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PMID: 22237206 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Cell death & disease ·Vol. 3 ·2012-01-12 ·Pages e249

Kang MA, So EY, Simons AL, Spitz DR, Ouchi T

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.

MeSH Terms
14-3-3 Proteins/genetics,metabolism Acetylcysteine/pharmacology Adaptor Proteins, Signal Transducing Adaptor Proteins, Vesicular Transport/antagonists & inhibitors,genetics,metabolism Antioxidants/pharmacology Cell Death Cell Line, Tumor Cytotoxins/toxicity DNA Damage Flow Cytometry Gene Expression/drug effects Histones/genetics,metabolism Humans NADPH Oxidase 1 NADPH Oxidases/antagonists & inhibitors,genetics,metabolism Phosphorylation Plasmids Reactive Oxygen Species/metabolism Signal Transduction/drug effects,genetics Transfection Zinostatin/toxicity rac1 GTP-Binding Protein/genetics,metabolism
Chemicals
14-3-3 Proteins Adaptor Proteins, Signal Transducing Adaptor Proteins, Vesicular Transport Antioxidants Cytotoxins H2AX protein, human Histones NOXA1 protein, human RAC1 protein, human Reactive Oxygen Species Zinostatin NADPH Oxidase 1 NADPH Oxidases NOX1 protein, human rac1 GTP-Binding Protein Acetylcysteine
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Kang M A
Department of Molecular Biosciences, IBIS Program, Northwestern University, Evanston, IL 60201, USA.
So E-Y
Simons A L
Spitz D R
Ouchi T
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Article Info
Journal
Cell death & disease
Abbr.
Cell Death Dis
ISSN
2041-4889
DOI
10.1038/cddis.2011.134
Published
2012-01-12
Epub
2012-00-12
Pages
e249
Language
English
Region
England
NLM ID
101524092
PMCID
PMC3270268
Subset
IM
Grants
NCI NIH HHS · R01CA133114 · United States
NCI NIH HHS · K01 CA134941 · United States
NCI NIH HHS · R01 CA133114 · United States
NCI NIH HHS · R01 CA90631 · United States
NCI NIH HHS · R01 CA090631 · United States
NCI NIH HHS · R01CA79892 · United States
NCI NIH HHS · T32 CA078586 · United States
NCI NIH HHS · R01 CA079892 · United States
NCI NIH HHS · K01CA134941 · United States
External Links
PubMed source DOI: 10.1038/cddis.2011.134 PMC Full Text View journal details
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