The research shows that a tiny modification in the genetic material, called ac4C, acts as a crucial defender, helping cells create protective storage units known as stress granules. These stress granules safeguard important genetic instructions when the cell is facing challenges. The new findings could help shed light on relevant molecular pathways that could be targeted in disease.

 

Stress granules are an integral part of the stress response that are formed from non-translating mRNAs aggregated with proteins. The researchers show that the RNA modification N4-acetylcytidine (ac4C) on mRNA associates with transcripts enriched in stress granules and that stress granule localized transcripts with ac4C are specifically translationally regulated. They also show that ac4C on mRNA can mediate localization of proteins to stress granules. Their results suggest that acetylation of mRNA regulates localization of both stress-sensitive transcripts and RNA-binding proteins to stress granules and adds to our understanding of the molecular mechanisms responsible for stress granule formation. Stress granules have been extensively studied, and it is well-established that they form when translation initiation is limited and a variety of roles for stress granules within the cell have been proposed. While stress granule assembly and disassembly can be regulated by various post-translational modifications the impact of RNA modifications on their formation, dispersal and function remains largely unclear.

 

The RNA modification N4-acetylcytidine (ac4C) has recently been shown to be deposited on mRNA and regulate translation efficiency. ac4C is conserved through all kingdoms of life and is induced upon several different stresses. ac4C is less abundant than other RNA modifications on mRNA and due to difficulties in precise and quantitative mapping its function and occurrence on mRNA has remained controversial. The researchers show in their publication that ac4C is enriched in stress granules and that acetylated transcripts are predominantly localized to stress granules in response to oxidative stress, proposing a model where acetylation of RNA can affect mRNA localization to stress granules, in part by affecting the translational release of mRNA from the ribosome, providing new insight into both the function and consequences of mRNA acetylation and mechanism of RNA localization to stress granules. The findings will promote the understanding of how the cells react to stress and which role RNA modifications play in the process.