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