Histone Mutants Separate R Loop Formation from Genome Instability Induction

Mol Cell. 2017 Jun 1;66(5):597-609.e5. doi: 10.1016/j.molcel.2017.05.014.


R loops have positive physiological roles, but they can also be deleterious by causing genome instability, and the mechanisms for this are unknown. Here we identified yeast histone H3 and H4 mutations that facilitate R loops but do not cause instability. R loops containing single-stranded DNA (ssDNA), versus RNA-DNA hybrids alone, were demonstrated using ssDNA-specific human AID and bisulfite. Notably, they are similar size regardless of whether or not they induce genome instability. Contrary to mutants causing R loop-mediated instability, these histone mutants do not accumulate H3 serine-10 phosphate (H3S10-P). We propose a two-step mechanism in which, first, an altered chromatin facilitates R loops, and second, chromatin is modified, including H3S10-P, as a requisite for compromising genome integrity. Consistently, these histone mutations suppress the high H3S10 phosphorylation and genomic instability of hpr1 and sen1 mutants. Therefore, contrary to what was previously believed, R loops do not cause genome instability by themselves.

Keywords: H3 serine-10 phosphorylation; R loops; RNA-DNA hybrids; chromatin; chromatin compaction; chromosome fragility; genome instability; histones H3 and H4.

MeSH terms

  • Chromatin / chemistry
  • Chromatin / genetics*
  • Chromatin / metabolism
  • Chromatin Assembly and Disassembly*
  • DNA Damage
  • DNA Helicases / genetics
  • DNA Helicases / metabolism
  • DNA, Fungal / chemistry
  • DNA, Fungal / genetics*
  • DNA, Fungal / metabolism
  • Genome, Fungal*
  • Genomic Instability*
  • Histones / chemistry
  • Histones / genetics*
  • Histones / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Nucleic Acid Conformation
  • Phosphorylation
  • Point Mutation*
  • Protein Conformation
  • Protein Processing, Post-Translational
  • RNA Helicases / genetics
  • RNA Helicases / metabolism
  • RNA, Fungal / chemistry
  • RNA, Fungal / genetics*
  • RNA, Fungal / metabolism
  • Saccharomyces cerevisiae / genetics*
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism
  • Structure-Activity Relationship


  • Chromatin
  • DNA, Fungal
  • HPR1 protein, S cerevisiae
  • Histones
  • Nuclear Proteins
  • RNA, Fungal
  • Saccharomyces cerevisiae Proteins
  • SEN1 protein, S cerevisiae
  • DNA Helicases
  • RNA Helicases