Please use this identifier to cite or link to this item: https://doi.org/10.1093/nar/gkaa1110
Title: Serine-70 phosphorylated Bcl-2 prevents oxidative stress-induced DNA damage by modulating the mitochondrial redox metabolism
Authors: Chong, S.J.F.
Iskandar, K. 
Lai, J.X.H. 
Qu, J. 
Raman, D. 
Valentin, R.
Herbaux, C.
Collins, M.
Low, I.C.C. 
Loh, T.
Davids, M.
Pervaiz, S. 
Issue Date: 2020
Publisher: Oxford University Press
Citation: Chong, S.J.F., Iskandar, K., Lai, J.X.H., Qu, J., Raman, D., Valentin, R., Herbaux, C., Collins, M., Low, I.C.C., Loh, T., Davids, M., Pervaiz, S. (2020). Serine-70 phosphorylated Bcl-2 prevents oxidative stress-induced DNA damage by modulating the mitochondrial redox metabolism. Nucleic Acids Research 48 (22) : 12727-12745. ScholarBank@NUS Repository. https://doi.org/10.1093/nar/gkaa1110
Rights: Attribution-NonCommercial 4.0 International
Abstract: Bcl-2 phosphorylation at serine-70 (S70pBcl2) confers resistance against drug-induced apoptosis. Nevertheless, its specific mechanism in driving drug-resistance remains unclear. We present evidence that S70pBcl2 promotes cancer cell survival by acting as a redox sensor and modulator to prevent oxidative stress-induced DNA damage and execution. Increased S70pBcl2 levels are inversely correlated with DNA damage in chronic lymphocytic leukemia (CLL) and lymphoma patient-derived primary cells as well as in reactive oxygen species (ROS)- or chemotherapeutic drug-treated cell lines. Bioinformatic analyses suggest that S70pBcl2 is associated with lower median overall survival in lymphoma patients. Empirically, sustained expression of the redox-sensitive S70pBcl2 prevents oxidative stress-induced DNA damage and cell death by suppressing mitochondrial ROS production. Using cell lines and lymphoma primary cells, we further demonstrate that S70pBcl2 reduces the interaction of Bcl-2 with the mitochondrial complex-IV subunit-5A, thereby reducing mitochondrial complex-IV activity, respiration and ROS production. Notably, targeting S70pBcl2 with the phosphatase activator, FTY720, is accompanied by an enhanced drug-induced DNA damage and cell death in CLL primary cells. Collectively, we provide a novel facet of the anti-apoptotic Bcl-2 by demonstrating that its phosphorylation at serine-70 functions as a redox sensor to prevent drug-induced oxidative stress-mediated DNA damage and execution with potential therapeutic implications. © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.
Source Title: Nucleic Acids Research
URI: https://scholarbank.nus.edu.sg/handle/10635/199239
ISSN: 0305-1048
DOI: 10.1093/nar/gkaa1110
Rights: Attribution-NonCommercial 4.0 International
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