Remarkable induction of UV-signature mutations at the 3'-cytosine of dipyrimidine sites except at 5'-TCG-3' in the UVB-exposed skin epidermis of xeroderma pigmentosum variant model mice

Hironobu Ikehata, Yumin Chang, Masayuki Yokoi, Masayuki Yamamoto, Fumio Hanaoka

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

The human POLH gene is responsible for the variant form of xeroderma pigmentosum (XP-V), a genetic disease highly susceptible to cancer on sun-exposed skin areas, and encodes DNA polymerase η (polη), which is specialized for translesion DNA synthesis (TLS) of UV-induced DNA photolesions. We constructed polη-deficient mice transgenic with lacZ mutational reporter genes to study the effect of Polh null mutation (Polh-/-) on mutagenesis in the skin after UVB irradiation. UVB induced lacZ mutations with remarkably higher frequency in the Polh-/- epidermis and dermis than in the wild-type (Polh+/+) and heterozygote. DNA sequences of a hundred lacZ mutants isolated from the epidermis of four UVB-exposed Polh-/- mice were determined and compared with mutant sequences from irradiated Polh+/+ mice. The spectra of the mutations in the two genotypes were both highly UV-specific and dominated by C→T transitions at dipyrimidines, namely UV-signature mutations. However, sequence preferences of the occurrence of UV-signature mutations were quite different between the two genotypes: the mutations occurred at a higher frequency preferentially at the 5'-TCG-3' sequence context than at the other dipyrimidine contexts in the Polh+/+ epidermis, whereas the mutations were induced remarkably and exclusively at the 3'-cytosine of almost all dipyrimidine contexts with no preference for 5'-TCG-3' in the Polh-/- epidermis. In addition, in Polh-/- mice, a small but remarkable fraction of G→T transversions was also observed exclusively at the 3'-cytosine of dipyrimidine sites, strongly suggesting that these transversions resulted not from oxidative damage but from UV photolesions. These results would reflect the characteristics of the error-prone TLS functioning in the bypass of UV photolesions in the absence of polη, which would be mediated by mechanisms based on the two-step model of TLS. On the other hand, the deamination model would explain well the mutation spectrum in the Polh+/+ genotype.

Original languageEnglish
Pages (from-to)112-122
Number of pages11
JournalDNA Repair
Volume22
DOIs
Publication statusPublished - 2014 Oct

Keywords

  • DNA polymerase η
  • Deamination model
  • Translesion DNA synthesis
  • Two-step model
  • UVB-induced mutation
  • Xeroderma pigmentosum variant

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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