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• W1807926820 abstract "Accumulation of mitochondrial DNA (mtDNA) damage could enhance the frequency of mitochondrial mutations and promote a variety of mitochondria-related diseases, including cancer. However, the mechanism(s) involved are not fully understood. Quantitative extended length PCR was used to compare mtDNA and nDNA damage in human lung H1299 cells expressing WT Bcl2 or vector-only control. mtAPE1 endonuclease activity was analyzed by AP oligonucleotide assay. mtDNA mutation was measured by single molecule PCR. Subcellular localization of Bcl2 and APE1 was analyzed by subcellular fractionation. Bcl2, an anti-apoptotic molecule and oncoprotein, effectively inhibits the endonuclease activity of mitochondrial APE1 (mtAPE1), leading to significant retardation of mtDNA repair and enhanced frequency of mtDNA mutations following exposure of cells to hydrogen peroxide (H2O2) or nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK, a carcinogen in cigarette smoke). Inversely, depletion of endogenous Bcl2 by RNA interference increases mtAPE1 endonuclease activity leading to accelerated mtDNA repair and decreased mtDNA mutation. Higher levels of mtAPE1 were observed in human lung cancer cells than in normal human bronchial epithelial cells (i.e. BEAS-2B). Bcl2 partially co-localizes with APE1 in the mitochondria of human lung cancer cells. Bcl2 directly interacts with mtAPE1 via its BH domains. Removal of any of the BH domains from Bcl2 abolishes Bcl2’s capacity to interact with mtAPE1 as well as its inhibitory effects on mtAPE1 activity and mtDNA repair. Based our findings, we propose that Bcl2 suppression of mtDNA repair occurs through direct interaction with mtAPE1 and inhibition of its endonuclease activity in mitochondria, which may contribute to enhanced mtDNA mutations and carcinogenesis." @default.
• W1807926820 created "2016-06-24" @default.
• W1807926820 creator A5002430008 @default.
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• W1807926820 date "2015-08-13" @default.
• W1807926820 modified "2023-09-27" @default.
• W1807926820 title "Bcl2 inhibition of mitochondrial DNA repair" @default.
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• W1807926820 doi "https://doi.org/10.1186/s12885-015-1594-1" @default.
• W1807926820 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4535531" @default.
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