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

Fang Yu, Jiangbo Wei, Xiaolong Cui, Chunjie Yu, Wei Ni, Jörg Bungert, Lizi Wu, Chuan He*, Zhijian Qian*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

105 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5779-5797
Number of pages19
JournalNucleic acids research
Volume49
Issue number10
DOIs
StatePublished - Jun 4 2021

ASJC Scopus subject areas

  • Genetics

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