Frequent recovery of triplet mutations in UVB-exposed skin epidermis of Xpc-knockout mice

Hironobu Ikehata, Yusuke Saito, Fumitaka Yanase, Toshio Mori, Osamu Nikaido, Tetsuya Ono

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

Mutations of the Xpc gene cause a deficiency in global genome repair, a subpathway of nucleotide excision repair (NER), in mammalian cells. We used transgenic mice harboring the λ-phage-based lacZ mutational reporter gene to study the effect of an Xpc null mutation (Xpc-/-) on damage induction, repair and mutagenesis in mouse skin epidermis after UVB irradiation. UVB induced equal amounts of cyclobutane pyrimidine dimers (CPDs) and pyrimidine(6-4)pyrimidone photoproducts (64PPs) in mouse skin epidermis of Xpc-/- and wild-type mice. CPDs were not significantly removed in either of the mouse genotypes by 12 h after irradiation, whereas removal of 64PPs was observed in the wild-type. Irradiation with 300 and 400 J/m2 UVB increased the lacZ mutant frequency in the Xpc-/- epidermis to at least twice as high as in the wild-type. Ninety-nine lacZ mutants isolated from the UVB-exposed epidermis of Xpc-/-mice were analyzed and compared with mutant sequences from irradiated wild-type mice. The spectra of the mutations in the two genotypes were both highly UV-specific and similar in the dominance of C → T transitions at dipyrimidine sites; however, Xpc-/- mice had a higher frequency of two-base tandem substitutions, including CC → TT mutations, three-base tandem substitutions and double base substitutions that were separated by one unchanged base in a three-base sequence (alternating mutations). These tandem/alternating mutations included a remarkably large number of triplet mutations, a recently reported, novel type of UV-specific mutation, characterized by multiple base substitutions or frameshifts within a three-nucleotide sequence containing a dipyrimidine. We concluded that the triplet mutation is a UV-specific mutation that preferably occurs in NER deficient genetic backgrounds.

Original languageEnglish
Pages (from-to)82-93
Number of pages12
JournalDNA Repair
Volume6
Issue number1
DOIs
Publication statusPublished - 2007 Jan 4
Externally publishedYes

Keywords

  • Skin cancer
  • Transgenic mouse
  • Triplet mutation
  • UVB
  • XPC
  • Xeroderma pigmentosum

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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