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Title: Nucleotide depletion reveals the impaired ribosomebiogenesis checkpoint as a barrier against DNA damage
Author: Pelletier, Joffrey
Riaño Canalias, Ferran
Almacellas i Canals, Eugènia
Mauvezin, Caroline
Samino, Sara
Feu i Coll, Sònia
Menoyo, Sandra
Domostegui Fernández, Ana
García Cajide, Marta
Salazar Soler, Ramón
Cortés, Constanza
Marcos, Ricard
Tauler Girona, Albert
Yanes, Oscar
Agell i Jané, Neus
Kozma, Sara C.
Gentilella, Antonio
Thomas, George
Keywords: Reparació de l'ADN
DNA repair
Issue Date: 2-Jun-2020
Publisher: EMBO Press
Abstract: 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.
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It is part of: The EMBO Journal, 2020, vol. 39, num. 13, p. e103838
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ISSN: 0261-4189
Appears in Collections:Articles publicats en revistes (Ciències Clíniques)
Articles publicats en revistes (Ciències Fisiològiques)
Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Articles publicats en revistes (Bioquímica i Fisiologia)
Publicacions de projectes de recerca finançats per la UE

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