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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
Summary
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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