The pluripotent-to-totipotent state transition in mESCs activates the intrinsic apoptotic pathway through DUX-induced DNA replication stress.

ABSTRACT: 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 intri

SUBMITTER: Jia S 

PROVIDER: S-EPMC11512989 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature