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Cellular imbalance of specific RNA-binding proteins associates with harmful R-loops

José Antonio Mérida-Cerro1, Guillaume Chevreux2, Benoit Palancade2

  • 1Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER), Universidad de Sevilla-CSIC-Universidad Pablo de Olavide, Seville, Spain.

Plos Genetics
|July 2, 2025
PubMed

Insights

Three RNA-binding proteins (RBPs) and RNA exosome component Dis3 impact R-loop homeostasis, preventing DNA damage and genomic instability. Dysregulation of RBPs or RNAs can cause R-loop-mediated damage, potentially linking to cancer.

Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • Nascent mRNA assembly into messenger ribonucleoprotein (mRNP) complexes is critical for cellular function.
  • R-loop homeostasis is essential for preventing genome instability.
  • Understanding the interplay between mRNP biogenesis and R-loop regulation is key to cellular health.

Purpose of the Study:

  • To identify RNA-binding proteins (RBPs) involved in maintaining R-loop homeostasis.
  • To investigate the role of specific RBPs and RNA exosome components in preventing DNA damage.
  • To explore the link between R-loop accumulation, RBP availability, and genomic instability.

Main Methods:

  • Expression analysis of RNA-binding proteins (RBPs) and RNA exosome components.
  • Analysis of R-loop formation under varying RBP and RNA exosome conditions.
  • Investigation of mRNP composition in relation to R-loop accumulation.

Main Results:

  • Rie1, Rim4, and She2 expression levels are crucial for limiting R-loop accumulation and preventing DNA damage.
  • Rim4 and She2 are found in CBP80-containing mRNPs when THO is absent.
  • Excess Dis3 impairs RNA exosome function, leading to R-loop accumulation from non-coding RNAs and genomic instability.

Conclusions:

  • Changes in RBP or RNA availability disrupt R-loop homeostasis, causing DNA damage.
  • R-loop-mediated DNA damage is linked to genomic instability.
  • Dysregulation of RBPs and R-loops may contribute to cancer development, as several RBPs are overexpressed in tumors.

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