Additive roles of XPA and MSH2 genes in UVB-induced skin tumorigenesis in mice

We have made xeroderma pigmentosum group A gene (XPA)-knockout mice (XPA^-/- mice). The XPA^-/- mice had no detectable activity for nucleotide excision repair (NER) and showed a high incidence of UVB-induced skin tumorigenesis. We have also found that cell lines derived from skin cancers in UVB-irradiated XPA^-/- mice become tolerant to UV-irradiation and showed abnormal UV-induced cell cycle checkpoints and decreased mismatch repair (MMR) activity. These results suggested that the MMR-downregulation may help cells escape killing by UV-irradiation and thus MMR-deficient clones are selected for during the tumorigenic transformation of XPA^-/- cells. In this report, we examined whether the incidence of UVB-induced skin tumorigenesis is enhanced in XPA^-/-MSH2^-/-, XPA^-/- and MSH2^-/- mice when compared with that in wild-type mice. Our results indicate that the MSH2-deficiency caused a high incidence of spontaneous and UVB-induced skin tumorigenesis and the XPA and MSH2 genes have additive roles in the UV-induced skin tumorigenesis.