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Deficiency in U5 small nuclear ribonucleoprotein particles (snRNPs) causes R-loops and cell cycle arrest. The Xrp1-Irbp18 heterodimer mediates this stress response, highlighting splicing

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Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • Co-transcriptional pre-mRNA processing by the spliceosome is crucial for gene expression and genome stability.
  • U5 small nuclear ribonucleoprotein particles (snRNPs) are essential components of the spliceosome.

Purpose of the Study:

  • To investigate the consequences of U5 snRNP deficiency in Drosophila imaginal cells.
  • To identify the molecular mechanisms linking spliceosome malfunction to cellular stress responses.

Main Methods:

  • Generating U5 snRNP-deficient Drosophila imaginal cells.
  • Transcriptome analysis (RNA-seq).
  • R-loop detection and quantification.
  • Western blotting for stress markers (JNK, p53).
  • RNA interference (RNAi) to knockdown Xrp1 and Irbp18.

Main Results:

  • U5 snRNP deficiency led to widespread transcriptome changes and mutagenic R-loop accumulation.
  • Cells exhibited stress responses, cell cycle arrest, increased protein translation, cell size, and apoptosis.
  • The Xrp1-Irbp18 heterodimer was identified as a key mediator of the stress program.
  • Knockdown of Xrp1 or Irbp18 reduced stress signaling, restored cell cycle, and inhibited apoptosis, but did not fix splicing defects.

Conclusions:

  • U5 snRNP malfunction triggers a DNA damage response pathway involving R-loops and the Xrp1-Irbp18 heterodimer.
  • Accurate splicing is essential for maintaining cellular and tissue homeostasis.
  • The Xrp1-Irbp18 heterodimer acts as a sensor for spliceosome defects and mediates stress-induced cellular senescence.