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

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

Author information

1
Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan. Electronic address: tyasuhara-tky@umin.ac.jp.
2
Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
3
Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
4
Division of Cellular Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
5
Division of Radiation Biology and Protection, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
6
Department of Bioregulation and Cellular Response, Graduate School of Medicine, Osaka University, Osaka, Japan; Institute for Advanced Co-Creation Studies, Osaka University, Osaka, Japan.
7
Education and Research Support Center, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan. Electronic address: shibata.at@gunma-u.ac.jp.
8
Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan. Electronic address: miyag-tky@umin.ac.jp.

Abstract

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

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PMID:
30245011
DOI:
10.1016/j.cell.2018.08.056
[Indexed for MEDLINE]
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