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

Autor: Fang Yu, Xiaolong Cui, Jiangbo Wei, Wei Ni, Chunjie Yu, Zhijian Qian, Lizi Wu, Jörg Bungert, Chuan He
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Protein sumoylation
MAPK/ERK pathway
X-linked Nuclear Protein
DNA Repair
DNA damage
DNA repair
AcademicSubjects/SCI00010
MAP Kinase Signaling System
SUMO protein
Apoptosis
Bone Marrow Cells
Methylation
03 medical and health sciences
Mice
0302 clinical medicine
Tandem Mass Spectrometry
Cell Line
Tumor
Demethylase activity
Genetics
Animals
Humans
RNA-Seq
Phosphorylation
RNA
Small Interfering
Gene
Molecular Biology
030304 developmental biology
0303 health sciences
biology
AlkB Homolog 5
RNA Demethylase
RNA-Binding Proteins
Sumoylation
Hydrogen Peroxide
Hematopoietic Stem Cells
Fanconi Anemia Complementation Group Proteins
Cell biology
Demethylation
Gene Expression Regulation
biology.protein
Demethylase
Reactive Oxygen Species
Protein Processing
Post-Translational
030217 neurology & neurosurgery
DNA Damage
Zdroj: Nucleic Acids Research
ISSN: 1362-4962
0305-1048
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: