Increased dietary cholesterol promotes enhanced mutagenesis in DNA polymerase kappa-deficient mice.
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.
Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9072, United States.
William D
WD
Singer
Lindsey C
LC
Osimiri
Errol C
EC
Friedberg
D000818:Animals; D002791:Cholesterol, Dietary / Q000008:administration & dosage* / Q000097:blood; D004249:DNA Damage; D004259:DNA-Directed DNA Polymerase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006937:Hypercholesterolemia / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016296:Mutagenesis; D059645:Mutation Rate; D017354:Point Mutation; D000099270:Y-Family DNA Polymerases
D002791:Cholesterol, Dietary; D004259:DNA-Directed DNA Polymerase; C498613:Polk protein, mouse; D000099270:Y-Family DNA Polymerases
DNA polymerase kappa; Mutagenesis; Polk(−/−) mice; Translesion DNA synthesis