RECQ-like helicases Sgs1 and BLM regulate R-loop-associated genome instability.
Emily Yun-Chia ChangCarolina A NovoaMaria J AristizabalYan CoulombeRomulo SegoviaRicha ChaturvediYaoqing ShenChristelle KeongAnnie S TamSteven J M JonesJean-Yves MassonMichael S KoborPeter C StirlingPublished in: The Journal of cell biology (2017)
Sgs1, the orthologue of human Bloom's syndrome helicase BLM, is a yeast DNA helicase functioning in DNA replication and repair. We show that SGS1 loss increases R-loop accumulation and sensitizes cells to transcription-replication collisions. Yeast lacking SGS1 accumulate R-loops and γ-H2A at sites of Sgs1 binding, replication pausing regions, and long genes. The mutation signature of sgs1Δ reveals copy number changes flanked by repetitive regions with high R-loop-forming potential. Analysis of BLM in Bloom's syndrome fibroblasts or by depletion of BLM from human cancer cells confirms a role for Sgs1/BLM in suppressing R-loop-associated genome instability across species. In support of a potential direct effect, BLM is found physically proximal to DNA:RNA hybrids in human cells, and can efficiently unwind R-loops in vitro. Together, our data describe a conserved role for Sgs1/BLM in R-loop suppression and support an increasingly broad view of DNA repair and replication fork stabilizing proteins as modulators of R-loop-mediated genome instability.
Keyphrases
- transcription factor
- copy number
- genome wide
- dna repair
- endothelial cells
- induced apoptosis
- mitochondrial dna
- circulating tumor
- dna damage
- induced pluripotent stem cells
- case report
- single molecule
- dna methylation
- signaling pathway
- oxidative stress
- dna binding
- cell free
- endoplasmic reticulum stress
- machine learning
- cell cycle arrest
- climate change
- cell proliferation
- bioinformatics analysis
- deep learning
- data analysis