Post-translational modification of RNA m6A demethylase ALKBH5 regulates ROS-induced DNA damage response.
Nucleic Acids Res
; 49(10): 5779-5797, 2021 06 04.
Article
en En
| MEDLINE
| ID: mdl-34048572
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Daño del ADN
/
Especies Reactivas de Oxígeno
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Reparación del ADN
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Desmetilasa de ARN, Homólogo 5 de AlkB
Idioma:
En
Revista:
Nucleic Acids Res
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos