Genetic linkage between Pol iota deficiency and increased susceptibility to lung tumors in mice

Pol iota is a member of the Y-family DNA polymerases, characterized by their capacity for translesion DNA synthesis and low fidelity base incorporation, and has therefore been assumed to play important roles in mutagenesis and carcinogenesis. In fact, the mouse Pol iota gene is located within the Par2 (pulmonary adenoma resistance 2) locus on distal chromosome 18, which we have identified as a major susceptibility locus regarding urethane induction of pulmonary adenomas. Indeed, Pol iota has been suggested to be a candidate for Par2 from both the genetic and biological standpoints. Taking advantage of 129X1/SvJ mice naturally deficient in Pol iota due to a nonsense mutation within the coding region of the gene, we here analyzed urethane-treated (A/J x 129X1/SvJ)F(1) x A/J backcross and (A/J x 129X1/SvJ)F(2) intercross mice and observed the defective 129X1/SvJ Pol iota allele to be genetically linked with an increased susceptibility to lung tumors relative to the A/J allele. Thus, among the already known mouse Pol iota alleles, the defective 129X1/SvJ allele is associated exclusively with the highest susceptibility to lung tumors. The result indicates a possibility that the Pol iota gene may participate in error-free repair of damaged DNA and prevention of lung tumor development.