An ISR-independent role of GCN2 prevents excessive ribosome biogenesis and mRNA translation.

ABSTRACT: The integrated stress response (ISR) is a corrective physiological programme to restore cellular homeostasis that is based on the attenuation of global protein synthesis and a resource-enhancing transcriptional programme. GCN2 is the oldest of four kinases that are activated by diverse cellular stresses to trigger the ISR and acts as the primary responder to amino acid shortage and ribosome collisions. Here, using a broad multi-omics approach, we uncover an ISR-independent role of GCN2. GCN2 inhibition or depletion in the absence of discernible stress causes excessive protein synthesis and ribosome biogenesis, perturbs the cellular translatome, and results in a dynamic and broad loss of metabolic homeostasis. Cancer cells that rely on GCN2 to keep protein synthesis in check under condition

SUBMITTER: Roman-Trufero M 

PROVIDER: S-EPMC11876863 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature