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 Citations (Scopus)

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 2013

Fingerprint

Dietary Cholesterol
Mutagenesis
Apolipoproteins E
DNA-Directed DNA Polymerase
Cholesterol
Nutrition
Guanine
Diet
Mutation Rate
Genes
Bacteriophages
DNA
Gene Knockout Techniques
Life Expectancy
Hypercholesterolemia
Transgenes
Tissue
Derivatives
Plasmas
Mutation

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Increased dietary cholesterol promotes enhanced mutagenesis in DNA polymerase kappa-deficient mice. / Singer, William D.; Osimiri, Lindsey C.; Friedberg, Errol C.

In: DNA Repair, Vol. 12, No. 10, 10.2013, p. 817-823.

Research output: Contribution to journalArticle

Singer, William D. ; Osimiri, Lindsey C. ; Friedberg, Errol C. / Increased dietary cholesterol promotes enhanced mutagenesis in DNA polymerase kappa-deficient mice. In: DNA Repair. 2013 ; Vol. 12, No. 10. pp. 817-823.
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