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

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, Philip Hieter, Michael S. Kobor, Jean-Yves Masson and Peter C. Stirling ()
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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
Franciele F. Busatto: Oncology Axis
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
Michael S. Kobor: BC Children’s Hospital Research Institute
Jean-Yves Masson: Oncology Axis
Peter C. Stirling: Terry Fox Laboratory, BC Cancer

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12271-w

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