Nucleotide depletion reveals the impaired ribosome biogenesis checkpoint as a barrier against DNA damage

Many oncogenes enhance nucleotide usage to increase ribosome content, DNA replication, and cell proliferation, but in parallel trigger p53 activation. Both the impaired ribosome biogenesis checkpoint (IRBC) and the DNA damage response (DDR) have been implicated in p53 activation following nucleotide...

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Bibliographic Details
Published in:The EMBO journal 2020-07, Vol.39 (13), p.e103838-n/a
Main Authors: Pelletier, Joffrey, Riaño‐Canalias, Ferran, Almacellas, Eugènia, Mauvezin, Caroline, Samino, Sara, Feu, Sonia, Menoyo, Sandra, Domostegui, Ana, Garcia‐Cajide, Marta, Salazar, Ramon, Cortés, Constanza, Marcos, Ricard, Tauler, Albert, Yanes, Oscar, Agell, Neus, Kozma, Sara C, Gentilella, Antonio, Thomas, George
Format: Article
Language:English
Subjects:
Activation
Biosynthesis
Cell proliferation
CHK1 protein
Cyclin-dependent kinase inhibitor p21
Damage
Degradation
Dehydrogenase
Dehydrogenases
Deoxyribonucleic acid
Depletion
Disruption
DNA
DNA biosynthesis
DNA Damage
G1 Phase Cell Cycle Checkpoints
Genomic instability
HCT116 Cells
Humans
IMPDH
Inhibition
Inosine monophosphate
IRBC
Nucleotides
Nucleotides - genetics
Nucleotides - metabolism
p21
p53
p53 Protein
Proteasomes
Ribosomes - genetics
Ribosomes - metabolism
S phase
Synthesis
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
Yeast
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Summary:Many oncogenes enhance nucleotide usage to increase ribosome content, DNA replication, and cell proliferation, but in parallel trigger p53 activation. Both the impaired ribosome biogenesis checkpoint (IRBC) and the DNA damage response (DDR) have been implicated in p53 activation following nucleotide depletion. However, it is difficult to reconcile the two checkpoints operating together, as the IRBC induces p21‐mediated G1 arrest, whereas the DDR requires that cells enter S phase. Gradual inhibition of inosine monophosphate dehydrogenase (IMPDH), an enzyme required for de novo GMP synthesis, reveals a hierarchical organization of these two checkpoints. We find that the IRBC is the primary nucleotide sensor, but increased IMPDH inhibition leads to p21 degradation, compromising IRBC‐mediated G1 arrest and allowing S phase entry and DDR activation. Disruption of the IRBC alone is sufficient to elicit the DDR, which is strongly enhanced by IMPDH inhibition, suggesting that the IRBC acts as a barrier against genomic instability. Synopsis How S‐phase DNA damage responses and G1 arrest via the impaired ribosome synthesis checkpoint (IRBC) cooperate in p53 activation upon nucleotide depletion has remained unclear. Different levels of inosine monophosphate dehydrogenase (IMPDH) inhibition now reveal a hierarchical organization of these two genomic instability barriers. Gradual inhibition of GMP synthesis by IMPDH inhibitors elicits primarily the IRBC, and secondarily ATR/Chk1 activation. Enhanced proteasomal p21 degradation upon severe nucleotide depletion overcomes IRBC‐dependent G1 arrest, leading to replicative stress. Cells exposed to prolonged IMPDH inhibition and replicative stress experience DNA damage. IRBC disruption alone can elicit DNA damage, which is strongly enhanced by IMPDH inhibition. Hierarchical organization of p21‐mediated G1 arrest and S‐phase DNA damage response signaling ensures genomic stability upon increasing inhibition of nucleotide synthesis enzyme IMPDH.
ISSN:0261-4189
1460-2075
DOI:10.15252/embj.2019103838