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

doi:10.1093/nar/gkab415

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.

Authors

Fang Yu^{1

2}, Jiangbo Wei^{3

4}, Xiaolong Cui^{3

4}, Chunjie Yu¹, Wei Ni⁵, Jörg Bungert², Lizi Wu⁵, Chuan He^{3

4}, Zhijian Qian^{1

2}

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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

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
DNA Damage* / drug effects
DNA Repair* / drug effects
DNA Repair* / genetics
Demethylation / drug effects
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
Phosphorylation
Protein Processing, Post-Translational
RNA, Small Interfering
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism
RNA-Seq
Reactive Oxygen Species / metabolism*
Sumoylation / drug effects
Tandem Mass Spectrometry
X-linked Nuclear Protein / genetics
X-linked Nuclear Protein / metabolism

Substances

FAAP20 protein, human
Fanconi Anemia Complementation Group Proteins
IGF2BP1 protein, human
RNA, Small Interfering
RNA-Binding Proteins
Reactive Oxygen Species
Hydrogen Peroxide
ALKBH5 protein, human
ALKBH5 protein, mouse
AlkB Homolog 5, RNA Demethylase
ATRX protein, human
X-linked Nuclear Protein

Abstract

Publication types

MeSH terms

Substances

Grants and funding