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

Melvin Pan, Christiane Zorbas, Maki Sugaya, Kensuke Ishiguro, Miki Kato, Miyuki Nishida, Hai-Feng Zhang, Marco M Candeias, Akimitsu Okamoto, Takamasa Ishikawa, Tomoyoshi Soga, Hiroyuki Aburatani, Juro Sakai, Yoshihiro Matsumura, Tsutomu Suzuki, Christopher G. Proud, Denis L. J. Lafontaine, Tsuyoshi Osawa
doi: https://doi.org/10.1101/2021.12.03.471189
Melvin Pan
1Division of Integrative Nutriomics and Oncology, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan
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Christiane Zorbas
2RNA Molecular Biology, Fonds de la Recherche Scientifique (F.R.S.-FNRS), Université Libre de Bruxelles (ULB), Biopark campus, 6041 Gosselies, Belgium
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Maki Sugaya
1Division of Integrative Nutriomics and Oncology, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan
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Kensuke Ishiguro
3Department of Chemistry and Biotechnology, Graduate School of Engineering, University of Tokyo, Tokyo 113-8656, Japan
4RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan
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Miki Kato
1Division of Integrative Nutriomics and Oncology, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan
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Miyuki Nishida
1Division of Integrative Nutriomics and Oncology, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan
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Hai-Feng Zhang
5Department of Molecular Oncology, BC Cancer, Vancouver V5Z 1L3, Canada
6Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver V6T 2B5, Canada
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Marco M Candeias
7Molecular and RNA Cancer Unit, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Akimitsu Okamoto
3Department of Chemistry and Biotechnology, Graduate School of Engineering, University of Tokyo, Tokyo 113-8656, Japan
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Takamasa Ishikawa
8Institute for Advanced Biosciences, Keio University, Tsuruoka 997-0052, Japan
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Tomoyoshi Soga
8Institute for Advanced Biosciences, Keio University, Tsuruoka 997-0052, Japan
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Hiroyuki Aburatani
9Genome Science Division, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan
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Juro Sakai
10Division of Metabolic Medicine, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan
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Yoshihiro Matsumura
10Division of Metabolic Medicine, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan
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Tsutomu Suzuki
3Department of Chemistry and Biotechnology, Graduate School of Engineering, University of Tokyo, Tokyo 113-8656, Japan
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Christopher G. Proud
11Lifelong Health, South Australian Health & Medical Research Institute, Adelaide, SA, 5000, Australia; School of Biomedical Sciences, University of Adelaide, Adelaide, SA, 5005, Australia
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Denis L. J. Lafontaine
2RNA Molecular Biology, Fonds de la Recherche Scientifique (F.R.S.-FNRS), Université Libre de Bruxelles (ULB), Biopark campus, 6041 Gosselies, Belgium
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Tsuyoshi Osawa
1Division of Integrative Nutriomics and Oncology, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan
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  • For correspondence: osawa@lsbm.org
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Summary

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.

Competing Interest Statement

The authors have declared no competing interest.

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Posted December 04, 2021.
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Glutamine deficiency in solid tumors confers resistance to ribosomal RNA synthesis inhibitors
Melvin Pan, Christiane Zorbas, Maki Sugaya, Kensuke Ishiguro, Miki Kato, Miyuki Nishida, Hai-Feng Zhang, Marco M Candeias, Akimitsu Okamoto, Takamasa Ishikawa, Tomoyoshi Soga, Hiroyuki Aburatani, Juro Sakai, Yoshihiro Matsumura, Tsutomu Suzuki, Christopher G. Proud, Denis L. J. Lafontaine, Tsuyoshi Osawa
bioRxiv 2021.12.03.471189; doi: https://doi.org/10.1101/2021.12.03.471189
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Glutamine deficiency in solid tumors confers resistance to ribosomal RNA synthesis inhibitors
Melvin Pan, Christiane Zorbas, Maki Sugaya, Kensuke Ishiguro, Miki Kato, Miyuki Nishida, Hai-Feng Zhang, Marco M Candeias, Akimitsu Okamoto, Takamasa Ishikawa, Tomoyoshi Soga, Hiroyuki Aburatani, Juro Sakai, Yoshihiro Matsumura, Tsutomu Suzuki, Christopher G. Proud, Denis L. J. Lafontaine, Tsuyoshi Osawa
bioRxiv 2021.12.03.471189; doi: https://doi.org/10.1101/2021.12.03.471189

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