Increased dietary cholesterol promotes enhanced mutagenesis in DNA polymerase kappa-deficient mice

• Mutation frequency of DNA increased in apoE−/−Polk−/− mouse organs after high cholesterol diet.
• The high cholesterol diet had no effect on mutation frequency of DNA in apoE−/−Polk+/+ mice.
• The mutations mainly consisted of G:C transversions.
• Cholesterol-induced guanine lesions are bypassed by Polκ in an error-free way.

DNA polymerase kappa (Polκ) bypasses planar polycyclic N2-guanine adducts in an error-free manner. Cholesterol derivatives may interact with DNA to form similarly bulky lesions. In accordance, these studies examined whether increased mutagenesis of DNA accompanies hypercholesterolemia in Polk−/− mice. These mice also carried apoE gene knockouts to ensure increased levels of plasma cholesterol following exposure to a high cholesterol diet. The mice carried a reporter transgene (the λ-phage cII gene) for subsequent quantitative analysis of mutagenesis in various tissues. We observed significantly increased mutation frequencies in several organs of apoE−/−Polk−/− mice following a high cholesterol diet, compared to those remaining on a standard diet. Regardless of dietary regime, the mutation frequency in many organs was significantly higher in apoE−/−Polk−/− than in apoE−/−Polk+/+ mice. As expected for polycyclic guanine adducts, the mutations mainly consisted of G:C transversions. The life expectancy of apoE−/−Polk−/− mice maintained on a high cholesterol diet was reduced compared to apoE−/−Polk+/+ mice. Overall, this study demonstrates a role for Polκ in bypass of cholesterol-induced guanine lesions.