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- Title
ROS-generating NADPH oxidase NOX4 is a critical mediator in oncogenic H-Ras-induced DNA damage and subsequent senescence.
- Authors
Weyemi, U; Lagente-Chevallier, O; Boufraqech, M; Prenois, F; Courtin, F; Caillou, B; Talbot, M; Dardalhon, M; Al Ghuzlan, A; Bidart, J-M; Schlumberger, M; Dupuy, C
- Abstract
Activated Ras oncogene induces DNA-damage response by triggering reactive oxygen species (ROS) production and this is critical for oncogene-induced senescence. Until now, little connections between oncogene expression, ROS-generating NADPH oxidases and DNA-damage response have emerged from different studies. Here we report that H-RasV12 positively regulates the NADPH oxidase system NOX4-p22phox that produces H2O2. Knocking down the NADPH oxidase with small interference RNA decreases H-RasV12-induced DNA-damage response detected by γ-H2A.X foci analysis. Using HyPer, a specific probe for H2O2, we detected an increase in H2O2 in the nucleus correlated with NOX4-p22phox perinuclear localization. DNA damage response can be caused not only by H-RasV12-driven accumulation of ROS but also by a replicative stress due to a sustained oncogenic signal. Interestingly, NOX4 downregulation by siRNA abrogated H-RasV12 regulation of CDC6 expression, an essential regulator of DNA replication. Moreover, senescence markers, such as senescence-associated heterochromatin foci, PML bodies, HP1β foci and p21 expression, induced under H-RasV12 activation were decreased with NOX4 inactivation. Taken together, our data indicate that NADPH oxidase NOX4 is a critical mediator in oncogenic H-RasV12-induced DNA-damage response and subsequent senescence.
- Subjects
RAS oncogenes; DNA damage; NADPH oxidase; REACTIVE oxygen species; SMALL interfering RNA; HETEROCHROMATIN; P21 gene; CELLULAR aging
- Publication
Oncogene, 2012, Vol 31, Issue 9, p1117
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/onc.2011.327