ROS-generating NADPH oxidase NOX4 is a critical mediator in oncogenic H-Ras-induced DNA damage and subsequent senescence

U. Weyemi, O. Lagente-Chevallier, M. Boufraqech, F. Prenois, F. Courtin, B. Caillou, M. Talbot, M. Dardalhon, A. Al Ghuzlan, J. M. Bidart, M. Schlumberger, C. Dupuy

Research output: Contribution to journalArticlepeer-review

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-p22 phox that produces H 2 O 2. 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 H 2 O 2, we detected an increase in H 2 O 2 in the nucleus correlated with NOX4-p22 phox 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.

Original languageEnglish (US)
Pages (from-to)1117-1129
Number of pages13
JournalOncogene
Volume31
Issue number9
DOIs
StatePublished - Mar 1 2012
Externally publishedYes

Keywords

  • DNA damage
  • NADPH oxidase NOX4
  • ROS
  • oncogenic H-RasV12
  • senescence

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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