PARP inhibition induces cytotoxicity in mESCs by activating endogenous retroviruses [ATAC-seq]

PARP inhibitors (PARPi) have been approved to treat patients with BRCA-deficient cancers via synthetic lethality. How PARPi kill BRCA-proficient cells remains an important unanswered question. Here we provide evidence that naïve murine embryonic stem cells, although being homologous-recombination potent, are very sensitive to PARPi such as Talazoparib (Tal). Tal acts on ARTD1 and activates p53 by blocking TOP2A dissociation from chromatin. Genome-wide CRISPR screening showed that the loss of TET1 reduces Tal induced cytotoxicity, which is recapitulated by the depletion of TDG. TET and TDG mediated DNA demethylation turnover renders the local chromatin accessible and facilitates p53 dependent transcription. Consequently, Tal treatment strongly activates the expression of endogenous retroviruses in a p53- and TET/TDG-dependent manner. The uncovered contribution of TET/TDG into Tal induced cytotoxicity sheds further light on future personalized medicine and suggests that TET/TDG mediated active DNA demethylation may represent a biomarker for the predication of sensitivity to PARPi.