Ints7 deficiency activates DNA damage response to elicit resurgence of endogenous retrovirus MERVL and anastasis of embryonic stem cells.

ABSTRACT: The murine endogenous retrovirus MERVL is dynamically activated in a small population of in vitro cultured mouse embryonic stem cells (mESCs) exhibiting totipotent-like features. Yet, the relationship between MERVL activation and cell fate decisions of mESCs is incompletely understood. Through a genome-wide knockout screen, we discovered that MERVL activity is intrinsically linked to DNA damage response pathways. Loss of Ints7, a backbone subunit of the Integrator complex, increased DNA damage and triggered MERVL expression. Mechanistically, Ints7 depletion induced phosphorylation of Kap1, increased chromatin accessibility at MERVL loci, and activated the p53-Dux axis to drive MERVL transcription. Intriguingly, DNA damage-induced MERVL resurgence followed the cleavage of caspase-3, often a

SUBMITTER: Shen Y 

PROVIDER: S-EPMC12370625 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature