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Conserved roles of RECQ-like helicases Sgs1 and BLM in preventing R-loop associated genome instability

Carolina A. Novoa, Emily Yun-Chia Chang, Maria J. Aristizabal, Yan Coulombe, Romulo Segovia, Yaoqing Shen, Christelle Keong, Steven J.M. Jones, Jean-Yves Masson, Michael S. Kobor, Peter C. Stirling
doi: https://doi.org/10.1101/119677
Carolina A. Novoa
1Terry Fox Laboratory, BC Cancer Agency, Vancouver BC, Canada V5Z 1L3
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Emily Yun-Chia Chang
1Terry Fox Laboratory, BC Cancer Agency, Vancouver BC, Canada V5Z 1L3
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Maria J. Aristizabal
2Centre for Molecular Medicine and Therapeutics, Vancouver BC, Canada V5Z 4H4
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Yan Coulombe
3Genome Stability Laboratory, CHU de Québec Research Center, HDQ Pavilion, Oncology Axis, 9 McMahon, Québec City, QC G1R 2J6, Canada
4Department of Molecular Biology, Medical Biochemistry and Pathology; Laval University Cancer Research Center, Québec City, QC G1V 0A6, Canada
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Romulo Segovia
1Terry Fox Laboratory, BC Cancer Agency, Vancouver BC, Canada V5Z 1L3
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Yaoqing Shen
5Michael Smith Genome Sciences Centre, Vancouver BC, Canada V5Z 4S6
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Christelle Keong
1Terry Fox Laboratory, BC Cancer Agency, Vancouver BC, Canada V5Z 1L3
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Steven J.M. Jones
5Michael Smith Genome Sciences Centre, Vancouver BC, Canada V5Z 4S6
6Department of Medical Genetics, University of British Columbia, Vancouver BC, Canada V6T 1Z4
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Jean-Yves Masson
3Genome Stability Laboratory, CHU de Québec Research Center, HDQ Pavilion, Oncology Axis, 9 McMahon, Québec City, QC G1R 2J6, Canada
4Department of Molecular Biology, Medical Biochemistry and Pathology; Laval University Cancer Research Center, Québec City, QC G1V 0A6, Canada
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Michael S. Kobor
2Centre for Molecular Medicine and Therapeutics, Vancouver BC, Canada V5Z 4H4
6Department of Medical Genetics, University of British Columbia, Vancouver BC, Canada V6T 1Z4
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Peter C. Stirling
1Terry Fox Laboratory, BC Cancer Agency, Vancouver BC, Canada V5Z 1L3
6Department of Medical Genetics, University of British Columbia, Vancouver BC, Canada V6T 1Z4
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  • For correspondence: pstirling@bccrc.ca
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Abstract

Sgs1 is a yeast DNA helicase functioning in DNA replication and repair, and is the orthologue of the human Bloom’s syndrome helicase BLM. Here we analyze the mutation signature associated with SGS1 deletion in yeast, and find frequent copy number changes flanked by regions of repetitive sequence and high R-loop forming potential. We show that loss of SGS1 increases R-loop accumulation and sensitizes cells to replication-transcription collisions. Accordingly, in sgs1Δ cells the genome-wide distribution of R-loops shifts to known sites of Sgs1 action, replication pausing regions, and to long genes. Depletion of the orthologous BLM helicase from human cancer cells also increases R-loop levels, and R-loop-associated genome instability. In support of a 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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Posted March 23, 2017.
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Conserved roles of RECQ-like helicases Sgs1 and BLM in preventing R-loop associated genome instability
Carolina A. Novoa, Emily Yun-Chia Chang, Maria J. Aristizabal, Yan Coulombe, Romulo Segovia, Yaoqing Shen, Christelle Keong, Steven J.M. Jones, Jean-Yves Masson, Michael S. Kobor, Peter C. Stirling
bioRxiv 119677; doi: https://doi.org/10.1101/119677
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Conserved roles of RECQ-like helicases Sgs1 and BLM in preventing R-loop associated genome instability
Carolina A. Novoa, Emily Yun-Chia Chang, Maria J. Aristizabal, Yan Coulombe, Romulo Segovia, Yaoqing Shen, Christelle Keong, Steven J.M. Jones, Jean-Yves Masson, Michael S. Kobor, Peter C. Stirling
bioRxiv 119677; doi: https://doi.org/10.1101/119677

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