Glutamine deficiency in solid tumor cells confers resistance to ribosomal RNA synthesis inhibitors

• Published in: Nature communications Vol. 13; no. 1; p. 3706
• Main Authors: Pan, Melvin, Zorbas, Christiane, Sugaya, Maki, Ishiguro, Kensuke, Kato, Miki, Nishida, Miyuki, Zhang, Hai-Feng, Candeias, Marco M., Okamoto, Akimitsu, Ishikawa, Takamasa, Soga, Tomoyoshi, Aburatani, Hiroyuki, Sakai, Juro, Matsumura, Yoshihiro, Suzuki, Tsutomu, Proud, Christopher G., Lafontaine, Denis L. J., Osawa, Tsuyoshi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.06.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/51; 13/89; 14/63; 631/67/327; 692/4028/67/1059/2326; 82/1; Apoptosis; Availability; Biosynthesis; Deprivation; DNA-directed RNA polymerase; Elongation; Glutamine; Humanities and Social Sciences; Inhibitors; multidisciplinary; Nucleoli; Nutrient availability; p53 Protein; Protein biosynthesis; Protein synthesis; Raf protein; Restoration; RNA polymerase; RNA processing; rRNA; Science; Science (multidisciplinary); Solid tumors; Transcription; Translation; Translation elongation; Tumor cells; Tumors; Yeast
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-31418-w

Ribosome biogenesis is an energetically expensive program that is dictated by nutrient availability. Here we report that nutrient deprivation severely impairs precursor ribosomal RNA (pre-rRNA) processing and leads to the accumulation of unprocessed rRNAs. Upon nutrient restoration, pre-rRNAs stored under starvation are processed into mature rRNAs that are utilized for ribosome biogenesis. Failure to accumulate pre-rRNAs under nutrient stress leads to perturbed ribosome assembly upon nutrient restoration and subsequent apoptosis via uL5/uL18-mediated activation of p53. Restoration of glutamine alone activates p53 by triggering uL5/uL18 translation. Induction of uL5/uL18 protein synthesis by glutamine is dependent on the translation factor eukaryotic elongation factor 2 (eEF2), which is in turn dependent on Raf/MEK/ERK signaling. Depriving cells of glutamine prevents the activation of p53 by rRNA synthesis inhibitors. Our data reveals a mechanism that tumor cells can exploit to suppress p53-mediated apoptosis during fluctuations in environmental nutrient availability. Small molecules that target RNA Polymerase I inhibit ribosome biogenesis to activate p53 through the nucleolar surveillance response pathway. Here, the authors show that p53 induction by ribosome stress is dependent on extracellular glutamine availability.