Mutation spectrum in UVB-exposed skin epidermis of a mildly-affected Xpg-deficient mouse.
A C-terminal 183 amino acid-truncated mutation of the mouse Xpg gene (XpgDeltaex15) 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 lambda-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 XpgDeltaex15-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.
Wang
Feng
F
Department of Radiotherapy, Graduate School of Medicine, Tohoku University, Sendai 980-8575, Japan.
Saito
Yusuke
Y
Shiomi
Tadahiro
T
Yamada
Shogo
S
Ono
Tetsuya
T
Ikehata
Hironobu
H
D000818:Animals; D004195:Disease Models, Animal; D004307:Dose-Response Relationship, Radiation; D004817:Epidermis / Q000528:radiation effects*; D005091:Exons / Q000235:genetics; D007763:Lac Operon; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D012867:Skin / Q000528:radiation effects*; D012878:Skin Neoplasms / Q000209:etiology; D014466:Ultraviolet Rays; D014983:Xeroderma Pigmentosum / Q000235:genetics*