Epitranscriptomic RNA modifications as active and dynamic regulators of the eukaryotic cellular stress response

Abstract

The cellular stress response allows eukaryotic cells to adapt to challenges such as heat shock, hypoxia, nutrient deprivation, oxidative damage, and viral infection. Traditionally studied through transcriptional and post-transcriptional mechanisms, stress responses are now recognized to also involve the epitranscriptome as an adaptable regulatory layer. This essay examines how the RNA modification machinery functions as an active and dynamic regulator of stress adaptation, focusing on five major RNA modifications: N6-methyladenosine (m6A), 5-methylcytosine (m5C), pseudouridine (Ψ), N4-acetylcytidine (ac4C), and adenosine-to-inosine (A-to-I) RNA editing. Mechanistic and genome-wide studies demonstrate that stress-induced RNA modifications regulate RNA splicing, stability, localization, and translation. Notably, m6A promotes selective translation of stress-responsive transcripts, while m5C preserves translational capacity by stabilizing mRNAs and protecting tRNAs. Pseudouridylation functions as a condition-dependent modification that modulates spliceosome activity and mRNA stability during metabolic stress, while ac4C and A-to-I editing contribute to stress granule dynamics and innate immune regulation. This essay will also explore how cancer cells use these pathways to sustain their metabolic reprogramming and develop drug resistance. Although there remain technical and conceptual barriers to fully understanding the function of RNA modifications as part of stress responses, it is clear from the current data that RNA modifications represent a class of active and dynamic regulators of cellular stress responses and therefore, potentially useful therapeutic targets.