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Histone H2AX deficiency causes neurobehavioral deficits and impaired redox homeostasis

ATM drives DNA repair by phosphorylating the histone variant H2AX. While ATM mutations elicit prominent neurobehavioral phenotypes, neural roles for H2AX have been elusive. We report impaired motor learning and balance in H2AX-deficient mice. Mitigation of reactive oxygen species (ROS) with N-acetyl...

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Autores principales: Weyemi, Urbain, Paul, Bindu D., Snowman, Adele M., Jailwala, Parthav, Nussenzweig, Andre, Bonner, William M., Snyder, Solomon H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906610/
https://www.ncbi.nlm.nih.gov/pubmed/29670103
http://dx.doi.org/10.1038/s41467-018-03948-9
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author Weyemi, Urbain
Paul, Bindu D.
Snowman, Adele M.
Jailwala, Parthav
Nussenzweig, Andre
Bonner, William M.
Snyder, Solomon H.
author_facet Weyemi, Urbain
Paul, Bindu D.
Snowman, Adele M.
Jailwala, Parthav
Nussenzweig, Andre
Bonner, William M.
Snyder, Solomon H.
author_sort Weyemi, Urbain
collection PubMed
description ATM drives DNA repair by phosphorylating the histone variant H2AX. While ATM mutations elicit prominent neurobehavioral phenotypes, neural roles for H2AX have been elusive. We report impaired motor learning and balance in H2AX-deficient mice. Mitigation of reactive oxygen species (ROS) with N-acetylcysteine (NAC) reverses the behavioral deficits. Mouse embryonic fibroblasts deficient for H2AX exhibit increased ROS production and failure to activate the antioxidant response pathway controlled by the transcription factor NRF2. The NRF2 targets GCLC and NQO1 are depleted in the striatum of H2AX knockouts, one of the regions most vulnerable to ROS-mediated damage. These findings establish a role for ROS in the behavioral deficits of H2AX knockout mice and reveal a physiologic function of H2AX in mediating influences of oxidative stress on NRF2-transcriptional targets and behavior.
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spelling pubmed-59066102018-04-20 Histone H2AX deficiency causes neurobehavioral deficits and impaired redox homeostasis Weyemi, Urbain Paul, Bindu D. Snowman, Adele M. Jailwala, Parthav Nussenzweig, Andre Bonner, William M. Snyder, Solomon H. Nat Commun Article ATM drives DNA repair by phosphorylating the histone variant H2AX. While ATM mutations elicit prominent neurobehavioral phenotypes, neural roles for H2AX have been elusive. We report impaired motor learning and balance in H2AX-deficient mice. Mitigation of reactive oxygen species (ROS) with N-acetylcysteine (NAC) reverses the behavioral deficits. Mouse embryonic fibroblasts deficient for H2AX exhibit increased ROS production and failure to activate the antioxidant response pathway controlled by the transcription factor NRF2. The NRF2 targets GCLC and NQO1 are depleted in the striatum of H2AX knockouts, one of the regions most vulnerable to ROS-mediated damage. These findings establish a role for ROS in the behavioral deficits of H2AX knockout mice and reveal a physiologic function of H2AX in mediating influences of oxidative stress on NRF2-transcriptional targets and behavior. Nature Publishing Group UK 2018-04-18 /pmc/articles/PMC5906610/ /pubmed/29670103 http://dx.doi.org/10.1038/s41467-018-03948-9 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
Weyemi, Urbain
Paul, Bindu D.
Snowman, Adele M.
Jailwala, Parthav
Nussenzweig, Andre
Bonner, William M.
Snyder, Solomon H.
Histone H2AX deficiency causes neurobehavioral deficits and impaired redox homeostasis
title Histone H2AX deficiency causes neurobehavioral deficits and impaired redox homeostasis
title_full Histone H2AX deficiency causes neurobehavioral deficits and impaired redox homeostasis
title_fullStr Histone H2AX deficiency causes neurobehavioral deficits and impaired redox homeostasis
title_full_unstemmed Histone H2AX deficiency causes neurobehavioral deficits and impaired redox homeostasis
title_short Histone H2AX deficiency causes neurobehavioral deficits and impaired redox homeostasis
title_sort histone h2ax deficiency causes neurobehavioral deficits and impaired redox homeostasis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906610/
https://www.ncbi.nlm.nih.gov/pubmed/29670103
http://dx.doi.org/10.1038/s41467-018-03948-9
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