Transcription-coupled nucleotide excision repair factors promote R-loop-induced genome instability

Mol Cell. 2014 Dec 18;56(6):777-85. doi: 10.1016/j.molcel.2014.10.020. Epub 2014 Nov 26.

Abstract

R-loops, consisting of an RNA-DNA hybrid and displaced single-stranded DNA, are physiological structures that regulate various cellular processes occurring on chromatin. Intriguingly, changes in R-loop dynamics have also been associated with DNA damage accumulation and genome instability; however, the mechanisms underlying R-loop-induced DNA damage remain unknown. Here we demonstrate in human cells that R-loops induced by the absence of diverse RNA processing factors, including the RNA/DNA helicases Aquarius (AQR) and Senataxin (SETX), or by the inhibition of topoisomerase I, are actively processed into DNA double-strand breaks (DSBs) by the nucleotide excision repair endonucleases XPF and XPG. Surprisingly, DSB formation requires the transcription-coupled nucleotide excision repair (TC-NER) factor Cockayne syndrome group B (CSB), but not the global genome repair protein XPC. These findings reveal an unexpected and potentially deleterious role for TC-NER factors in driving R-loop-induced DNA damage and genome instability.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Damage
  • DNA Repair Enzymes / genetics
  • DNA Repair Enzymes / metabolism
  • DNA Repair*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Endonucleases / genetics
  • Endonucleases / metabolism
  • Genome, Human
  • Genomic Instability*
  • HeLa Cells
  • Humans
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • RNA Replicase / genetics
  • RNA Replicase / metabolism
  • RNA, Fungal / genetics
  • RNA, Fungal / metabolism
  • Saccharomyces cerevisiae / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic

Substances

  • DNA excision repair protein ERCC-5
  • DNA-Binding Proteins
  • Nuclear Proteins
  • RNA, Fungal
  • Transcription Factors
  • xeroderma pigmentosum group F protein
  • RNA Replicase
  • Endonucleases
  • DNA Repair Enzymes