Year: 2026
Type: preprint
Abstract: ABSTRACT 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.
Authors: Shino Murakami, Samie R. Jaffrey
Institutions: Cornell University, Weill Cornell Medicine
Language: English
Topic: RNA modifications and cancer
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7172494919