UV-B Radiation Induces Epithelial Tumors in Mice Lacking DNA Polymerase η and Mesenchymal Tumors in Mice Deficient for DNA Polymerase ι

ABSTRACT DNA polymerase η (Pol η) is the product of the Polh gene, which is responsible for the group variant of xeroderma pigmentosum, a rare inherited recessive disease which is characterized by susceptibility to sunlight-induced skin cancer. We recently reported in a study of Polh mutant mice that Pol η is involved in the somatic hypermutation of immunoglobulin genes, but the cancer predisposition of Polh −/− mice has not been examined until very recently. Another translesion synthesis polymerase, Pol ι, a Pol η paralog encoded by the Poli gene, is naturally deficient in the 129 mouse strain, and the function of Pol ι is enigmatic. Here, we generated Polh Poli double-deficient mice and compared the tumor susceptibility of them with Polh- or Poli-deficient animals under the same genetic background. While Pol ι deficiency does not influence the UV sensitivity of mouse fibroblasts irrespective of Polh genotype, Polh Poli double-deficient mice show slightly earlier onset of skin tumor formation. Intriguingly, histological diagnosis after chronic treatment with UV light reveals that Pol ι deficiency leads to the formation of mesenchymal tumors, such as sarcomas, that are not observed in Polh −/− mice. These results suggest the involvement of the Pol η and Pol ι proteins in UV-induced skin carcinogenesis.