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Mitochondrial DNA Integrity Is Maintained by APE1 in Carcinogen-Induced Colorectal Cancer
Joan Ballista-Hernández1, Margaly Martínez-Ferrer2, Roman Vélez3
1Department of Pharmacology and Toxicology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.
Abstract:
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 (Apex1+/-) 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 Apex1+/-animals were observed. However, Apex1+/- mice had slower repair kinetics in addition to decreased mtDNA abundance. Tumors were also induced using multiple AOM doses, and both WT and Apex1+/-animals exhibited significant loss in mtDNA abundance. Surprisingly, no major differences in mtDNA lesions were observed in tumors from WT and Apex1+/- animals, whereas a significant increase in nuclear DNA lesions was detected in tumors from Apex1+/- mice. Finally, tumors from Apex1+/- 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.Implications: AOM, a colorectal cancer carcinogen, generates damage to the mitochondrial genome, and the BER enzyme APE1 is required to maintain its integrity. Mol Cancer Res; 15(7); 831-41. ©2017 AACR.
Insights
The base excision repair enzyme APE1 is crucial for maintaining mitochondrial DNA (mtDNA) integrity against damage from azoxymethane (AOM), a colorectal cancer carcinogen. Impaired APE1 function leads to increased nuclear DNA damage and tumor development.
Area of Science:
- Mitochondrial biology
- Cancer research
- DNA repair mechanisms
Background:
- Mitochondrial DNA (mtDNA) integrity alterations are observed in cancers, but their role in tumorigenesis is unclear.
- The base excision repair (BER) enzyme APE1 plays a role in DNA repair.
Purpose of the Study:
- To investigate the role of APE1 in protecting mtDNA from damage induced by azoxymethane (AOM), a colorectal cancer carcinogen.
- To determine the impact of APE1 deficiency on AOM-induced colorectal tumorigenesis.
Main Methods:
- Utilized a transgenic mouse model haploinsufficient for the apurinic/apyrimidinic endonuclease 1 (Apex1) gene.
- Assessed mtDNA damage and repair kinetics using qPCR after AOM exposure.
- Analyzed mtDNA and nuclear DNA lesions, mtDNA abundance, and tumor characteristics in wild-type (WT) and Apex1+/- mice.
Main Results:
- Apex1+/- mice exhibited slower repair kinetics and decreased mtDNA abundance following AOM exposure.
- Both WT and Apex1+/- mice showed significant loss in mtDNA abundance in tumors.
- Tumors from Apex1+/- mice displayed increased nuclear DNA lesions, higher proliferation, and abnormal histology, despite similar mtDNA lesions compared to WT.
Conclusions:
- APE1 is essential for maintaining mtDNA integrity during AOM-induced colorectal cancer.
- APE1 deficiency contributes to colorectal tumorigenesis through increased nuclear DNA damage and altered cellular proliferation.