Abstract
RAD52-mediated processing of R-loops initiates high-fidelity DNA repair in actively transcribed regions.
Major finding: RAD52-mediated processing of R-loops initiates high-fidelity DNA repair in actively transcribed regions.
Mechanism: RAD52 recruits BRCA1 to antagonize RIF1–53BP1 and facilitate high-fidelity double strand break repair.
Impact: Transcription-associated homologous recombination repair prevents induction of genomic alterations by NHEJ.
It is essential that DNA double strand breaks (DSB) are accurately repaired in transcriptionally active regions of the genome. DSB repair can occur via nonhomologous end joining (NHEJ), an error-prone pathway, or homologous recombination repair (HRR). HRR proteins preferentially accumulate at DSBs in transcriptionally active regions, but the mechanisms underlying the preference for HRR over NHEJ have not been determined. In S. cerevisiae, DNA–RNA hybrids formed in the vicinity of DSBs can promote HRR, but it is not clear if this occurs in human cells. Consistent with previous findings, Yasuhara, Kato, and colleagues found that in human cells DSBs were predominantly repaired by HRR in transcriptionally active regions. This DSB repair was dependent on ongoing transcription and termed transcription associated HRR (TA-HRR). TA-HRR required RAD52 for induction, and this process prevented the induction of gene alterations by aberrant NHEJ. Impairing TA-HRR resulted in an NHEJ-dependent increase in genomic alterations. Mechanistically, RAD52 recruited BRCA1 to antagonize the RIF1-53BP1 complex and initiate TA-HRR. The recruitment of RAD52 and BRCA1 required DNA–RNA hybrids, termed R-loops, which were formed upon the induction of DSBs in actively transcribed regions. RAD52 and the endonuclease XPG processed the R-loops to initiate TA-HRR. Taken together, these findings suggest that the presence of R-loops around DSBs in transcriptionally active regions of the genome may facilitate accurate repair via RAD52 and XPG-mediated processing, protecting the critical regions from aberrant repair by NHEJ.
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