c-Myc Can Induce DNA Damage, Increase Reactive Oxygen Species, and Mitigate p53 Function
Open accessAbstract
Oncogene overexpression activates p53 by a mechanism posited to involve uncharacterized hyperproliferative signals. We determined whether such signals produce metabolic perturbations that generate DNA damage, a known p53 inducer. Biochemical, cytological, cell cycle, and global gene expression analyses revealed that brief c-Myc activation can induce DNA damage prior to S phase in normal human fibroblasts. Damage correlated with induction of reactive oxygen species (ROS) without induction of apoptosis. Deregulated c-Myc partially disabled the p53-mediated DNA damage response, enabling cells with damaged genomes to enter the cycle, resulting in poor clonogenic survival. An antioxidant reduced ROS, decreased DNA damage and p53 activation, and improved survival. We propose that oncogene activation can induce DNA damage and override damage controls, thereby accelerating tumor progression via genetic instability.
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Established oncogenes K-RAS and c-MYC induce intracellular ROS and have been shown to stabilize Nrf2.
“Moreover, established oncogenes such as K-RAS and c-MYC, which had been previously demonstrated to induce intracellular ROS56,57, have been recently shown to stabilize Nrf258.”
From ROS in cancer therapy: the bright side of the moon (2020) · cites this paper as [57]
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- Authors
- Vafa, O., Wade, M., Kern, S., Beeche, M., Pandita, T. K., Hampton, G. M., & Wahl, G. M.
- Affiliations
- Salk Institute for Biological Studies (US)
- Genomics Institute of the Novartis Research Foundation (US)
- Columbia University (US)
- Corresponding author
- Wahl, Geoffrey M.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2002-05
- Volume
- 9
- Issue
- 5
- Pages
- 1031-1044
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W1965009601
- Cited by
- 876
- References
- 13
- Citations by year
- 2026: 20 · 2025: 26 · 2024: 28 · 2023: 39 · 2022: 32 · 2021: 43 · 2020: 29 · 2019: 25 · 2018: 36 · 2017: 36 · 2016: 34 · 2015: 37 · 2014: 49 · 2013: 47 · 2012: 41
- FWCI
- 16.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- c-Myc, p53, DNA damage, reactive oxygen species, DNA damage response, oncogene activation, cell cycle, clonogenic survival, antioxidants, genomic instability, tumor progression, fibroblasts
- MeSH terms
- Cells, Cultured, DNA Damage, Fibroblasts, Gene Expression Regulation, Humans, Tumor Suppressor Protein p53, Proto-Oncogene Proteins c-myc, Reactive Oxygen Species, In Situ Nick-End Labeling
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