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Identification of universal and cell-type specific p53 DNA binding

BACKGROUND: The tumor suppressor p53 is a major regulator of the DNA damage response and has been suggested to selectively bind and activate cell-type specific gene expression programs. However recent studies and meta-analyses of genomic data propose largely uniform, and condition independent p53 bi...

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Autores principales: Hafner, Antonina, Kublo, Lyubov, Tsabar, Michael, Lahav, Galit, Stewart-Ornstein, Jacob
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027055/
https://www.ncbi.nlm.nih.gov/pubmed/32070277
http://dx.doi.org/10.1186/s12860-020-00251-8
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author Hafner, Antonina
Kublo, Lyubov
Tsabar, Michael
Lahav, Galit
Stewart-Ornstein, Jacob
author_facet Hafner, Antonina
Kublo, Lyubov
Tsabar, Michael
Lahav, Galit
Stewart-Ornstein, Jacob
author_sort Hafner, Antonina
collection PubMed
description BACKGROUND: The tumor suppressor p53 is a major regulator of the DNA damage response and has been suggested to selectively bind and activate cell-type specific gene expression programs. However recent studies and meta-analyses of genomic data propose largely uniform, and condition independent p53 binding and thus question the selective and cell-type dependent function of p53. RESULTS: To systematically assess the cell-type specificity of p53, we measured its association with DNA in 12 p53 wild-type cancer cell lines, from a range of epithelial linages, in response to ionizing radiation. We found that the majority of bound sites were occupied across all cell lines, however we also identified a subset of binding sites that were specific to one or a few cell lines. Unlike the shared p53-bound genome, which was not dependent on chromatin accessibility, the association of p53 with these atypical binding sites was well explained by chromatin accessibility and could be modulated by forcing cell state changes such as the epithelial-to-mesenchymal transition. CONCLUSIONS: Our study reconciles previous conflicting views in the p53 field, by demonstrating that although the majority of p53 DNA binding is conserved across cell types, there is a small set of cell line specific binding sites that depend on cell state.
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spelling pubmed-70270552020-02-25 Identification of universal and cell-type specific p53 DNA binding Hafner, Antonina Kublo, Lyubov Tsabar, Michael Lahav, Galit Stewart-Ornstein, Jacob BMC Mol Cell Biol Research Article BACKGROUND: The tumor suppressor p53 is a major regulator of the DNA damage response and has been suggested to selectively bind and activate cell-type specific gene expression programs. However recent studies and meta-analyses of genomic data propose largely uniform, and condition independent p53 binding and thus question the selective and cell-type dependent function of p53. RESULTS: To systematically assess the cell-type specificity of p53, we measured its association with DNA in 12 p53 wild-type cancer cell lines, from a range of epithelial linages, in response to ionizing radiation. We found that the majority of bound sites were occupied across all cell lines, however we also identified a subset of binding sites that were specific to one or a few cell lines. Unlike the shared p53-bound genome, which was not dependent on chromatin accessibility, the association of p53 with these atypical binding sites was well explained by chromatin accessibility and could be modulated by forcing cell state changes such as the epithelial-to-mesenchymal transition. CONCLUSIONS: Our study reconciles previous conflicting views in the p53 field, by demonstrating that although the majority of p53 DNA binding is conserved across cell types, there is a small set of cell line specific binding sites that depend on cell state. BioMed Central 2020-02-18 /pmc/articles/PMC7027055/ /pubmed/32070277 http://dx.doi.org/10.1186/s12860-020-00251-8 Text en © The Author(s) 2020 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Hafner, Antonina
Kublo, Lyubov
Tsabar, Michael
Lahav, Galit
Stewart-Ornstein, Jacob
Identification of universal and cell-type specific p53 DNA binding
title Identification of universal and cell-type specific p53 DNA binding
title_full Identification of universal and cell-type specific p53 DNA binding
title_fullStr Identification of universal and cell-type specific p53 DNA binding
title_full_unstemmed Identification of universal and cell-type specific p53 DNA binding
title_short Identification of universal and cell-type specific p53 DNA binding
title_sort identification of universal and cell-type specific p53 dna binding
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027055/
https://www.ncbi.nlm.nih.gov/pubmed/32070277
http://dx.doi.org/10.1186/s12860-020-00251-8
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