Glutamine deficiency in solid tumors confers resistance to ribosomal RNA synthesis inhibitors

Pan, M.; Zorbas, C.; Sugaya, M.; Ishiguro, K.; Kato, M.; Nishida, M.; Zhang, H.; Candeias, M. M.; Okamoto, A.; Ishikawa, T.; Soga, T.; Aburatani, H.; Sakai, J.; Matsumura, Y.; Suzuki, T.; Proud, C. G.; Lafontaine, D. L. G.; Osawa, T.

doi:10.1101/2021.12.03.471189

bioRxiv · 10.1101/2021.12.03.471189

Glutamine deficiency in solid tumors confers resistance to ribosomal RNA synthesis inhibitors

Pan, M.·Zorbas, C.·Sugaya, M.·Ishiguro, K.·Kato, M.·Nishida, M.·Zhang, H.·Candeias, M. M.·Okamoto, A.·Ishikawa, T.·Soga, T.·Aburatani, H.·Sakai, J.·Matsumura, Y.·Suzuki, T.·Proud, C. G.·Lafontaine, D. L. G.·Osawa, T.

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Abstract

Ribosome biogenesis involves the processing of precursor ribosomal RNAs (pre-rRNAs) and sequential assembly with ribosomal proteins. Here we report that nutrient deprivation severely impairs pre-rRNA processing and leads to the accumulation of unprocessed rRNAs. Upon nutrient restoration, the accumulated pre-rRNAs are processed into mature rRNAs that are utilized for ribosome biogenesis. Failure to accumulate pre-rRNAs under nutrient deprivation leads to perturbed ribosome assembly during 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 was dependent on the translation factor eukaryotic elongation factor 2 (eEF2), which was in turn dependent on Raf/MEK/ERK signalling. Depriving cells of glutamine prevents the activation of p53 by rRNA synthesis inhibitors. Our data reveals a mechanism that cancer cells can exploit to suppress p53-mediated apoptosis during fluctuations in environmental nutrient availability.

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Pan, M., Zorbas, C., Sugaya, M., Ishiguro, K., Kato, M., Nishida, M., Zhang, H., Candeias, M. M., Okamoto, A., Ishikawa, T., Soga, T., Aburatani, H., Sakai, J., Matsumura, Y., Suzuki, T., Proud, C. G., Lafontaine, D. L. G., Osawa, T.. 2021-12-04. Glutamine deficiency in solid tumors confers resistance to ribosomal RNA synthesis inhibitors. https://doi.org/10.1101/2021.12.03.471189

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