ArticleLife science alliance2025
An ISR-independent role of GCN2 prevents excessive ribosome biogenesis and mRNA translation.
Article in Life science alliance, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
What it found
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
6 citing papers in PubMed.
- GCN2 in proteostasis: structural logic, signalling networks and disease.The FEBS journal · 2026Review
- A multilayered stress-response circuit: The mammalian mitochondrial UPR.The FEBS journal · 2026Review
- Identification of Changes in the Transcriptome Profile of Human Hepatoma HepG2 Cells Exposed to Combined Sorafenib and Cannabis Treatment.International journal of molecular sciences · 2026Article
- Elevated GCN2 levels in cancer cells confer protection from mitotic stress and faster cell movement.Cellular oncology (Dordrecht, Netherlands) · 2026Article
- A Novel Potent and Selective GCN2 Inhibitor, APL-4098, Has Antileukemic Activity through Dysregulation of Mitochondrial Function.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- The protein kinases family in fungi: adaptability, virulence and conservation between species.Frontiers in microbiology · 2025Review
Corrections and comments
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Authors and funding
19 authors.
Funding
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.