that BRD8 is involved not only in p53-dependent gene suppression, but also in the maintenance of genome stability. Nature Publishing Group UK 2018-09-20 /pmc/articles/PMC6147888/ /pubmed/30237520 http://dx.doi.org/10.1038/s41598-018-32323-3 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Lashgari, Anahita Fauteux, Myriam Maréchal, Alexandre Gaudreau, Luc Cellular Depletion of BRD8 Causes p53-Dependent Apoptosis and Induces a DNA Damage Response in Non-Stressed Cells |
title | Cellular Depletion of BRD8 Causes p53-Dependent Apoptosis and Induces a DNA Damage Response in Non-Stressed Cells |
title_full | Cellular Depletion of BRD8 Causes p53-Dependent Apoptosis and Induces a DNA Damage Response in Non-Stressed Cells |
title_fullStr | Cellular Depletion of BRD8 Causes p53-Dependent Apoptosis and Induces a DNA Damage Response in Non-Stressed Cells |
title_full_unstemmed | Cellular Depletion of BRD8 Causes p53-Dependent Apoptosis and Induces a DNA Damage Response in Non-Stressed Cells |
title_short | Cellular Depletion of BRD8 Causes p53-Dependent Apoptosis and Induces a DNA Damage Response in Non-Stressed Cells |
title_sort | cellular depletion of brd8 causes p53-dependent apoptosis and induces a dna damage response in non-stressed cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6147888/ https://www.ncbi.nlm.nih.gov/pubmed/30237520 http://dx.doi.org/10.1038/s41598-018-32323-3 |
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