@article{6e0f4af776cb4f44ab429035e7e789be,
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.",
author = "Omid Vafa and Mark Wade and Suzanne Kern and Michelle Beeche and Pandita, {Tej K.} and Hampton, {Garret M.} and Wahl, {Geoffrey M.}",
note = "Funding Information: We thank Dean Felsher (Stanford University) for providing NHF-MycER and NHF-BABE and HPV E6 derivatives and Rat1aMycER, John Petrini (University of Wisconsin) for antibodies against hMre11 and p95, Bill Bonner (NIH) for antibodies against phosphorylated H2AX, David Chambers and Kelly Hardwicke (Salk Institute) for their assistance in flow cytometry analyses, Sonu Dhar (Columbia University) for PCC analyses, Dr. Gretchen Jimenez (Salk Institute/Vical) for independent confirmation of several results, Lisa Sapinoso (GINRF) for excellent technical assistance, Dr Franck Toledo (Salk Institute) for comments on the manuscript, Dr. David J. Lockhart (GINRF) for advice and suggestions on analysis of the microarray data and for providing us with version 4.5 of the NfueGGo filtering software, and Ms. Ta'Neashia Morrell (Salk Institute) for administrative assistance. This work was supported by the California Research Program from the UC Regents (O.V.) and by a grant from the National Institutes of Health (G.M.W.).",
year = "2002",
doi = "10.1016/S1097-2765(02)00520-8",
language = "English (US)",
volume = "9",
pages = "1031--1044",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "5",
}