ATR kinase supports normal proliferation in the early S phase by preventing replication resource exhaustion.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
19 06 2023
19 06 2023
Historique:
received:
16
08
2022
accepted:
08
06
2023
medline:
21
6
2023
pubmed:
20
6
2023
entrez:
19
6
2023
Statut:
epublish
Résumé
The ATR kinase, which coordinates cellular responses to DNA replication stress, is also essential for the proliferation of normal unstressed cells. Although its role in the replication stress response is well defined, the mechanisms by which ATR supports normal cell proliferation remain elusive. Here, we show that ATR is dispensable for the viability of G0-arrested naïve B cells. However, upon cytokine-induced proliferation, Atr-deficient B cells initiate DNA replication efficiently, but by mid-S phase they display dNTP depletion, fork stalling, and replication failure. Nonetheless, productive DNA replication and dNTP levels can be restored in Atr-deficient cells by suppressing origin firing, such as partial inhibition of CDC7 and CDK1 kinase activities. Together, these findings indicate that ATR supports the proliferation of normal unstressed cells by tempering the pace of origin firing during the early S phase to avoid exhaustion of dNTPs and importantly also other replication factors.
Identifiants
pubmed: 37336885
doi: 10.1038/s41467-023-39332-5
pii: 10.1038/s41467-023-39332-5
pmc: PMC10279696
doi:
Substances chimiques
Protein Serine-Threonine Kinases
EC 2.7.11.1
Cell Cycle Proteins
0
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
3618Subventions
Organisme : NCI NIH HHS
ID : R01 CA158073
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA253126
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA271595
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI136581
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA013696
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA254403
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA275184
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA226852
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA215067
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA174653
Pays : United States
Organisme : NIAID NIH HHS
ID : F31 AI157884
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI162633
Pays : United States
Commentaires et corrections
Type : UpdateOf
Informations de copyright
© 2023. The Author(s).
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