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Here, we show that DSBR-proficient, na\u00efve 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.<\/jats:p>","DOI":"10.1093\/nar\/gkag537","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T11:19:27Z","timestamp":1779794367000},"source":"Crossref","is-referenced-by-count":1,"title":["PARP1 inhibition in na\u00efve mouse embryonic stem cells induces viral mimicry"],"prefix":"10.1093","volume":"54","author":[{"given":"Jianming","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Biomedicine, University of Basel , Mattenstrasse 28, 4058 Basel ,","place":["Switzerland"]},{"name":"Department of Molecular Mechanisms of Disease, University of Z\u00fcrich , Winterthurerstrasse 190, 8057 Zurich 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