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MRE11-RAD50-NBS1 promotes Fanconi Anemia R-loop suppression at transcription-replication conflicts

Emily Yun-Chia Chang1, Shuhe Tsai1, Maria J Aristizabal2

  • 1Terry Fox Laboratory, BC Cancer, Vancouver, V5Z 1L3, Canada.

Nature Communications
|September 21, 2019
PubMed

Insights

Cells use anti-R-loop mechanisms to prevent DNA replication stress. Researchers found the MRE11-RAD50-NBS1 complex suppresses R-loops during transcription-replication conflicts, revealing a new role in genome stability.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • Ectopic R-loops trigger DNA replication stress and genome instability.
  • Ribonuclease H (RNaseH) enzymes degrade RNA in R-loops, acting as a key anti-R-loop mechanism.
  • Understanding comprehensive anti-R-loop strategies is crucial for genome maintenance.

Purpose of the Study:

  • To identify novel anti-R-loop mechanisms beyond RNaseH.
  • To investigate the role of DNA replication fork maintenance factors in R-loop suppression.
  • To elucidate the function of the MRE11-RAD50-NBS1 complex in R-loop regulation.

Main Methods:

  • Genome-wide trigenic interaction screen in yeast lacking RNaseH (RNH1 and RNH201).
  • Fitness analysis of genes in the absence of RNaseH.
  • Investigating the MRE11-RAD50-NBS1 complex's role in R-loop suppression at transcription-replication conflicts.

Main Results:

  • Identified over 100 genes essential for fitness when RNaseH is absent.
  • Discovered enrichment of DNA replication fork maintenance factors, including the MRE11-RAD50-NBS1 complex.
  • Demonstrated that the MRE11-RAD50-NBS1 complex suppresses R-loops and associated DNA damage during transcription-replication conflicts via a non-nucleolytic MRE11 function.

Conclusions:

  • The MRE11-RAD50-NBS1 complex plays a novel role in suppressing R-loops at transcription-replication conflicts.
  • This function of MRE11 is important for the Fanconi Anemia pathway's R-loop suppression.
  • The study highlights MRE11-RAD50-NBS1 in directing tolerance mechanisms crucial for genome stability.

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