Ogusucu R, et al. (2009) Superoxide Dismutase 1-mediated Production of Ethanol- and DNA-derived Radicals in Yeasts Challenged with Hydrogen Peroxide: MOLECULAR INSIGHTS INTO THE GENOME INSTABILITY OF PEROXIREDOXIN-NULL STRAINS. J Biol Chem 284(9):5546-56
Abstract: Peroxiredoxins are receiving increasing attention as defenders against oxidative damage and sensors of hydrogen peroxide-mediated signaling events. In the yeast Saccharomyces cerevisiae, deletion of one or more isoforms of the peroxiredoxins is not lethal but compromises genome stability by mechanisms that remain under scrutiny. Here, we show that cytosolic peroxiredoxin-null cells (tsa1tsa2) are more resistant to hydrogen peroxide than WT cells, and consume it faster under fermentative conditions. Also, tsa1tsa2 cells produced higher yields of the 1-hydroxyethyl radical from oxidation of the glucose metabolite ethanol, as proved by spin-trapping experiments. A major role for Fenton chemistry in radical formation was excluded by comparing WT and tsa1tsa2 cells with respect to their levels of total and chelatable metal ions, and of radical produced in the presence of chelators. The main route for 1-hydroxyethyl radical formation was ascribed to the peroxidase activity of Cu,Zn-superoxide dismutase (Sod1), whose expression and activity increased about five- and two-fold, respectively, in tsa1tsa2 compared to WT cells. Accordingly, over-expression of human Sod1 in WT yeasts led to increased 1-hydroxyethyl radical production. Relevantly, tsa1tsa2 cells challenged with hydrogen peroxide contained higher levels of DNA-derived radicals and adducts as monitored by immuno-spin trapping and incorporation of 14C from glucose into DNA, respectively. The results indicate that part of hydrogen peroxide consumption by tsa1tsa2 cells is mediated by induced Sod1, which oxidizes ethanol to the 1-hydroxyethyl radical, which, in turn, leads to increased DNA damage. Overall, our studies provide a pathway to account for the hypermutability of peroxiredoxin-null strains.
|Status: Published||Type: Journal Article||PubMed ID: 19106092|
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