ROS-generating NADPH oxidase NOX4 is a critical mediator in oncogenic H-Ras-induced DNA damage and subsequent senescence
Open accessAbstract
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.
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ROS can damage DNA directly or through oxidative lesions that increase replication fork collapse by preventing its progression, thereby exacerbating the formation of DNA breaks and DDR activation.
“ROS can damage DNA directly or through oxidative lesions that increase replication fork collapse by preventing its progression, thereby exacerbating the formation of DNA breaks and DDR activation [121,122].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [122]
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References 47 · Cited by 285
Research works printed but not linked: 1
- Vafa O Wade M Kern S Beeche M Pandita TK Hampton GM 2002 c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: a mechanism for oncogene-induced genetic instability Mol Cell 9 1031 1044 12049739
- 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.
- Affiliations
- Université Paris-Sud (FR)
- Institut Gustave Roussy (FR)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Dupuy, C
- Venue
- Oncogene
- Published
- 2011-08-15
- Volume
- 31
- Issue
- 9
- Pages
- 1117-1129
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC3307059
- OpenAlex
- W2065621982
- Cited by
- 285
- References
- 47
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 16 · 2023: 17 · 2022: 13 · 2021: 21 · 2020: 21 · 2019: 27 · 2018: 26 · 2017: 20 · 2016: 22 · 2015: 25 · 2014: 25 · 2013: 20 · 2012: 19
- FWCI
- 13.96
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (unspecified)
- Locations
- Oncogene (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Association pour la Recherche sur le Cancer
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Ligue Contre le Cancer
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- NOX4, NADPH oxidase, H-Ras V12, oncogenic Ras, reactive oxygen species, hydrogen peroxide, DNA damage response, oncogene-induced senescence, replicative stress, CDC6, DNA replication, senescence-associated heterochromatin foci, PML bodies, HP1β, p21
- MeSH terms
- NADPH Oxidase 4, Chromobox Protein Homolog 5, DNA Damage, Humans, Hydrogen Peroxide, Oxidation-Reduction, Proto-Oncogene Proteins p21(ras), Cellular Senescence, Reactive Oxygen Species, NADPH Oxidases, Cell Cycle Checkpoints
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