Журнал канцерогенеза и мутагенеза

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Mitochondrial Apoptosis Reduces Mutagenesis Regardless Oxidative Stress

Marco Giorgio, Antonella Ruggiero and Pier Giuseppe Pelicci

Upon oxidative stress DNA accumulates adducts and breaks that activate the genome damage response to repair, arrest and eventually suicide the damaged cell. Indeed, challenges with exogenous pro-oxidants increase mutations and reduce survival. Thus, the amounts of pro-oxidants generated by endogenous oxygen metabolism are thought to affect mutation frequency. However, oxidative stress induces cell death, clearing damaged cells. The LacZ reporter system has been used previously to detect mutation rate in flies and mice. Recently, we have measured in vivo spontaneous mutation rate in mice with reduced mitochondrial ROS production and cell death rate, by crossing p66Shc or Cyclophilin D knockout mice, characterized by reduced intracellular concentration of reactive oxygen species and by impaired apoptosis, with a transgenic line harboring multiple copies of the LacZ mutation reporter gene. Results indicated that the inhibition of endogenous oxidative stress and the following induced apoptosis increased genome rearrangements suggesting that specific genetic sets, in precise environments, determine somatic mutations rate.