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 accompanying a process known as anastasis-cell survival after transient apoptotic signaling. Collectively, our study uncovered that MERVL activation in mESCs is integrated into the cellular circuit for decision-making in response to DNA damage, suggesting that sublethal caspase activation can influence the developmental potential of stem cells.