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Nucleotide depletion reveals the impaired ribosome biogenesis checkpoint as a barrier against DNA damage
Author(s) -
Pelletier Joffrey,
RiañoCanalias Ferran,
Almacellas Eugènia,
Mauvezin Caroline,
Samino Sara,
Feu Sonia,
Menoyo Sandra,
Domostegui Ana,
GarciaCajide Marta,
Salazar Ramon,
Cortés Constanza,
Marcos Ricard,
Tauler Albert,
Yanes Oscar,
Agell Neus,
Kozma Sara C,
Gentilella Antonio,
Thomas George
Publication year - 2020
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2019103838
Subject(s) - biology , g2 m dna damage checkpoint , dna damage , microbiology and biotechnology , genetics , dna , dna repair , chek1 , biogenesis , cell cycle checkpoint , gene , cell cycle
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.