Yra1-bound RNA-DNA hybrids cause orientation-independent transcription-replication collisions and telomere instability

Genes Dev. 2018 Jul 1;32(13-14):965-977. doi: 10.1101/gad.311274.117. Epub 2018 Jun 28.


R loops are an important source of genome instability, largely due to their negative impact on replication progression. Yra1/ALY is an abundant RNA-binding factor conserved from yeast to humans and required for mRNA export, but its excess causes lethality and genome instability. Here, we show that, in addition to ssDNA and ssRNA, Yra1 binds RNA-DNA hybrids in vitro and, when artificially overexpressed, can be recruited to chromatin in an RNA-DNA hybrid-dependent manner, stabilizing R loops and converting them into replication obstacles in vivo. Importantly, an excess of Yra1 increases R-loop-mediated genome instability caused by transcription-replication collisions regardless of whether they are codirectional or head-on. It also induces telomere shortening in telomerase-negative cells and accelerates senescence, consistent with a defect in telomere replication. Our results indicate that RNA-DNA hybrids form transiently in cells regardless of replication and, after stabilization by excess Yra1, compromise genome integrity, in agreement with a two-step model of R-loop-mediated genome instability. This work opens new perspectives to understand transcription-associated genome instability in repair-deficient cells, including tumoral cells.

Keywords: R loop; Yra1; telomeres; transcription–replication collision.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromatin / metabolism
  • Chromosomal Instability / genetics*
  • DNA Replication*
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism*
  • Nucleic Acid Hybridization
  • Protein Binding
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / genetics*
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Telomere / genetics*
  • Telomere / metabolism
  • Transcription, Genetic*


  • Chromatin
  • Nuclear Proteins
  • RNA-Binding Proteins
  • Saccharomyces cerevisiae Proteins
  • YRA1 protein, S cerevisiae