PT  - JOURNAL ARTICLE
AU  - Melvin Pan
AU  - Christiane Zorbas
AU  - Maki Sugaya
AU  - Kensuke Ishiguro
AU  - Miki Kato
AU  - Miyuki Nishida
AU  - Hai-Feng Zhang
AU  - Marco M Candeias
AU  - Akimitsu Okamoto
AU  - Takamasa Ishikawa
AU  - Tomoyoshi Soga
AU  - Hiroyuki Aburatani
AU  - Juro Sakai
AU  - Yoshihiro Matsumura
AU  - Tsutomu Suzuki
AU  - Christopher G. Proud
AU  - Denis L. J. Lafontaine
AU  - Tsuyoshi Osawa
TI  - Glutamine deficiency in solid tumors confers resistance to ribosomal RNA synthesis inhibitors
AID  - 10.1101/2021.12.03.471189
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.12.03.471189
4099  - http://biorxiv.org/content/early/2021/12/04/2021.12.03.471189.short
4100  - http://biorxiv.org/content/early/2021/12/04/2021.12.03.471189.full
AB  - 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 StatementThe authors have declared no competing interest.