Role of APE1 in the Repair of DNA Lesions Induced by Axozymethane in Mouse Liver

Base Excision Repair (BER) is a critical process for genomic maintenance, and deficiencies in this process has been linked to premature aging, metabolic defects and cancer.  Azoxymethane (AOM) is a commonly used carcinogen for the study of cancer in rodents and the liver plays an important role in its bioactivation. AOM induces DNA adducts that can lead to mutations and carcinogenesis. In BER, APE1 is responsible for the processing of the cytotoxic abasic sites among other DNA lesions. In mice, homozygous deletion of the Apex1 gene (which encodes APEl) is embryonic lethal but heterozygous animals (Apex1^+/-) have a normal lifespan. Our aim was to study the role of APE1 in the repair of DNA lesions induced by AOM in the liver.  We isolated DNA from 6-month-old C57BL/6 WT and Apex1^+/- mice that were treated with a single AOM dose (10 mg/kg) and sacrificed 24, 48 and 72 hours after treatment.  To quantify nuclear DNA (nDNA) lesions in liver tissue we applied a PCR based assay (QPCR).   Our data show partial repair of nDNA lesions in both WT and Apex1^+/- mice sacrificed at 48h after AOM injection. Lesions persisted and were not fully repaired 72 hours after treatment in both strains as compared to their respective saline treated controls. A two tailed ANOVA analysis showed no significant differences between genotypes. These results are in contrast with previous results indicating that AOM-induced nDNA lesions are efficiently repaired in colonic crypts, suggesting that liver is a major target of AOM. Supported by R25GM061838, 2G12RR003051 and U54CA096297.