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Imbalancing the DNA Base Excision Repair Pathway in the Mitochondria; Targeting and Overexpressing N-Methylpurine DNA Glycosylase in Mitochondria Leads to Enhanced Cell Killing¹

Departments of Pediatrics [M. L. F., M. R. K.] and Biochemistry and Molecular Biology [M. L. F., M. R. K.], Herman B. Wells Center for Pediatric Research [M. L. F., M. R. K.], and Department of Microbiology [Y. R. S., M. L. S.], Indiana University School of Medicine, Indianapolis, Indiana 46202

The DNA base excision repair (BER) pathway is responsible for the repair of alkylation and oxidative DNA damage.The short-patch BER pathway, beginning with the simple glycosylase N-methylpurine DNA glycosylase (MPG), is responsible for the removal of damaged bases such as 3-methyladenine and 1,N⁶-ethenoadenine from the DNA after alkylation or oxidative DNA damage. The resulting apurinic site is further processed by the other members in the pathway, resulting in the insertion of the correct nucleotide. If apurinic sites accumulate, they are mutagenic and cytotoxic to the cell. To evaluate its efficacy in sensitizing breast cancer cells to chemotherapy, MPG has been overexpressed in the breast cancer cell line, MDA-MB231. With MPG overexpression, an increase in DNA damage and increased cytotoxicity to methyl methanesulfonate as well as increased apoptosis levels was observed in these cells. Because mitochondrial DNA has been shown to be more sensitive to DNA damage than nuclear DNA, a construct containing mitochondrial-targeted MPG using the human manganese superoxide dismutase mitochondrial-targeting sequence was made. Overexpression of the mitochondrially targeted MPG dramatically increased the breast cancer cells’ sensitivity to methyl methanesulfonate. In conclusion, we believe that the increase in sensitivity to DNA damage by overexpression of nuclear MPG is because of an imbalance in the BER pathway, and an even greater increase in cell sensitivity is observed when mitochondrial DNA is targeted.

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