RT Journal Article
SR Electronic
T1 MRE11-RAD50-NBS1 activates Fanconi Anemia R-loop suppression at transcription-replication conflicts
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 472654
DO 10.1101/472654
A1 Emily Yun-chia Chang
A1 James P. Wells
A1 Shu-Huei Tsai
A1 Yan Coulombe
A1 Yujia A. Chan
A1 Yi Dan Zhu
A1 Louis-Alexandre Fournier
A1 Philip Hieter
A1 Jean-Yves Masson
A1 Peter C. Stirling
YR 2018
UL http://biorxiv.org/content/early/2018/11/17/472654.abstract
AB 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 such as RAD50. We show in yeast and human cells that R-loops accumulate during RAD50 depletion. In human cancer cell models, we find that RAD50 and its partners in the MRE11-RAD50-NBS1 complex regulate R-loop-associated DNA damage and replication stress. We show that a non-nucleolytic function of MRE11 is important for R-loop suppression via activation of PCNA-ubiquitination by RAD18 and recruiting anti-R-loop helicases in the Fanconi Anemia pathway. This work establishes a novel role for MRE11-RAD50-NBS1 in directing tolerance mechanisms of transcription-replication conflicts.