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

TY - JOUR

T1 - An ISR-independent role of GCN2 prevents excessive ribosome biogenesis and mRNA translation

AU - Román-Trufero, Mónica

AU - Kleijn, Istvan T.

AU - Blighe, Kevin

AU - Zhou, Jinglin

AU - Saavedra-García, Paula

AU - Gaffar, Abigail

AU - Christoforou, Marilena

AU - Bellotti, Axel

AU - Abrahams, Joel

AU - Atrih, Abdelmadjid

AU - Lamont, Douglas

AU - Gierlinski, Marek

AU - Jayaprakash, Pooja

AU - Michel, Audrey M.

AU - Aboagye, Eric O.

AU - Yuneva, Mariia

AU - Masson, Glenn R.

AU - Shahrezaei, Vahid

AU - Auner, Holger W.

N1 - Publisher Copyright: © 2025 Román-Trufero et al.

PY - 2025/5

Y1 - 2025/5

N2 - 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 conditions of full nutrient availability depend on GCN2 for survival and unrestricted tumour growth. Our observations describe an ISR-independent role of GCN2 in reg-ulating the cellular proteome and translatome and suggest new avenues for cancer therapies based on unleashing excessive mRNA translation.

AB - 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 conditions of full nutrient availability depend on GCN2 for survival and unrestricted tumour growth. Our observations describe an ISR-independent role of GCN2 in reg-ulating the cellular proteome and translatome and suggest new avenues for cancer therapies based on unleashing excessive mRNA translation.

UR - https://www.scopus.com/pages/publications/86000266103

U2 - 10.26508/lsa.202403014

DO - 10.26508/lsa.202403014

M3 - Article

C2 - 40032489

AN - SCOPUS:86000266103

SN - 2575-1077

VL - 8

JO - Life Science Alliance

JF - Life Science Alliance

IS - 5

M1 - e202403014

ER -