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J Cell Biol. 2017 Dec 4;216(12):3991-4005. doi: 10.1083/jcb.201703168. Epub 2017 Oct 17.

RECQ-like helicases Sgs1 and BLM regulate R-loop-associated genome instability.

Author information

1
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada.
2
Centre for Molecular Medicine and Therapeutics, Vancouver, Canada.
3
Genome Stability Laboratory, Centre Hospitalier Universitaire de Québec Research Center, Québec City, Canada.
4
Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University Cancer Research Center, Québec City, Canada.
5
Michael Smith Genome Sciences Centre, Vancouver, Canada.
6
Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
7
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada pstirling@bccrc.ca.

Abstract

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.

PMID:
29042409
PMCID:
PMC5716281
DOI:
10.1083/jcb.201703168
[Indexed for MEDLINE]
Free PMC Article

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