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Splicing stress-driven cell death via Z-form nucleic acids

Marat Pavlyukov1, Juan Valcárcel2

  • 1Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.

Molecular Cell
|May 2, 2025
PubMed

Insights

Inhibitors of pre-messenger RNA (mRNA) splicing trigger cell death by forming Z-form nucleic acid hybrids. These structures activate the ZBP1 protein, initiating innate immune responses.

Area of Science:

  • Molecular Biology
  • Immunology
  • Cell Death Research

Background:

  • Pre-messenger RNA (mRNA) splicing is crucial for gene expression.
  • Dysregulation of splicing can lead to cellular dysfunction and disease.

Purpose of the Study:

  • To investigate the cellular consequences of inhibiting pre-mRNA splicing.
  • To identify the molecular mechanisms underlying splicing inhibitor-induced cell death.

Main Methods:

  • Treatment of cells with pre-mRNA splicing inhibitors.
  • Analysis of nucleic acid structures, including RNA-RNA and DNA-RNA hybrids.
  • Investigation of Z-nucleic acid recognition by ZBP1.
  • Assessment of innate immune signaling activation.

Main Results:

  • Splicing inhibitors induce the formation of Z-form RNA-RNA and DNA-RNA hybrids.
  • The protein ZBP1 recognizes these Z-nucleic acids.
  • ZBP1 activation leads to the initiation of innate immune signaling pathways.

Conclusions:

  • Inhibitors of pre-mRNA splicing can trigger cell death through the formation of Z-nucleic acid hybrids.
  • ZBP1 acts as a sensor for these aberrant nucleic acid structures, activating innate immunity.

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