RESUMO
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.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Endonucleases/metabolismo , Proteínas Nucleares/metabolismo , Proteína Rad52 de Recombinação e Reparo de DNA/metabolismo , Reparo de DNA por Recombinação/fisiologia , Fatores de Transcrição/metabolismo , Linhagem Celular , DNA/genética , Quebras de DNA de Cadeia Dupla , Dano ao DNA , Reparo do DNA por Junção de Extremidades , Reparo do DNA , Proteínas de Ligação a DNA/fisiologia , Endonucleases/fisiologia , Recombinação Homóloga , Humanos , Proteínas Nucleares/genética , Proteínas Nucleares/fisiologia , RNA/genética , Proteína Rad52 de Recombinação e Reparo de DNA/genética , Fatores de Transcrição/fisiologiaRESUMO
The roles of RNA in the DNA damage response are emerging. We highlight findings from our recent study demonstrating the mechanism for transcription-associated homologous recombination repair (TA-HRR) of DNA double-strand breaks and the critical role of R-loops in TA-HRR.