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

Stephen Jun Fei Chong1,2, Kartini Iskandar1, Jolin Xiao Hui Lai1

  • 1Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore.

Nucleic Acids Research
|November 27, 2020
PubMed

Insights

Phosphorylation of Bcl-2 at serine-70 (S70pBcl2) protects cancer cells from drug-induced apoptosis by sensing and modulating oxidative stress. This mechanism prevents DNA damage and cell death, offering new therapeutic strategies.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Redox Biology

Background:

  • Bcl-2 phosphorylation at serine-70 (S70pBcl2) is linked to drug resistance in cancer.
  • The precise mechanism by which S70pBcl2 promotes drug resistance is not fully understood.

Purpose of the Study:

  • To elucidate the role of S70pBcl2 in conferring resistance to drug-induced apoptosis.
  • To investigate the mechanism of S70pBcl2 as a redox sensor and modulator of oxidative stress.

Main Methods:

  • Correlation analysis of S70pBcl2 levels with DNA damage in patient-derived cells and cell lines.
  • Bioinformatic analysis of S70pBcl2 and patient survival data.
  • Experimental assessment of S70pBcl2's effect on mitochondrial reactive oxygen species (ROS) production and DNA damage.
  • Investigation of Bcl-2 interaction with mitochondrial complex-IV subunit-5A.
  • Treatment with phosphatase activator FTY720 to target S70pBcl2.

Main Results:

  • Increased S70pBcl2 levels inversely correlate with DNA damage in chronic lymphocytic leukemia (CLL) and lymphoma cells.
  • S70pBcl2 suppresses mitochondrial ROS production, preventing oxidative stress-induced DNA damage and cell death.
  • S70pBcl2 reduces Bcl-2 interaction with mitochondrial complex-IV, decreasing respiration and ROS production.
  • Targeting S70pBcl2 with FTY720 enhances drug-induced DNA damage and cell death in CLL cells.
  • S70pBcl2 is associated with lower overall survival in lymphoma patients.

Conclusions:

  • S70pBcl2 functions as a redox sensor, preventing oxidative stress-mediated DNA damage and apoptosis.
  • This phosphorylation site offers a novel mechanism for Bcl-2-mediated drug resistance.
  • Targeting S70pBcl2 presents a potential therapeutic strategy for overcoming drug resistance in hematological malignancies.

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