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Updated: Jun 5, 2026
Visualization and Quantitative Analysis of Genotoxin-Induced PARP1/PARP2 Activation in Cells Using a Fluorescent Fusion Protein-Based Reporter
Published on: April 17, 2026
PARP1 inhibition in naïve mouse embryonic stem cells induces viral mimicry
Jianming Xu1,2, Simon D Schwarz1, Kapila Gunasekera2,3
1Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland.
Abstract:
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.
Insights
PARP1/2 inhibitors (PARPi) cause DNA damage sensitivity in mouse embryonic stem cells (mESC) through a p53-controlled pathway involving DNA demethylation and retroviral element activation. This reveals a novel mechanism linking DNA repair, demethylation, and cellular response to PARPi.
Area of Science:
- Molecular Biology
- Cancer Biology
- Genetics
Background:
- PARP1/2 inhibitors (PARPi) are effective cancer therapeutics leveraging synthetic lethality in DNA repair-deficient cells.
- Naïve pluripotent mouse embryonic stem cells (mESC) possess intact DNA double-strand break repair (DSBR) mechanisms.
Purpose of the Study:
- To investigate the sensitivity of DSBR-proficient mESC to PARPi.
- To elucidate the molecular mechanisms underlying mESC sensitivity to PARPi.
Main Methods:
- Treatment of mESC with talazoparib and olaparib.
- Analysis of DNA stress signaling (ATM), p53 pathway, TET-TDG-dependent transcription, and endogenous retroviral element (ERV) expression.
- Assessment of viral mimicry markers (type I interferon, necroptosis, caspase activation).
- Depletion studies of p53, TET, and TDG to assess PARPi resistance.
Main Results:
- DSBR-proficient mESC exhibit high sensitivity to PARPi.
- PARPi treatment activates ATM-mediated DNA stress signaling.
- A p53-controlled, TET-TDG-dependent transcriptional program is induced, leading to ERV de-repression.
- Accumulation of double-stranded RNAs triggers viral mimicry responses, including interferon and necroptosis.
- Depletion of p53, TET, or TDG confers resistance to PARPi in mESC.
Conclusions:
- Active DNA demethylation is a critical mediator of PARPi sensitivity in mESC.
- DNA stress can induce ERV expression in cells with accessible chromatin.
- These findings provide mechanistic insights into PARPi sensitivity beyond DSBR defects.
