Journal
JOURNAL OF CELL BIOLOGY
Volume 216, Issue 12, Pages 3991-4005Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201703168
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Funding
- Canadian Cancer Society [703263]
- Canadian Institutes of Health Research [MOP-136982, 363317]
- Natural Sciences and Engineering Research Council of Canada [RGP IN 402095-11]
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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 gamma-H2A at sites of Sgs1 binding, replication pausing regions, and long genes. The mutation signature of sgs1 Delta 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.
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