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Doxorubicin impacts chromatin binding of HMGB1, Histone H1 and retinoic acid receptor

Doxorubicin (Dox), a widely used anticancer DNA-binding drug, affects chromatin in multiple ways, and these effects contribute to both its efficacy and its dose-limiting side effects, especially cardiotoxicity. Here, we studied the effects of Dox on the chromatin binding of the architectural protein...

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Autores principales: Bosire, Rosevalentine, Fadel, Lina, Mocsár, Gábor, Nánási, Péter, Sen, Pialy, Sharma, Anshu Kumar, Naseem, Muhammad Umair, Kovács, Attila, Kugel, Jennifer, Kroemer, Guido, Vámosi, György, Szabó, Gábor
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9110345/
https://www.ncbi.nlm.nih.gov/pubmed/35577872
http://dx.doi.org/10.1038/s41598-022-11994-z
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author Bosire, Rosevalentine
Fadel, Lina
Mocsár, Gábor
Nánási, Péter
Sen, Pialy
Sharma, Anshu Kumar
Naseem, Muhammad Umair
Kovács, Attila
Kugel, Jennifer
Kroemer, Guido
Vámosi, György
Szabó, Gábor
author_facet Bosire, Rosevalentine
Fadel, Lina
Mocsár, Gábor
Nánási, Péter
Sen, Pialy
Sharma, Anshu Kumar
Naseem, Muhammad Umair
Kovács, Attila
Kugel, Jennifer
Kroemer, Guido
Vámosi, György
Szabó, Gábor
author_sort Bosire, Rosevalentine
collection PubMed
description Doxorubicin (Dox), a widely used anticancer DNA-binding drug, affects chromatin in multiple ways, and these effects contribute to both its efficacy and its dose-limiting side effects, especially cardiotoxicity. Here, we studied the effects of Dox on the chromatin binding of the architectural proteins high mobility group B1 (HMGB1) and the linker histone H1, and the transcription factor retinoic acid receptor (RARα) by fluorescence recovery after photobleaching (FRAP) and fluorescence correlation spectroscopy (FCS) in live cells. At lower doses, Dox increased the binding of HMGB1 to DNA while decreasing the binding of the linker histone H1. At higher doses that correspond to the peak plasma concentrations achieved during chemotherapy, Dox reduced the binding of HMGB1 as well. This biphasic effect is interpreted in terms of a hierarchy of competition between the ligands involved and Dox-induced local conformational changes of nucleosome-free DNA. Combined, FRAP and FCS mobility data suggest that Dox decreases the overall binding of RARα to DNA, an effect that was only partially overcome by agonist binding. The intertwined interactions described are likely to contribute to both the effects and side effects of Dox.
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spelling pubmed-91103452022-05-18 Doxorubicin impacts chromatin binding of HMGB1, Histone H1 and retinoic acid receptor Bosire, Rosevalentine Fadel, Lina Mocsár, Gábor Nánási, Péter Sen, Pialy Sharma, Anshu Kumar Naseem, Muhammad Umair Kovács, Attila Kugel, Jennifer Kroemer, Guido Vámosi, György Szabó, Gábor Sci Rep Article Doxorubicin (Dox), a widely used anticancer DNA-binding drug, affects chromatin in multiple ways, and these effects contribute to both its efficacy and its dose-limiting side effects, especially cardiotoxicity. Here, we studied the effects of Dox on the chromatin binding of the architectural proteins high mobility group B1 (HMGB1) and the linker histone H1, and the transcription factor retinoic acid receptor (RARα) by fluorescence recovery after photobleaching (FRAP) and fluorescence correlation spectroscopy (FCS) in live cells. At lower doses, Dox increased the binding of HMGB1 to DNA while decreasing the binding of the linker histone H1. At higher doses that correspond to the peak plasma concentrations achieved during chemotherapy, Dox reduced the binding of HMGB1 as well. This biphasic effect is interpreted in terms of a hierarchy of competition between the ligands involved and Dox-induced local conformational changes of nucleosome-free DNA. Combined, FRAP and FCS mobility data suggest that Dox decreases the overall binding of RARα to DNA, an effect that was only partially overcome by agonist binding. The intertwined interactions described are likely to contribute to both the effects and side effects of Dox. Nature Publishing Group UK 2022-05-16 /pmc/articles/PMC9110345/ /pubmed/35577872 http://dx.doi.org/10.1038/s41598-022-11994-z Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Bosire, Rosevalentine
Fadel, Lina
Mocsár, Gábor
Nánási, Péter
Sen, Pialy
Sharma, Anshu Kumar
Naseem, Muhammad Umair
Kovács, Attila
Kugel, Jennifer
Kroemer, Guido
Vámosi, György
Szabó, Gábor
Doxorubicin impacts chromatin binding of HMGB1, Histone H1 and retinoic acid receptor
title Doxorubicin impacts chromatin binding of HMGB1, Histone H1 and retinoic acid receptor
title_full Doxorubicin impacts chromatin binding of HMGB1, Histone H1 and retinoic acid receptor
title_fullStr Doxorubicin impacts chromatin binding of HMGB1, Histone H1 and retinoic acid receptor
title_full_unstemmed Doxorubicin impacts chromatin binding of HMGB1, Histone H1 and retinoic acid receptor
title_short Doxorubicin impacts chromatin binding of HMGB1, Histone H1 and retinoic acid receptor
title_sort doxorubicin impacts chromatin binding of hmgb1, histone h1 and retinoic acid receptor
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9110345/
https://www.ncbi.nlm.nih.gov/pubmed/35577872
http://dx.doi.org/10.1038/s41598-022-11994-z
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