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

• Published in: DNA repair Vol. 12; no. 10; pp. 817 - 823
• Main Authors: Singer, William D., Osimiri, Lindsey C., Friedberg, Errol C.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-10-2013
• Subjects: Animals; Cholesterol, Dietary - administration & dosage; Cholesterol, Dietary - blood; DNA Damage; DNA polymerase kappa; DNA-Directed DNA Polymerase - deficiency; DNA-Directed DNA Polymerase - genetics; DNA-Directed DNA Polymerase - metabolism; DNA-Directed DNA Polymerase - physiology; Hypercholesterolemia - genetics; Hypercholesterolemia - metabolism; Mice; Mice, Knockout; Mutagenesis; Mutation Rate; Point Mutation; Polk−/− mice; Translesion DNA synthesis; DNA polymerase kappa; Translesion DNA synthesis; Polk−/− mice; Mutagenesis; Polk(−/−) mice
• ISSN: 1568-7864; 1568-7856
• DOI: 10.1016/j.dnarep.2013.07.010

•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.