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

• Published in: Cell 2018-10, Vol.175 (2), p.558-570.e11
• Main Authors: Yasuhara, Takaaki, Kato, Reona, Hagiwara, Yoshihiko, Shiotani, Bunsyo, Yamauchi, Motohiro, Nakada, Shinichiro, Shibata, Atsushi, Miyagawa, Kiyoshi
• Format: Article
• Language: English
• Subjects: Cell Line; DNA - genetics; DNA Breaks, Double-Stranded; DNA Damage; DNA double-strand break; DNA End-Joining Repair; DNA Repair; DNA-Binding Proteins - metabolism; DNA-Binding Proteins - physiology; DNA-RNA hybrid; Endonucleases - metabolism; Endonucleases - physiology; genomic instability; Homologous Recombination; Humans; non-homologous end-joining; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Nuclear Proteins - physiology; R-loop; Rad52; Rad52 DNA Repair and Recombination Protein - genetics; Rad52 DNA Repair and Recombination Protein - metabolism; Recombinational DNA Repair - physiology; RNA - genetics; Transcription Factors - metabolism; Transcription Factors - physiology; transcription-associated homologous recombination repair; XPG
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2018.08.056

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. [Display omitted] •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 Human Rad52 and R-loop facilitate high-fidelity DNA repair in actively transcribed regions.