Serine-70 phosphorylated Bcl-2 prevents oxidative stress-induced DNA damage by modulating the mitochondrial redox metabolism

  • Nucleic Acids Res. 2020 Dec 16;48(22):12727-12745. doi: 10.1093/nar/gkaa1110.
Stephen Jun Fei Chong  1  2 ,  Kartini Iskandar  1 ,  Jolin Xiao Hui Lai  1 ,  Jianhua Qu  1 ,  Deepika Raman  1 ,  Rebecca Valentin  2 ,  Charles Herbaux  2 ,  Mary Collins  2 ,  Ivan Cherh Chiet Low  1 ,  Thomas Loh  3 ,  Matthew Davids  2 ,  Shazib Pervaiz  1  4  5  6
Affiliations
  • 1. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore.
  • 2. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 3. Department of Otolaryngology, National University of Healthcare System (NUHS), Singapore, Singapore.
  • 4. NUS Graduate School of Integrative Science and Engineering, NUS, Singapore, Singapore.
  • 5. National University Cancer Institute, NUHS, Singapore, Singapore.
  • 6. Faculté de Médecine, Université de Paris, Paris, France.
PMID: 33245769 DOI: 10.1093/nar/gkaa1110
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.

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