PARP1 inhibition activates endogenous retroviruses and cell death in embryonic stem cells

PARP inhibitors (PARPi) have been approved for cancer therapy based on synthetic lethality with genetic defects in DNA double-strand break repair (DSBR). How PARP inhibition affects DSBR proficient cells has remained uncertain. Here, we show that DSBR proficient murine embryonic stem cells (mESC) are hypersensitive to PARPi such as Talazoparib (Tal) when compared to differentiated cell types. Tal cytotoxicity is dependent on p53, activated by the ATM dependent DNA damage response. CRISPR screening identified the 5-methylcytosine hydroxylases TET1/2 as mediators of p53-dependent cytotoxicity, implicating a role of active DNA demethylation. We show that downstream of Tal-induced p53 activation, TET and TDG facilitate transcriptional activation of p53 targets, including also endogenous retroviral elements, eliciting an interferon response and necroptosis. The data establish a role of active DNA demethylation in the response of mESC to PARPi, providing mechanistic insights into potential genetic and epigenetic effects of PARPi-based therapies on DSBR proficient cells.