Post-translational modification of RNA m6A demethylase ALKBH5 regulates ROS-induced DNA damage response.
Post-translational modification of RNA m6A demethylase ALKBH5 regulates ROS-induced DNA damage response.
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DOI：
10.1093/nar/gkab415
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发表时间：
2021-06-04
影响因子：
14.9
通讯作者：
Qian Z
中科院分区：
文献类型：
--
作者：
Yu F;Wei J;Cui X;Yu C;Ni W;Bungert J;Wu L;He C;Qian Z
忠实的基因组完整性维护在细胞存活中起着至关重要的作用。在这里，我们发现RNA去甲基化酶ALKBH5是在活性氧（ROS）诱导的应激过程中保护细胞免受DNA损伤和凋亡的关键调节因子。我们发现ROS通过调节ALKBH5翻译后修饰（PTMs）显著诱导全球mRNA n6 -甲基腺苷（m6A）水平，从而快速有效地诱导数千个参与包括DNA损伤修复在内的各种生物过程的基因。从机制上来说，ROS通过激活ERK/JNK信号通路促进ALKBH5的SUMOylation，从而通过阻断底物可及性抑制ALKBH5 m6A去甲基化酶活性。此外，ERK/JNK/ALKBH5-PTMs/m6A轴在小鼠体内造血干细胞（HSPCs）中被ROS激活，提示该分子通路在维持HSPCs基因组稳定性中的生理作用。总之，我们的研究揭示了一种涉及ALKBH5 PTMs和mRNA m6A水平增加的分子机制，该机制在ROS反应中保护细胞的基因组完整性。
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.
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