Journal Article

Murine Prkdc Polymorphisms Impact DNA-PKcs Function

Ramaiah, Lila, Bailey, Susan M, Desaintes, Christian, Weil, Michael M, Dregalla, Ryan C, Fabre, Kristin M, Ullrich, Robert L

2011

Overview

Polymorphic variants of DNA repair genes can increase the carcinogenic potential of exposure to ionizing radiation. Two single nucleotide polymorphisms (SNPs) in Prkdc, the gene encoding the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), have been identified in BALB/c mice and linked to reduced DNA-PKcs activity and mammary cancer susceptibility. We examined three additional mouse strains to better define the roles of the BALB/c Prkdc SNPs (R2140C and M3844V). One is a congenic strain (C.B6) that has the C57BL/6 Prkdc allele on a BALB/c background, and the other is a congenic strain (B6.C) that has the BALB/c variant Prkdc allele on a C57BL/6 background. We also examined the LEWES mouse strain, which possesses only one of the BALB/c Prkdc SNPs (M3844V). Our results demonstrate that both Prkdc SNPs are responsible for deficient DNA-PKcs protein expression, DNA repair and telomere function, while the LEWES SNP affects only DNA-PKcs expression and repair capacity. These studies provide insight into the separation of function between the two BALB/c SNPs as well as direct evidence that SNPs positioned within Prkdc can significantly influence DNA-PKcs function involving DNA repair capacity, telomere end-capping, and potentially cancer susceptibility.

• Publisher: The Radiation Research Society,Radiation Research Society
• Subject: Alleles / Animals / Breast cancer / Cancer / Cell cycle / DNA / DNA - genetics / DNA repair / DNA Repair - physiology / DNA-Activated Protein Kinase - genetics / DNA-Binding Proteins - genetics / Fibroblasts / Irradiation / Mice / Mice, Inbred BALB C / Mice, Inbred C57BL / Mice, Transgenic / Mutation - genetics / Nuclear Proteins - genetics / Polymerase chain reaction / Polymorphism, Single Nucleotide - genetics / REGULAR ARTICLES / Species Specificity / Telomeres