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  • 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 research (2021-05-29)
Fang Yu, Jiangbo Wei, Xiaolong Cui, Chunjie Yu, Wei Ni, Jörg Bungert, Lizi Wu, Chuan He, Zhijian Qian
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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