MRE11-RAD50-NBS1 promotes Fanconi Anemia R-loop suppression at transcription-replication conflicts.
Emily Yun-Chia ChangShuhe TsaiMaria J AristizabalJames P WellsYan CoulombeFranciele F BusattoYujia A ChanArun KumarYi Dan ZhuAlan Ying-Hsu WangLouis-Alexandre FournierPhilip HieterMichael S KoborJean-Yves MassonPeter C StirlingPublished in: Nature communications (2019)
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.
Keyphrases
- dna damage
- transcription factor
- genome wide
- dna repair
- chronic kidney disease
- induced apoptosis
- oxidative stress
- signaling pathway
- body composition
- physical activity
- high throughput
- cell cycle arrest
- metabolic syndrome
- iron deficiency
- insulin resistance
- cell free
- endoplasmic reticulum stress
- skeletal muscle
- single molecule
- nucleic acid
- pi k akt
- circulating tumor cells