DNA polymerase iota (
pol iota) is a conserved Y family
enzyme that is implicated in translesion DNA synthesis (TLS) but whose cellular functions remain uncertain. To test the hypothesis that
pol iota performs TLS in cells, we compared UV-induced mutagenesis in primary fibroblasts derived from wild-type mice to mice lacking functional pol eta,
pol iota, or both. A deficiency in mouse
DNA polymerase eta (pol eta) enhanced UV-induced
Hprt mutant frequencies. This enhanced UV-induced mutagenesis and UV-induced mutagenesis in wild-type cells were strongly diminished in cells deficient in
pol iota, indicating that
pol iota participates in the bypass of UV photoproducts in cells. Moreover, a clear strand bias among UV-induced base substitutions was observed in wild-type cells that was diminished in pol eta- and
pol iota-deficient mouse cells and abolished in cells deficient in both
enzymes. These data suggest that these
enzymes bypass UV photoproducts in an asymmetric manner. To determine whether
pol iota status affects
cancer susceptibility, we compared the UV-induced
skin cancer susceptibility of wild-type mice to mice lacking functional pol eta,
pol iota, or both. Although
pol iota deficiency alone had no effect, UV-induced skin
tumors in pol eta-deficient mice developed 4 weeks earlier in mice concomitantly deficient in
pol iota. Collectively, these data reveal functions for
pol iota in bypassing UV photoproducts and in delaying the onset of UV-induced
skin cancer.