TY - JOUR T1 - Glutamine deficiency in solid tumors confers resistance to ribosomal RNA synthesis inhibitors JF - bioRxiv DO - 10.1101/2021.12.03.471189 SP - 2021.12.03.471189 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 Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/12/04/2021.12.03.471189.abstract N2 - 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. ER -