Bcl2 inhibition of mitochondrial DNA repair

BMC Cancer

Research Article

Maohua Xie¹  Xingming Deng¹  Paul W. Doetsch² 

[1] Division of Cancer Biology, Departments of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, 30322, Atlanta, GA, USA;Division of Cancer Biology, Departments of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, 30322, Atlanta, GA, USA;Biochemistry, Emory University School of Medicine and Winship Cancer Institute of Emory University, 30322, Atlanta, GA, USA;

关键词: Bcl2;    APE1;    Mitochondrial DNA repair;    Mitochondrial DNA mutation;    Carcinogenesis;   

DOI  :  10.1186/s12885-015-1594-1

 received in 2014-08-29, accepted in 2015-08-06,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundAccumulation 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.MethodsQuantitative 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.ResultsBcl2, 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.ConclusionsBased 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.

【 授权许可】

CC BY   
© Xie et al. 2015