Widespread Cap-Unmethylated mRNAs Revealed by Metabolic Stress

Although traditionally viewed as constitutive, we developed a mass spectrometry-based method to demonstrate that in both yeast and mammalian cells, a substantial population of mRNAs lack cap methylation in response to SAM-limiting conditions. Through developing two transcriptome-wide approaches, we found that methylation is enriched on specific transcripts and uncovered an unexpected connection between histone H3K36me3 and cap methylation.

Remarkably, cap-unmethylated mRNAs exhibit features of canonical mRNAs—they are polyadenylated, exported to the cytosol, and translated. Enforced cap methylation reduces cell growth under SAM limitation, suggesting that unmethylated mRNAs confer an adaptive advantage during stress. These findings reveal mRNA cap methylation as a dynamic, regulated modification and a previously underappreciated layer of gene expression control.