2. Academic Validation
  3. Post-translational modification of RNA m6A demethylase ALKBH5 regulates ROS-induced DNA damage response

Post-translational modification of RNA m6A demethylase ALKBH5 regulates ROS-induced DNA damage response

  • Nucleic Acids Res. 2021 Jun 4;49(10):5779-5797. doi: 10.1093/nar/gkab415.
Fang Yu 1 2,  Jiangbo Wei 3 4,  Xiaolong Cui 3 4,  Chunjie Yu 1,  Wei Ni 5,  Jörg Bungert 2,  Lizi Wu 5,  Chuan He 3 4,  Zhijian Qian 1 2
Affiliations

Affiliations

  • 1 Department of Medicine, UF Health Cancer Center, University of Florida, Gainesville, FL 32610, USA.
  • 2 Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32610, USA.
  • 3 Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA.
  • 4 Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA.
  • 5 Department of Molecular Genetics and Microbiology, UF Genetic Institute, University of Florida, FL 32610, USA.
PMID: 34048572 DOI: 10.1093/nar/gkab415
Abstract

Faithful genome integrity maintenance plays an essential role in cell survival. Here, we identify the RNA demethylase ALKBH5 as a key regulator that protects cells from DNA damage and Apoptosis during Reactive Oxygen Species (ROS)-induced stress. We find that ROS significantly induces global mRNA N6-methyladenosine (m6A) levels by modulating ALKBH5 post-translational modifications (PTMs), leading to the rapid and efficient induction of thousands of genes involved in a variety of biological processes including DNA damage repair. Mechanistically, ROS promotes ALKBH5 SUMOylation through activating ERK/JNK signaling, leading to inhibition of ALKBH5 m6A demethylase activity by blocking substrate accessibility. Moreover, ERK/JNK/ALKBH5-PTMs/m6A axis is activated by ROS in hematopoietic stem/progenitor cells (HSPCs) in vivo in mice, suggesting a physiological role of this molecular pathway in the maintenance of genome stability in HSPCs. Together, our study uncovers a molecular mechanism involving ALKBH5 PTMs and increased mRNA m6A levels that protect genomic integrity of cells in response to ROS.

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