UV-B radiation induces epithelial tumors in mice lacking DNA polymerase eta and mesenchymal tumors in mice deficient for DNA polymerase iota

Mol Cell Biol. 2006 Oct;26(20):7696-706. doi: 10.1128/MCB.01076-06. Epub 2006 Aug 5.

Abstract

DNA polymerase eta (Pol eta) 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 eta 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 iota, a Pol eta paralog encoded by the Poli gene, is naturally deficient in the 129 mouse strain, and the function of Pol iota 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 iota 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 iota 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 eta and Pol iota proteins in UV-induced skin carcinogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Cell Transformation, Neoplastic / pathology
  • Cell Transformation, Neoplastic / radiation effects*
  • Cells, Cultured
  • DNA-Directed DNA Polymerase / deficiency*
  • DNA-Directed DNA Polymerase / genetics
  • DNA-Directed DNA Polymerase / metabolism
  • Epithelial Cells / enzymology*
  • Epithelial Cells / pathology
  • Epithelial Cells / radiation effects*
  • Fibroblasts
  • Mesoderm / enzymology
  • Mesoderm / pathology*
  • Mice
  • Mice, Knockout
  • Mutation / genetics
  • Skin Neoplasms / enzymology*
  • Skin Neoplasms / genetics
  • Skin Neoplasms / pathology

Substances

  • DNA polymerase iota
  • DNA-Directed DNA Polymerase
  • Rad30 protein