The error-prone DNA polymerase [iota] provides quantitative resistance to lung tumorigenesis and mutagenesis in mice

Opposite undamaged nucleotide T, DNA polymerase [iota] (Pol[iota]) preferentially incorporates G rather than A, violating the Watson-Crick rule. Although the actual biological role of Pol[iota] remains enigmatic, we have identified its coding gene as a candidate for pulmonary adenoma resistance 2 (Par2), a mouse quantitative trait locus modulating chemically induced lung tumor susceptibility. Notably, the most tumor-sensitive Par2 allele possessed by the 129X1/SvJ mouse is associated with a loss-of-function mutation in Pol[iota]. To determine whether the nonfunctional Pol[iota] is responsible for the 129X1/SvJ-specific Par2 phenotype, we knocked out Pol[iota] in a C57BL/6J mouse carrying a less tumor-sensitive Par2 allele. Disruption of the C57BL/6J Pol[iota] conferred 129X1/SvJ-like sensitivity on the C57BL/6J Par2 locus and increased the in vivo mutation frequency in the lung, providing definitive proof that Pol[iota] causes the Par2 effect and inhibits tumorigenesis and mutagenesis, despite its extreme replication infidelity.