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

作者：Emily Yun‐Chia Chang, Shuhe Tsai, Maria J. Aristizabal, James P. Wells, Yan Coulombe, Franciele Faccio Busatto, Yujia A. Chan, Arun Kumar, Yi Dan Zhu, Alan Ying-Hsu Wang, Louis-Alexandre Fournier, Philip Hieter, Michael S. Kobor, Jean‐Yves Masson, Peter C. Stirling · 发表于：Nature Communications · 年份：2019 · DOI：10.1038/s41467-019-12271-w · 被引用次数：102 · 研究领域：DNA Repair Mechanisms、Fungal and yeast genetics research、Photosynthetic Processes and Mechanisms

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.