ROS-induced R loops trigger a transcription-coupled but BRCA1/2-independent homologous recombination pathway through CSB

Nat Commun. 2018 Oct 8;9(1):4115. doi: 10.1038/s41467-018-06586-3.


Actively transcribed regions of the genome are protected by transcription-coupled DNA repair mechanisms, including transcription-coupled homologous recombination (TC-HR). Here we used reactive oxygen species (ROS) to induce and characterize TC-HR at a transcribed locus in human cells. As canonical HR, TC-HR requires RAD51. However, the localization of RAD51 to damage sites during TC-HR does not require BRCA1 and BRCA2, but relies on RAD52 and Cockayne Syndrome Protein B (CSB). During TC-HR, RAD52 is recruited by CSB through an acidic domain. CSB in turn is recruited by R loops, which are strongly induced by ROS in transcribed regions. Notably, CSB displays a strong affinity for DNA:RNA hybrids in vitro, suggesting that it is a sensor of ROS-induced R loops. Thus, TC-HR is triggered by R loops, initiated by CSB, and carried out by the CSB-RAD52-RAD51 axis, establishing a BRCA1/2-independent alternative HR pathway protecting the transcribed genome.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • BRCA1 Protein / genetics
  • BRCA1 Protein / metabolism
  • BRCA2 Protein / genetics
  • BRCA2 Protein / metabolism
  • Base Sequence
  • Cell Line, Tumor
  • DNA / genetics
  • DNA / metabolism
  • DNA Damage
  • DNA Helicases / genetics
  • DNA Helicases / metabolism*
  • DNA Repair
  • DNA Repair Enzymes / genetics
  • DNA Repair Enzymes / metabolism*
  • HEK293 Cells
  • Homologous Recombination*
  • Humans
  • Poly-ADP-Ribose Binding Proteins / genetics
  • Poly-ADP-Ribose Binding Proteins / metabolism*
  • Rad51 Recombinase / genetics
  • Rad51 Recombinase / metabolism
  • Rad52 DNA Repair and Recombination Protein / genetics
  • Rad52 DNA Repair and Recombination Protein / metabolism
  • Reactive Oxygen Species / metabolism*
  • Sequence Homology, Amino Acid
  • Transcription, Genetic*


  • BRCA1 Protein
  • BRCA1 protein, human
  • BRCA2 Protein
  • BRCA2 protein, human
  • Poly-ADP-Ribose Binding Proteins
  • RAD52 protein, human
  • Rad52 DNA Repair and Recombination Protein
  • Reactive Oxygen Species
  • DNA
  • Rad51 Recombinase
  • DNA Helicases
  • ERCC6 protein, human
  • DNA Repair Enzymes