m ⁶ A 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 N ⁶ -methyladenosine (m ⁶ A)-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 m ⁶ A-mRNAs. m ⁶ A-mRNA degradation is a translation-dependent process and translation repression during the ISR stabilizes m ⁶ A-mRNAs. Consequently, the ISR leads to increased m ⁶ A-mRNA expression, thereby upregulating their protein output despite overall diminished translation. Notably, stabilization of m ⁶ A-mRNAs by m ⁶ A 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 m ⁶ A during the ISR.