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The inflammasome sensor NLRP3 interacts with REV7 to maintain genome integrity through homologous recombination

Delphine Burlet1,2,3,4, Md Muntaz Khan1,2,3,4, Sabine Hacot1,2,3,4

  • 1INSERM U1052, Centre de Recherche en Cancérologie de Lyon, F-69000 Lyon, France.

Nucleic Acids Research
|July 4, 2025
PubMed

Insights

The inflammasome sensor NLRP3 promotes DNA repair pathway selection for genome stability. NLRP3 deficiency impairs homologous recombination, increasing sensitivity to PARP inhibitors, but REV7 loss restores this repair pathway.

Area of Science:

  • Molecular Biology
  • DNA Repair Mechanisms
  • Innate Immunity

Background:

  • DNA double-strand breaks (DSBs) are critical DNA lesions that can lead to genome instability and cancer.
  • DSB repair occurs via non-homologous end joining (NHEJ) or homologous recombination (HR), with pathway choice influenced by DNA end resection.
  • The shieldin complex inhibits resection, favoring NHEJ.

Purpose of the Study:

  • To investigate the role of the inflammasome sensor NLRP3 in regulating DNA double-strand break repair pathway selection.
  • To elucidate the mechanism by which NLRP3 influences homologous recombination (HR) efficiency.
  • To determine the therapeutic implications of NLRP3's role in DSB repair, particularly concerning PARP inhibitors (PARPi).

Main Methods:

  • Assessed HR efficiency using RAD51 foci formation and functional HR assays in cells with and without NLRP3.
  • Investigated the interaction between NLRP3 and REV7, a component of the shieldin complex.
  • Evaluated the sensitivity of NLRP3-deficient cells to Poly-ADP-ribose polymerase (PARP) inhibitors (PARPi) and their relationship with BRCA1 deficiency and REV7 status.

Main Results:

  • NLRP3 facilitates DNA end resection, thereby promoting the homologous recombination (HR) pathway in an inflammasome-independent manner.
  • NLRP3 depletion significantly reduces HR efficiency and increases sensitivity to PARP inhibitors (PARPi), mirroring HR-deficient cancer cells.
  • NLRP3 interacts with REV7, and its absence leads to increased REV7 recruitment to DSBs, impairing HR. Loss of REV7 in NLRP3-depleted cells restores HR and confers PARPi resistance.

Conclusions:

  • NLRP3 plays a critical role in promoting DNA end resection and favoring the HR pathway for DSB repair, independent of its inflammasome function.
  • NLRP3 deficiency sensitizes cells to PARP inhibitors (PARPi) due to impaired HR, highlighting a potential therapeutic vulnerability.
  • The interaction between NLRP3 and REV7 in regulating DSB repair pathway choice offers new insights into maintaining genome integrity and developing cancer therapies.

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