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

William D. Singer, Lindsey C. Osimiri, Errol C. Friedberg

Research output: Contribution to journalArticle

9 Scopus citations

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 languageEnglish (US)
Pages (from-to)817-823
Number of pages7
JournalDNA repair
Volume12
Issue number10
DOIs
StatePublished - Oct 1 2013

Keywords

  • DNA polymerase kappa
  • Mutagenesis
  • Polk mice
  • Translesion DNA synthesis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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