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.

We thank all the members of the Hanaoka laboratory at Osaka University for their critical discussions and comments. We also thank Kazuo Hara, Department of Pathology, Aichi Medical University, Japan, for valuable discussion about skin lesions.

This work was supported by KAKENHI (Grant-in Aid for Scientific Research) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (17012003 to M.T., 12CE2007 to H.K., and 17013053 to F.H.), by the Human Frontier Science Program, and by Solution Oriented Research for Science and Technology from the Japan Science and Technology Agency. This work was also supported by the Bioarchitect Research Project and the Chemical Biology Project of RIKEN.