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PARP1 trapping activates ATM-mediated NF-κB signaling independent of replication in response to TOP1 blockade

Elodie Bournique1, Ambrocio Sanchez1, Kim Ha1

  • 1Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA 92697, United States.

Nucleic Acids Research
|June 4, 2026
PubMed

Insights

Combining PARP inhibitors with topoisomerase 1 (TOP1) inhibitors enhances NF-κB activation. This occurs via distinct DNA damage pathways, revealing PARP1

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • DNA Damage Response

Background:

  • Nuclear factor-kappa B (NF-κB) pathway activation is central to inflammation.
  • Genotoxic stresses activate NF-κB, but mechanisms linking DNA damage to activation are unclear.
  • Topoisomerase 1 (TOP1) inhibition is a genotoxic stress that activates NF-κB.

Purpose of the Study:

  • To elucidate the mechanisms of NF-κB activation by TOP1 inhibition.
  • To investigate the role of PARP inhibitors in modulating TOP1-induced NF-κB signaling.
  • To identify therapeutic opportunities for enhancing anti-cancer therapy efficacy.

Main Methods:

  • Cellular treatments with TOP1 and PARP inhibitors.
  • Analysis of ATM-mediated NF-κB signaling pathways.
  • Investigation of replication-dependent and independent pathways.
  • Assessment of PARP1 trapping at DNA lesions.

Main Results:

  • TOP1 inhibition activates ATM-mediated NF-κB signaling via replication-dependent and independent pathways.
  • PARP inhibitors significantly enhance TOP1-induced NF-κB activation.
  • PARP1 trapping at DNA lesions, not enzymatic activity, mediates this enhancement.
  • This mechanism mimics the cellular response to TDP1 depletion.

Conclusions:

  • PARP1 acts as an NF-κB activator when trapped at TOP1-induced DNA lesions.
  • PARP inhibitors can potentiate inflammatory responses.
  • Combining PARP and TOP1 inhibitors offers a potential strategy to improve cancer therapy efficacy.

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