PARP1 inhibition in naïve mouse embryonic stem cells induces viral mimicry

PARP1/2 inhibitors (PARPi) are effective in cancer therapy due to their synthetic lethality in cells with defects in DNA double-strand break repair (DSBR). Here, we show that DSBR-proficient, naïve pluripotent mouse embryonic stem cells (mESC) exhibit high sensitivity towards PARP1/2 inhibition by talazoparib and olaparib. This sensitivity results from a two-tiered response of mESC to PARPi, starting with the activation of DNA stress signalling via ATM and followed by a p53-controlled, TET-TDG-dependent transcriptional response, including the de-repression of endogenous retroviral elements (ERVs). The resulting accumulation of double-stranded RNAs then elicits hallmarks of viral mimicry, marked by induction of type I interferon and necroptosis responses, alongside caspase activation. Accordingly, depletion of p53, TET, or TDG confers PARPi resistance in mESC. These findings highlight active DNA demethylation as a critical mediator of PARPi sensitivity in mESC and provide mechanistic insight into how DNA stress drives ERV expression in cells with accessible chromatin.