A p53-Dependent Checkpoint Induced upon DNA Damage Alters Cell Fate during hiPSC Differentiation.
DNA-damage response
checkpoint
definitive endoderm
differentiation
hESC
hiPSC
p53
Journal
Stem cell reports
ISSN: 2213-6711
Titre abrégé: Stem Cell Reports
Pays: United States
ID NLM: 101611300
Informations de publication
Date de publication:
13 10 2020
13 10 2020
Historique:
received:
17
04
2020
revised:
07
08
2020
accepted:
07
08
2020
pubmed:
6
9
2020
medline:
1
7
2021
entrez:
5
9
2020
Statut:
ppublish
Résumé
The ability of human induced pluripotent stem cells (hiPSCs) to differentiate in vitro to each of the three germ layer lineages has made them an important model of early human development and a tool for tissue engineering. However, the factors that disturb the intricate transcriptional choreography of differentiation remain incompletely understood. Here, we uncover a critical time window during which DNA damage significantly reduces the efficiency and fidelity with which hiPSCs differentiate to definitive endoderm. DNA damage prevents the normal reduction of p53 levels as cells pass through the epithelial-to-mesenchymal transition, diverting the transcriptional program toward mesoderm without induction of an apoptotic response. In contrast, TP53-deficient cells differentiate to endoderm with high efficiency after DNA damage, suggesting that p53 enforces a "differentiation checkpoint" in early endoderm differentiation that alters cell fate in response to DNA damage.
Identifiants
pubmed: 32888504
pii: S2213-6711(20)30334-9
doi: 10.1016/j.stemcr.2020.08.003
pmc: PMC7561492
pii:
doi:
Substances chimiques
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
827-835Subventions
Organisme : Medical Research Council
ID : MC_PC_17230
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_12009
Pays : United Kingdom
Organisme : Medical Research Council
ID : U105178808
Pays : United Kingdom
Organisme : National Centre for the Replacement, Refinement and Reduction of Animals in Research
ID : NC/T2T0419
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0701448
Pays : United Kingdom
Organisme : Medical Research Council
ID : U105178808
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_EX_MR/S300001/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_U105178808
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : National Centre for the Replacement, Refinement and Reduction of Animals in Research
ID : NC/N001540/1
Pays : United Kingdom
Informations de copyright
Copyright © 2020 MRC Laboratory of Molecular Biology. Published by Elsevier Inc. All rights reserved.
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