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

  • Emily Yun-Chia Chang
    Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada 1
  • Carolina A. Novoa
    Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada 1
  • Maria J. Aristizabal
    Centre for Molecular Medicine and Therapeutics, Vancouver, Canada 2
  • Yan Coulombe
    Genome Stability Laboratory, Centre Hospitalier Universitaire de Québec Research Center, Québec City, Canada 3
  • Romulo Segovia
    Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada 1
  • Richa Chaturvedi
    Genome Stability Laboratory, Centre Hospitalier Universitaire de Québec Research Center, Québec City, Canada 3
  • Yaoqing Shen
    Michael Smith Genome Sciences Centre, Vancouver, Canada 5
  • Christelle Keong
    Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada 1
  • Annie S. Tam
    Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada 1
  • Steven J.M. Jones
    Michael Smith Genome Sciences Centre, Vancouver, Canada 5
  • Jean-Yves Masson
    Genome Stability Laboratory, Centre Hospitalier Universitaire de Québec Research Center, Québec City, Canada 3
  • Michael S. Kobor
    Centre for Molecular Medicine and Therapeutics, Vancouver, Canada 2
  • 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>

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