2. Academic Validation
  3. MRE11-RAD50-NBS1 promotes Fanconi Anemia R-loop suppression at transcription-replication conflicts

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

  • Nat Commun. 2019 Sep 19;10(1):4265. doi: 10.1038/s41467-019-12271-w.
Emily Yun-Chia Chang 1,  Shuhe Tsai 1,  Maria J Aristizabal 2,  James P Wells 1,  Yan Coulombe 3 4,  Franciele F Busatto 3 4,  Yujia A Chan 5,  Arun Kumar 1,  Yi Dan Zhu 1,  Alan Ying-Hsu Wang 1,  Louis-Alexandre Fournier 1,  Philip Hieter 6 7,  Michael S Kobor 2,  Jean-Yves Masson 3 4,  Peter C Stirling 8 9
Affiliations

Affiliations

  • 1 Terry Fox Laboratory, BC Cancer, Vancouver, V5Z 1L3, Canada.
  • 2 Centre for Molecular Medicine and Therapeutics, BC Children's Hospital Research Institute, Vancouver, V5Z 4H4, Canada.
  • 3 Centre Hospitalier Universitaire de Québec-Universite Laval, Oncology Axis, Quebec City, G1R 2J6, Canada.
  • 4 Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University Cancer Research Center, Quebec City, G1V 0A6, Canada.
  • 5 The Broad Institute of MIT and Harvard University, Cambridge, MA, 02142, USA.
  • 6 Michael Smith Laboratories, University of British Columbia, Vancouver, V6T 1Z4, Canada.
  • 7 Department of Medical Genetics, University of British Columbia, Vancouver, V5Z 4H4, Canada.
  • 8 Terry Fox Laboratory, BC Cancer, Vancouver, V5Z 1L3, Canada. pstirling@bccrc.ca.
  • 9 Department of Medical Genetics, University of British Columbia, Vancouver, V5Z 4H4, Canada. pstirling@bccrc.ca.
PMID: 31537797 DOI: 10.1038/s41467-019-12271-w
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.

Figures