Mutation frequencies and spectra in DNA polymerase η-deficient mice

The low-fidelity polymerase eta (pol eta) is required for bypass of UV-induced pyrimidine dimers inserting adenine nucleotides opposite these lesions. Mutations in the pol eta gene are responsible for the genetic defect in xeroderma pigmentosum variant patients. To study if the lack of pol eta significantly elevates spontaneous mutation frequency in various organs and tissues of the mouse, we crossed pol eta-deficient mice with transgenic mice harboring a chromosomally integrated lacZ-plasmid reporter construct. In cultured embryonic fibroblasts from the lacZ-polq(-/-) mice, 2.5 J/m(2) UV irradiation induced similar to 5-fold more mutations than in cells from lacZ control mice, in which an similar to 3-fold increase in mutation frequency was found compared with the normal level. Whereas untreated cells harbored mainly 1-bp deletions, LTV induced both transitions and transversions, with the latter type more highly represented in the pol eta-null cells than in the controls. No difference in mutation induction between the pol eta-null cells and the wild-type cells was observed after treatment with N-ethyl-N-nitrosourea. Having shown the validity of the lacZ model to accurately identify pol eta-associated mutagenesis, we then determined the mutant frequency at the lacZ locus in liver, spleen, and small intestine of 12-month-old animals. No differences were found between pol eta-null, heterozygons, or littermate control mice. We conclude that the pol eta defect is specific for UV damage and has no effect on in vivo mutagenesis in mice.