Base excision repair deficiency caused by polymerase beta haploinsufficiency: accelerated DNA damage and increased mutational response to carcinogens.

Abstract:

The base excision repair pathway (BER) is believed to maintain genomic integrity by repairing DNA damage arising spontaneously or induced by oxidizing and alkylating agents. To establish the role of DNA polymerase beta (beta-pol) in BER and beta-pol-dependent BER in maintaining genomic stability, we have measured the impact of a gene-targeted disruption in the beta-pol gene on DNA repair capacity and on in vivo sensitivity to carcinogens. We have extensively phenotyped the DNA beta-pol heterozygous (beta-pol(+/-)) mouse as expressing approximately 50% less beta-pol mRNA and protein and as exhibiting an equivalent reduction in the specific activity of beta-pol. We measured BER activity by in vitro G:U mismatch and (8-OH)G:C repair and find that there is a significant reduction in the ability of extracts from beta-pol(+/-) mice to repair these types of DNA damage. In vivo, the beta-pol(+/-) mice sustain higher levels of DNA single-strand breaks as well as increased chromosomal aberrations as compared with beta-pol(+/+) littermates. Additionally, we show that reduction in beta-pol expression and BER activity results in increased mutagenicity of dimethyl sulfate as evidenced by a 2-fold increase in LacI mutation frequency. Importantly, the beta-pol(+/-) mice do not exhibit increased sensitivity to DNA damage induced by N-nitroso-N-ethylurea, ionizing radiation, or UV radiation, which induce damage processed by alternative repair pathways, demonstrating that this model is specifically a BER-deficient model.

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