Nucleotide depletion reveals the impaired ribosome biogenesis checkpoint as a barrier against DNA damage.
IRBC
IMPDH
nucleotides
p21
p53
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
01 07 2020
01 07 2020
Historique:
received:
26
10
2019
revised:
07
03
2020
accepted:
14
04
2020
pubmed:
3
6
2020
medline:
7
4
2021
entrez:
3
6
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32484960
doi: 10.15252/embj.2019103838
pmc: PMC7327477
doi:
Substances chimiques
Nucleotides
0
TP53 protein, human
0
Tumor Suppressor Protein p53
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e103838Subventions
Organisme : Ministerio de Economía, Industria y Competitividad, Gobierno de España (MINECO)
ID : SAF2016-76239-R
Organisme : NCI NIH HHS
ID : R21 CA191814
Pays : United States
Organisme : HHS | NIH | National Cancer Institute (NCI)
ID : R01-CA191814
Organisme : Fundación Científica Asociación Española Contra el Cáncer (AECC)
ID : GCB-142035THOM
Organisme : European Commission (EC)
ID : PCIG10-GA-2011-304160
Organisme : Ministerio de Economía, Industria y Competitividad, Gobierno de España (MINECO)
ID : SAF2017-84301-P
Organisme : Government of Catalonia | Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR)
ID : AGAUR-2017 SGR 01743
Organisme : Fondation ARC pour la Recherche sur le Cancer (ARC)
ID : SAE20140601346
Organisme : MEC | Instituto de Salud Carlos III (ISCIII)
ID : RD12/0036/0049
Organisme : Ministerio de Economía, Industria y Competitividad, Gobierno de España (MINECO)
ID : SAF2014-52162-P
Organisme : Government of Catalonia | Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR)
ID : 2014SGR-870
Informations de copyright
© 2020 The Authors. Published under the terms of the CC BY 4.0 license.
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