DNA damage induces reactive oxygen species generation through the H2AX-Nox1/Rac1 pathway |
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| Authors: | M A Kang E-Y So A L Simons D R Spitz T Ouchi |
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| Institution: | 1Department of Molecular Biosciences, IBIS Program, Northwestern University, Evanston, IL 60201, USA;2Department of Medicine, Systems Biology Program, NUHS, University of Chicago, Evanston, IL 60201, USA;3Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA;4Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA |
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| Abstract: | 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. |
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| Keywords: | DNA damage H2AX Nox1 Rac1 ROS |
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