Abstract
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.
Original language | English (US) |
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Pages (from-to) | 817-823 |
Number of pages | 7 |
Journal | DNA repair |
Volume | 12 |
Issue number | 10 |
DOIs | |
State | Published - Oct 2013 |
Keywords
- DNA polymerase kappa
- Mutagenesis
- Polk mice
- Translesion DNA synthesis
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology