title: c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: a mechanism for oncogene-induced genetic instability.
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.
authors.affiliation: The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Omid
authors.initials: O
authors.lastname: Vafa
authors.forename: Mark
authors.initials: M
authors.lastname: Wade
authors.forename: Suzanne
authors.initials: S
authors.lastname: Kern
authors.forename: Michelle
authors.initials: M
authors.lastname: Beeche
authors.forename: Tej K
authors.initials: TK
authors.lastname: Pandita
authors.forename: Garret M
authors.initials: GM
authors.lastname: Hampton
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Wahl
mesh_terms: D002478:Cells, Cultured; D004249:DNA Damage; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D020287:In Situ Nick-End Labeling; D016271:Proto-Oncogene Proteins c-myc / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53