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

Feng Wang, Yusuke Saito, Tadahiro Shiomi, Shogo Yamada, Tetsuya Ono, Hironobu Ikehata

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)107-116
Number of pages10
JournalEnvironmental and Molecular Mutagenesis
Volume47
Issue number2
DOIs
Publication statusPublished - 2006 Mar

Keywords

  • Muta mouse
  • NER
  • Skin cancer
  • Transgenic mouse
  • Triplet mutation
  • Xeroderma pigmentosum

ASJC Scopus subject areas

  • Epidemiology
  • Genetics(clinical)
  • Health, Toxicology and Mutagenesis

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