2. Academic Validation
  3. An ISR-independent role of GCN2 prevents excessive ribosome biogenesis and mRNA translation

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

  • Life Sci Alliance. 2025 Mar 3;8(5):e202403014. doi: 10.26508/lsa.202403014.
Mónica Román-Trufero 1 2 3,  Istvan T Kleijn 4,  Kevin Blighe 5,  Jinglin Zhou 2,  Paula Saavedra-García 2,  Abigail Gaffar 2,  Marilena Christoforou 2,  Axel Bellotti 1,  Joel Abrahams 6,  Abdelmadjid Atrih 7,  Douglas Lamont 7,  Marek Gierlinski 8,  Pooja Jayaprakash 9,  Audrey M Michel 9,  Eric O Aboagye 6,  Mariia Yuneva 3,  Glenn R Masson 10,  Vahid Shahrezaei 4,  Holger W Auner 11 2 3 12
Affiliations

Affiliations

  • 1 Division of Haematology and Central Haematology Laboratory, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
  • 2 Hugh and Josseline Langmuir Centre for Myeloma Research, Department of Immunology and Inflammation, Imperial College London, London, UK.
  • 3 The Francis Crick Institute, London, UK.
  • 4 Department of Mathematics, Imperial College London, London, UK.
  • 5 Clinical Bioinformatics Research, London, UK.
  • 6 Department of Surgery and Cancer, Imperial College London, London, UK.
  • 7 FingerPrints Proteomics Facility, School of Life Sciences, University of Dundee, Dundee, UK.
  • 8 Data Analysis Group, Division of Computational Biology, School of Life Sciences, University of Dundee, Dundee, UK.
  • 9 EIRNA Bio Ltd, Cork, Ireland.
  • 10 Division of Cancer Research, School of Medicine, University of Dundee, Dundee, UK.
  • 11 Division of Haematology and Central Haematology Laboratory, Lausanne University Hospital (CHUV), Lausanne, Switzerland holger.auner@chuv.ch.
  • 12 Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
PMID: 40032489 DOI: 10.26508/lsa.202403014
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 conditions of full nutrient availability depend on GCN2 for survival and unrestricted tumour growth. Our observations describe an ISR-independent role of GCN2 in regulating the cellular proteome and translatome and suggest new avenues for Cancer therapies based on unleashing excessive mRNA translation.

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