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

作者：Emily Yun‐Chia Chang, Carolina Novoa, Maria J. Aristizabal, Yan Coulombe, Romulo Segovia, Richa Chaturvedi, Yaoqing Shen, Christelle Keong, Annie Tam, Steven J.M. Jones, Jean‐Yves Masson, Michael S. Kobor, Peter C. Stirling · 发表于：The Journal of Cell Biology · 年份：2017 · DOI：10.1083/jcb.201703168 · 被引用次数：125 · 研究领域：DNA Repair Mechanisms、Genetic factors in colorectal cancer、Mitochondrial Function and Pathology

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.