Telomere erosion in human pluripotent stem cells leads to ATR-mediated mitotic catastrophe.
Journal
The Journal of cell biology
ISSN: 1540-8140
Titre abrégé: J Cell Biol
Pays: United States
ID NLM: 0375356
Informations de publication
Date de publication:
07 06 2021
07 06 2021
Historique:
received:
02
11
2020
revised:
03
03
2021
accepted:
15
03
2021
entrez:
14
4
2021
pubmed:
15
4
2021
medline:
12
10
2021
Statut:
ppublish
Résumé
It is well established that short telomeres activate an ATM-driven DNA damage response that leads to senescence in terminally differentiated cells. However, technical limitations have hampered our understanding of how telomere shortening is signaled in human stem cells. Here, we show that telomere attrition induces ssDNA accumulation (G-strand) at telomeres in human pluripotent stem cells (hPSCs), but not in their differentiated progeny. This led to a unique role for ATR in the response of hPSCs to telomere shortening that culminated in an extended S/G2 cell cycle phase and a longer period of mitosis, which was associated with aneuploidy and mitotic catastrophe. Loss of p53 increased resistance to death, at the expense of increased mitotic abnormalities in hPSCs. Taken together, our data reveal an unexpected dominant role of ATR in hPSCs, combined with unique cell cycle abnormalities and, ultimately, consequences distinct from those observed in their isogenic differentiated counterparts.
Identifiants
pubmed: 33851958
pii: 211982
doi: 10.1083/jcb.202011014
pmc: PMC8050844
pii:
doi:
Substances chimiques
Cell Cycle Proteins
0
TP53 protein, human
0
Tumor Suppressor Protein p53
0
ATR protein, human
EC 2.7.11.1
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NCI NIH HHS
ID : R01 CA174904
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM101149
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL007088
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL137793
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA237263
Pays : United States
Informations de copyright
© 2021 Vessoni et al.
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