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Transcription-replication conflict resolution by nuclear RNA interference.

Teri Cheng1, Benjamin Roche2, Farida Abderahmane3

  • 1Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA; School of Biological Sciences, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.

Molecular Cell
|October 29, 2025
PubMed
Summary
This summary is machine-generated.

Dicer processes R-loops, which form at transcription-replication collisions, to release paused RNA polymerase and maintain genome stability. This mechanism is crucial for resolving replication stress and preventing instability.

Keywords:
ArgonauteDicerR-loopsRNA interferenceRNA polymerase pausingRNA-DNA hybridsRNase Hfission yeast Schizosaccharomyces pombereplication stresstranscription

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Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • Nuclear RNA interference (RNAi) is vital for heterochromatin silencing.
  • Dicer (a protein) also enhances genome stability by releasing RNA polymerase during replication stress.
  • R-loops are DNA:RNA structures that form at transcription-replication collisions.

Purpose of the Study:

  • To investigate the role of Dicer in processing R-loops and maintaining genome stability.
  • To understand how R-loops contribute to genome instability in the absence of Dicer.
  • To explore the function of Argonaute (Ago1) in R-loop-mediated genome instability.

Main Methods:

  • Analysis of R-loop processing by Dcr1 in RNase H-deficient cells.
  • Genetic studies to assess genome instability in Dicer-deficient cells.
  • Genome-wide analysis of replication intermediates, DNA/RNA ends, and fork processivity.

Main Results:

  • Dcr1 processes R-loops at transcriptional start and end sites, releasing paused RNA polymerase.
  • Accumulation of R-loops in RNase H-deficient cells generates small RNAs (sRNAs) similar to cancer-associated sdRNAs.
  • Nascent transcription-associated R-loops contribute to genome instability without Dicer.
  • Argonaute (Ago1) exacerbates genome instability by binding R-loops; its removal alleviates replication stress.
  • Dicer resolves head-on transcription-replication collisions, suggesting an ancient role in DNA replication.

Conclusions:

  • Dicer plays a critical role in resolving R-loops and mitigating replication stress, thereby maintaining genome stability.
  • The findings reveal a conserved mechanism linking RNA processing, R-loop resolution, and DNA replication.
  • Dicer's function in resolving transcription-replication collisions highlights its ancient evolutionary role in genome maintenance.