Mitochondrial DNA Integrity Is Maintained by APE1 in Carcinogen-Induced Colorectal Cancer.

Changes in mitochondrial DNA (mtDNA) integrity have been reported in many cancers; however, the contribution of mtDNA integrity to tumorigenesis is not well understood. We used a transgenic mouse model that is haploinsufficient for the apurinic/apyrimidinic endonuclease 1 () gene, which encodes the base excision repair (BER) enzyme APE1, to determine its role in protecting mtDNA from the effects of azoxymethane (AOM), a carcinogen used to induce colorectal cancer. Repair kinetics of AOM-induced mtDNA damage was evaluated using qPCR after a single AOM dose and a significant induction in mtDNA lesions in colonic crypts from both wild-type (WT) and animals were observed. However, mice had slower repair kinetics in addition to decreased mtDNA abundance. Tumors were also induced using multiple AOM doses, and both WT and animals exhibited significant loss in mtDNA abundance. Surprisingly, no major differences in mtDNA lesions were observed in tumors from WT and animals, whereas a significant increase in nuclear DNA lesions was detected in tumors from mice. Finally, tumors from mice displayed an increased proliferative index and histologic abnormalities. Taken together, these results demonstrate that APE1 is important for preventing changes in mtDNA integrity during AOM-induced colorectal cancer. AOM, a colorectal cancer carcinogen, generates damage to the mitochondrial genome, and the BER enzyme APE1 is required to maintain its integrity. .