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- Emily Yun-Chia Chang
- Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada 1
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- Carolina A. Novoa
- Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada 1
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- Maria J. Aristizabal
- Centre for Molecular Medicine and Therapeutics, Vancouver, Canada 2
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- Yan Coulombe
- Genome Stability Laboratory, Centre Hospitalier Universitaire de Québec Research Center, Québec City, Canada 3
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- Romulo Segovia
- Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada 1
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- Richa Chaturvedi
- Genome Stability Laboratory, Centre Hospitalier Universitaire de Québec Research Center, Québec City, Canada 3
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- Yaoqing Shen
- Michael Smith Genome Sciences Centre, Vancouver, Canada 5
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- Christelle Keong
- Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada 1
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- Annie S. Tam
- Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada 1
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- Steven J.M. Jones
- Michael Smith Genome Sciences Centre, Vancouver, Canada 5
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- Jean-Yves Masson
- Genome Stability Laboratory, Centre Hospitalier Universitaire de Québec Research Center, Québec City, Canada 3
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- Michael S. Kobor
- Centre for Molecular Medicine and Therapeutics, Vancouver, Canada 2
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- Peter C. Stirling
- Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada 1
抄録
<jats:p>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.</jats:p>
収録刊行物
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- Journal of Cell Biology
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Journal of Cell Biology 216 (12), 3991-4005, 2017-10-17
Rockefeller University Press