MRE11-RAD50-NBS1 promotes Fanconi Anemia R-loop suppression at transcription–replication conflicts
| Autor: | Arun Kumar, Yan Coulombe, Maria J. Aristizabal, Jean-Yves Masson, Shuhe Tsai, Yi Dan Zhu, Peter C. Stirling, Louis-Alexandre Fournier, Emily Yun-Chia Chang, Philip Hieter, Yujia Alina Chan, Michael S. Kobor, Franciele F. Busatto, Alan Ying-Hsu Wang, James P. Wells |
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| Rok vydání: | 2019 |
| Předmět: |
Genomic instability
DNA Replication 0301 basic medicine Genome instability Transcription Genetic R-loop DNA damage Science Ribonuclease H General Physics and Astronomy Cell Cycle Proteins Biology Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine Schizosaccharomyces Humans lcsh:Science Gene MRE11 Homologue Protein Multidisciplinary DNA damage and repair DNA replication Nuclear Proteins food and beverages Stalled forks General Chemistry DNA Replication Fork Acid Anhydride Hydrolases Cell biology DNA-Binding Proteins enzymes and coenzymes (carbohydrates) Fanconi Anemia 030104 developmental biology MRN complex 030220 oncology & carcinogenesis Rad50 lcsh:Q R-Loop Structures DNA Damage |
| Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-15 (2019) Nature Communications |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-019-12271-w |
| Popis: | 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. Accumulations of R-loops can lead to genome instability. Here the authors reveal a role for the MRN complex in suppressing R-loops and associated DNA damage at transcription–replication conflicts. |
| Databáze: | OpenAIRE |
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