DNA damage induces reactive oxygen species generation through the H2AX-Nox1/Rac1 pathway

DNA damage induces reactive oxygen species generation through the H2AX-Nox1/Rac1 pathway

The DNA damage response (DDR) cascade and ROS (reactive oxygen species) signaling are both involved in the induction of cell death after DNA damage, but a mechanistic link between these two pathways has not been clearly elucidated. This study demonstrates that ROS induction after treatment of cells...

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Main Authors: Kang, M A, So, E-Y, Simons, A L, Spitz, D R, Ouchi, T
Format: Online
Language:English
Published: Nature Publishing Group 2012
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3270268/
id pubmed-3270268
recordtype oai_dc
spelling pubmed-32702682012-02-02 DNA damage induces reactive oxygen species generation through the H2AX-Nox1/Rac1 pathway Kang, M A So, E-Y Simons, A L Spitz, D R Ouchi, T Original Article The DNA damage response (DDR) cascade and ROS (reactive oxygen species) signaling are both involved in the induction of cell death after DNA damage, but a mechanistic link between these two pathways has not been clearly elucidated. This study demonstrates that ROS induction after treatment of cells with neocarzinostatin (NCS), an ionizing radiation mimetic, is at least partly mediated by increasing histone H2AX. Increased levels of ROS and cell death induced by H2AX overexpression alone or DNA damage leading to H2AX accumulation are reduced by treating cells with the antioxidant N-Acetyl-L-Cysteine (NAC), the NADP(H) oxidase (Nox) inhibitor DPI, expression of Rac1N17, and knockdown of Nox1, but not Nox4, indicating that induction of ROS by H2AX is mediated through Nox1 and Rac1 GTPase. H2AX increases Nox1 activity partly by reducing the interaction between a Nox1 activator NOXA1 and its inhibitor 14-3-3zeta. These results point to a novel role of histone H2AX that regulates Nox1-mediated ROS generation after DNA damage. Nature Publishing Group 2012-01 2012-01-12 /pmc/articles/PMC3270268/ /pubmed/22237206 http://dx.doi.org/10.1038/cddis.2011.134 Text en Copyright © 2012 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Kang, M A
So, E-Y
Simons, A L
Spitz, D R
Ouchi, T
spellingShingle Kang, M A
So, E-Y
Simons, A L
Spitz, D R
Ouchi, T
DNA damage induces reactive oxygen species generation through the H2AX-Nox1/Rac1 pathway
author_facet Kang, M A
So, E-Y
Simons, A L
Spitz, D R
Ouchi, T
author_sort Kang, M A
title DNA damage induces reactive oxygen species generation through the H2AX-Nox1/Rac1 pathway
title_short DNA damage induces reactive oxygen species generation through the H2AX-Nox1/Rac1 pathway
title_full DNA damage induces reactive oxygen species generation through the H2AX-Nox1/Rac1 pathway
title_fullStr DNA damage induces reactive oxygen species generation through the H2AX-Nox1/Rac1 pathway
title_full_unstemmed DNA damage induces reactive oxygen species generation through the H2AX-Nox1/Rac1 pathway
title_sort dna damage induces reactive oxygen species generation through the h2ax-nox1/rac1 pathway
description The DNA damage response (DDR) cascade and ROS (reactive oxygen species) signaling are both involved in the induction of cell death after DNA damage, but a mechanistic link between these two pathways has not been clearly elucidated. This study demonstrates that ROS induction after treatment of cells with neocarzinostatin (NCS), an ionizing radiation mimetic, is at least partly mediated by increasing histone H2AX. Increased levels of ROS and cell death induced by H2AX overexpression alone or DNA damage leading to H2AX accumulation are reduced by treating cells with the antioxidant N-Acetyl-L-Cysteine (NAC), the NADP(H) oxidase (Nox) inhibitor DPI, expression of Rac1N17, and knockdown of Nox1, but not Nox4, indicating that induction of ROS by H2AX is mediated through Nox1 and Rac1 GTPase. H2AX increases Nox1 activity partly by reducing the interaction between a Nox1 activator NOXA1 and its inhibitor 14-3-3zeta. These results point to a novel role of histone H2AX that regulates Nox1-mediated ROS generation after DNA damage.
publisher Nature Publishing Group
publishDate 2012
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3270268/
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