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High Frequency Induction of CC to TT Tandem Mutations in DNA Repair-proficient Mammalian Cells

Authors

  • Amy M. Skinner,

    1. Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR
    2. Center for Research on Occupational and Environmental Toxicology (CROET), Oregon Health and Sciences University, Portland, OR
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  • Mitchell S. Turker

    Corresponding author
    1. Center for Research on Occupational and Environmental Toxicology (CROET), Oregon Health and Sciences University, Portland, OR
    2. Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR
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* turkerm@ohsu.edu (Mitchell Turker)

Abstract

The CC to TT tandem mutation is induced by UV radiation exposure, though at relatively low frequencies when compared with the more commonly induced C to T mutation. Induction of the tandem mutation by UV is enhanced in mammalian cells with certain genetic deficiencies; however, conditions have not been described in which the frequency of this mutation is enhanced in DNA repair-proficient mammalian cells. For this study, an integrated construct that detects C to T and CC to TT mutations at a single codon in mouse Aprt was used to examine UVB mutagenesis under various conditions. Oxidative stress, in the form of intracellular hydrogen peroxide, increased the frequency of UVB-induced CC to TT mutations. Surprisingly, exposure of the cells to two antioxidants (N-acetylcysteine and trolox), either alone or in combination, also enhanced UVB induction of CC to TT tandem mutations. These results demonstrate, for the first time, that the frequency of UVB-induced CC to TT tandem mutations can be enhanced dramatically in DNA repair-proficient mammalian cells, and suggest that the enhancing effect does not require direct damage to DNA.

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