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

Area of Science:

• Molecular Biology
• Epigenetics
• Cellular Stress Response

Background:

• Genome integrity is vital for cell survival and is threatened by various stressors.
• Reactive oxygen species (ROS) are a major source of cellular damage, impacting DNA and cellular processes.
• N6-methyladenosine (m6A) is a critical mRNA modification influencing gene expression and cellular responses.

Purpose of the Study:

• To identify key regulators involved in maintaining genome integrity under ROS-induced stress.
• To elucidate the role of RNA demethylase ALKBH5 in cellular protection against ROS.
• To investigate the molecular mechanisms linking ROS, ALKBH5, and mRNA m6A modification in maintaining genomic stability.

Main Methods:

• Investigated the impact of ROS on global mRNA m6A levels and ALKBH5 activity.
• Utilized cell culture models and in vivo mouse studies focusing on hematopoietic stem/progenitor cells (HSPCs).
• Analyzed post-translational modifications (PTMs) of ALKBH5, including SUMOylation, and associated signaling pathways (ERK/JNK).

Main Results:

• ROS induces global mRNA m6A levels by modulating ALKBH5 PTMs, leading to the upregulation of DNA damage repair genes.
• ROS promotes ALKBH5 SUMOylation via ERK/JNK signaling, inhibiting its demethylase activity and increasing m6A levels.
• The ERK/JNK/ALKBH5-PTMs/m6A axis is activated by ROS in mouse HSPCs, highlighting its physiological relevance in maintaining genome stability.

Conclusions:

• ALKBH5 acts as a crucial regulator protecting cells from DNA damage and apoptosis during ROS stress.
• Post-translational modifications of ALKBH5, specifically SUMOylation, are key to its regulatory function under oxidative stress.
• The study reveals a novel molecular mechanism involving ALKBH5 PTMs and altered mRNA m6A levels that safeguard genomic integrity.