The pluripotent-to-totipotent state transition in mESCs activates the intrinsic apoptotic pathway through DUX-induced DNA replication stress.
Pmaip1
DNA replication stress
Intrinsic apoptosis
R-loops
Totipotency
Journal
Cellular and molecular life sciences : CMLS
ISSN: 1420-9071
Titre abrégé: Cell Mol Life Sci
Pays: Switzerland
ID NLM: 9705402
Informations de publication
Date de publication:
26 Oct 2024
26 Oct 2024
Historique:
received:
25
06
2024
accepted:
30
09
2024
revised:
11
09
2024
medline:
26
10
2024
pubmed:
26
10
2024
entrez:
26
10
2024
Statut:
epublish
Résumé
The pluripotent mouse embryonic stem cell (mESCs) can transit into the totipotent-like state, and the transcription factor DUX is one of the master regulators of this transition. Intriguingly, this transition in mESCs is accompanied by massive cell death, which significantly impedes the establishment and maintenance of totipotent cells in vitro, yet the underlying mechanisms of this cell death remain largely elusive. In this study, we found that the totipotency transition in mESCs triggered cell death through the upregulation of DUX. Specifically, R-loops are accumulated upon DUX induction, which subsequently lead to DNA replication stress (RS) in mESCs. This RS further activates p53 and PMAIP1, ultimately leading to Caspase-9/7-dependent intrinsic apoptosis. Notably, inhibiting this intrinsic apoptosis not only mitigates cell death but also enhances the efficiency of the totipotency transition in mESCs. Our findings thus elucidate one of the mechanisms underlying cell apoptosis during the totipotency transition in mESCs and provide a strategy for optimizing the establishment and maintenance of totipotent cells in vitro.
Identifiants
pubmed: 39460804
doi: 10.1007/s00018-024-05465-z
pii: 10.1007/s00018-024-05465-z
doi:
Substances chimiques
Homeodomain Proteins
0
Tumor Suppressor Protein p53
0
Caspase 9
EC 3.4.22.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
440Subventions
Organisme : Intellectual Property Fund of Zhejiang University
ID : None
Organisme : Natural Science Foundation of Zhejiang Province
ID : LZ24C120001
Organisme : General Program of National Natural Science Foundation of China
ID : 32270852
Organisme : General Program of National Natural Science Foundation of China
ID : 32470840
Organisme : National Key R&D Program of China
ID : 2021YFC2700101
Organisme : Cao Guangbiao High Science and Technology Foundation, Zhejiang University
ID : Cao Guangbiao High Science and Technology Foundation, Zhejiang University
Informations de copyright
© 2024. The Author(s).
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