Mutation spectrum in UVB-exposed skin epidermis of a mildly-affectedXpg-deficient mouse

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Abstract
A C‐terminal 183 amino acid‐truncated mutation of the mouse Xpg gene (XpgΔex15) gives rise to a partial deficiency in nucleotide excision repair in homozygously affected cells. We studied the effect of this mutation on UVB‐induced mutagenesis in mouse skin, using transgenic mice harboring λ‐phage‐based bacterial lacZ genes as a mutational reporter. UVB increased the lacZ mutant frequency in the epidermis moderately in the homozygous mutant mice, but significantly higher than in the wild‐type or the heterozygous mice, whereas background mutant frequencies were not appreciably different among the three mouse genotypes. Ninety‐eight lacZ mutant sequences isolated from the UVB‐exposed epidermis of the XpgΔex15‐homozygous mice were analyzed and compared with mutant sequences from the wild‐type mice. The spectra of the mutations in the two mouse genotypes were not significantly different, and they were highly UV‐specific. There were frequent C → T transitions at dipyrimidine sites and several CC → TT tandem mutations, although the UV‐specific mutations occurred more frequently at CpG sites in the mutant mice. The distribution of the mutations observed in the lacZ transgene and the preferred sequence context of the UV‐specific C → T mutations (5′‐TC‐3′ > 5′‐CC‐3′ > 5′‐CT‐3′) in the Xpg‐mutant mice were similar to those found in the wild‐type mice. Despite these similarities, we detected a previously unrecognized type of the UV‐induced mutation only in the Xpg mutant (6/98 in the mutation spectrum of the mutant vs. 0/76 in the wild‐type; P = 0.035), which is characterized by multiple base substitutions or frameshifts within a three‐nucleotide sequence containing a dipyrimidine. We propose that this putative new class of mutation, which we refer to as a “triplet mutation”, is characteristic of UV‐induced mutation in an excision‐repair‐deficient background. Environ. Mol. Mutagen., 2006.

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