m6A pathway suppression reprograms gene expression during the integrated stress response

The integrated stress response (ISR) orchestrates cellular adaptations through translational repression and upregulation of ATF4, a transcription factor. However, ATF4 only accounts for a minority of ISR-induced gene-expression changes. Here we show that the ISR reshapes the transcriptome by stabilizing N6-methyladenosine (m6A)-containing mRNAs that are normally unstable. We show that mRNA stabilization, not transcription activation, explains much of the transcriptome response during the ISR, and that this stabilization selectively occurs on m6A-mRNAs. m6A-mRNA degradation is a translation-dependent process and translation repression during the ISR stabilizes m6A-mRNAs. Consequently, the ISR leads to increased m6A-mRNA expression, thereby upregulating their protein output despite overall diminished translation. Notably, stabilization of m6A-mRNAs by m6A depletion is sufficient to induce transcriptomic and proteomic features of amino acid-depleted cells. Together, our study identifies the direct coordination of translation suppression and transcriptome reprogramming through m6A during the ISR.