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

Author

Listed:
  • Emily Yun-Chia Chang

    (Terry Fox Laboratory, BC Cancer)

  • Shuhe Tsai

    (Terry Fox Laboratory, BC Cancer)

  • Maria J. Aristizabal

    (BC Children’s Hospital Research Institute)

  • James P. Wells

    (Terry Fox Laboratory, BC Cancer)

  • Yan Coulombe

    (Oncology Axis
    Laval University Cancer Research Center)

  • Franciele F. Busatto

    (Oncology Axis
    Laval University Cancer Research Center)

  • Yujia A. Chan

    (The Broad Institute of MIT and Harvard University)

  • Arun Kumar

    (Terry Fox Laboratory, BC Cancer)

  • Yi Zhu

    (Terry Fox Laboratory, BC Cancer)

  • Alan Ying-Hsu Wang

    (Terry Fox Laboratory, BC Cancer)

  • Louis-Alexandre Fournier

    (Terry Fox Laboratory, BC Cancer)

  • Philip Hieter

    (University of British Columbia
    University of British Columbia)

  • Michael S. Kobor

    (BC Children’s Hospital Research Institute)

  • Jean-Yves Masson

    (Oncology Axis
    Laval University Cancer Research Center)

  • Peter C. Stirling

    (Terry Fox Laboratory, BC Cancer
    University of British Columbia)

Abstract

Ectopic R-loop accumulation causes DNA replication stress and genome instability. To avoid these outcomes, cells possess a range of anti-R-loop mechanisms, including RNaseH that degrades the RNA moiety in R-loops. To comprehensively identify anti-R-loop mechanisms, we performed a genome-wide trigenic interaction screen in yeast lacking RNH1 and RNH201. We identified >100 genes critical for fitness in the absence of RNaseH, which were enriched for DNA replication fork maintenance factors including the MRE11-RAD50-NBS1 (MRN) complex. While MRN has been shown to promote R-loops at DNA double-strand breaks, we show that it suppresses R-loops and associated DNA damage at transcription–replication conflicts. This occurs through a non-nucleolytic function of MRE11 that is important for R-loop suppression by the Fanconi Anemia pathway. This work establishes a novel role for MRE11-RAD50-NBS1 in directing tolerance mechanisms at transcription–replication conflicts.

Suggested Citation

  • Emily Yun-Chia Chang & Shuhe Tsai & Maria J. Aristizabal & James P. Wells & Yan Coulombe & Franciele F. Busatto & Yujia A. Chan & Arun Kumar & Yi Zhu & Alan Ying-Hsu Wang & Louis-Alexandre Fournier & , 2019. "MRE11-RAD50-NBS1 promotes Fanconi Anemia R-loop suppression at transcription–replication conflicts," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12271-w
    DOI: 10.1038/s41467-019-12271-w
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