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c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: a mechanism for
Omid Vafa1, Mark Wade, Suzanne Kern
1The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Abstract:
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.
Insights
Oncogene activation, like c-Myc, causes DNA damage and reactive oxygen species (ROS) in cells. Antioxidants can mitigate this damage, suggesting a role in cancer progression.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- Oncogene overexpression, such as c-Myc, is known to activate p53.
- The precise signals linking oncogene activation to p53 activation remain unclear.
- Hyperproliferative signals are hypothesized to mediate this activation through metabolic perturbations and DNA damage.
Purpose of the Study:
- To investigate if oncogene-induced hyperproliferative signals cause metabolic perturbations leading to DNA damage.
- To determine the role of reactive oxygen species (ROS) in this process.
- To understand how deregulated c-Myc affects the DNA damage response and cell survival.
Main Methods:
- Biochemical assays
- Cytological analysis
- Cell cycle analysis
- Global gene expression profiling
- Treatment with antioxidants
Main Results:
- Brief c-Myc activation induced DNA damage and ROS in human fibroblasts before S phase, without triggering apoptosis.
- Deregulated c-Myc impaired the p53-mediated DNA damage response, allowing cells with damaged DNA to proliferate.
- Antioxidant treatment reduced ROS, DNA damage, and p53 activation, improving cell survival.
Conclusions:
- Oncogene activation can directly induce DNA damage and metabolic perturbations, including ROS production.
- Dysregulation of the DNA damage response by oncogenes accelerates tumor progression through genetic instability.
- Targeting ROS may offer a therapeutic strategy to counteract oncogene-driven cancer development.