Cell
Volume 175, Issue 2, 4 October 2018, Pages 558-570.e11
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Article
Human Rad52 Promotes XPG-Mediated R-loop Processing to Initiate Transcription-Associated Homologous Recombination Repair

https://doi.org/10.1016/j.cell.2018.08.056Get rights and content
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Highlights

  • DSB repair via TA-HRR prevents gene alterations caused by aberrant NHEJ

  • DNA-RNA hybrid-dependent recruitment of Rad52 is the key step to initiate TA-HRR

  • R-loop processing by Rad52 and XPG is critical for the initiation of TA-HRR

  • Rad52 recruits BRCA1 to antagonize the RIF1-53BP1 complex during TA-HRR

Summary

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

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

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