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

• Published in: Nucleic acids research 2021-06, Vol.49 (10), p.5779-5797
• Main Authors: Yu, Fang, Wei, Jiangbo, Cui, Xiaolong, Yu, Chunjie, Ni, Wei, Bungert, Jörg, Wu, Lizi, He, Chuan, Qian, Zhijian
• Format: Article
• Language: English
• Subjects: AlkB Homolog 5, RNA Demethylase - genetics; AlkB Homolog 5, RNA Demethylase - metabolism; Animals; Apoptosis - drug effects; Apoptosis - genetics; Bone Marrow Cells - drug effects; Bone Marrow Cells - metabolism; Cell Line, Tumor; Demethylation - drug effects; DNA Damage - drug effects; DNA Repair - drug effects; DNA Repair - genetics; Fanconi Anemia Complementation Group Proteins - genetics; Fanconi Anemia Complementation Group Proteins - metabolism; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Humans; Hydrogen Peroxide - pharmacology; MAP Kinase Signaling System - drug effects; Methylation - drug effects; Mice; Molecular Biology; Phosphorylation; Protein Processing, Post-Translational; Reactive Oxygen Species - metabolism; RNA, Small Interfering; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; RNA-Seq; Sumoylation - drug effects; Tandem Mass Spectrometry; X-linked Nuclear Protein - genetics; X-linked Nuclear Protein - metabolism
• ISSN: 0305-1048; 1362-4962
• 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.