Human Rad52 Promotes XPG-Mediated R-loop Processing to Initiate Transcription-Associated Homologous Recombination Repair

Cell. 2018 Oct 4;175(2):558-570.e11. doi: 10.1016/j.cell.2018.08.056. Epub 2018 Sep 20.


Given that genomic DNA exerts its function by being transcribed, it is critical for the maintenance of homeostasis that DNA damage, such as double-strand breaks (DSBs), within transcriptionally active regions undergoes accurate repair. However, it remains unclear how this is achieved. Here, we describe a mechanism for transcription-associated homologous recombination repair (TA-HRR) in human cells. The process is initiated by R-loops formed upon DSB induction. We identify Rad52, which is recruited to the DSB site in a DNA-RNA-hybrid-dependent manner, as playing pivotal roles in promoting XPG-mediated R-loop processing and initiating subsequent repair by HRR. Importantly, dysfunction of TA-HRR promotes DSB repair via non-homologous end joining, leading to a striking increase in genomic aberrations. Thus, our data suggest that the presence of R-loops around DSBs within transcriptionally active regions promotes accurate repair of DSBs via processing by Rad52 and XPG to protect genomic information in these critical regions from gene alterations.

Keywords: DNA double-strand break; DNA-RNA hybrid; R-loop; Rad52; XPG; genomic instability; non-homologous end-joining; transcription-associated homologous recombination repair.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • DNA / genetics
  • DNA Breaks, Double-Stranded
  • DNA Damage
  • DNA End-Joining Repair
  • DNA Repair
  • DNA-Binding Proteins / metabolism*
  • DNA-Binding Proteins / physiology
  • Endonucleases / metabolism*
  • Endonucleases / physiology
  • Homologous Recombination
  • Humans
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Nuclear Proteins / physiology
  • RNA / genetics
  • Rad52 DNA Repair and Recombination Protein / genetics
  • Rad52 DNA Repair and Recombination Protein / metabolism*
  • Recombinational DNA Repair / physiology*
  • Transcription Factors / metabolism*
  • Transcription Factors / physiology


  • DNA excision repair protein ERCC-5
  • DNA-Binding Proteins
  • Nuclear Proteins
  • RAD52 protein, human
  • Rad52 DNA Repair and Recombination Protein
  • Transcription Factors
  • RNA
  • DNA
  • Endonucleases