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Novel DNA repair mechanism maintains human genome How human cells suppress cancer development

March 25, 2019

The presence of R-loops leads to accurate DNA repair
The presence of R-loops leads to accurate DNA repair
The cover painting with the note tag "Rad52" in Chinese characters shows that men on a broken ship (DNA double-strand breaks, DSBs) at sea (huge human genome with numerous waves representing chromatin and DNA) are led by trajectories of flying fish (R-loops) points to the study’s important finding that the presence of R-loops around DSBs and its recognition by Rad52 promote accurate repair of DSBs in human cells.
© 2019 Takaaki Yasuhara, artwork by Space-Time Inc., Sofa Graphic Design.

University of Tokyo researchers and their collaborators have demonstrated that a special structure that forms when DNA is damaged helps to restore it. Human cells have a mechanism for recognizing this structure, consisting of DNA and RNA, which promotes accurate repair of damaged DNA. The study’s findings point to a mechanism in human cells that protects them from diseases like cancer caused by genomic abnormalities.

Scientific studies have revealed that only small areas of our huge genome are utilized, with the frequently transcribed genomic regions being the most important part of our genome. It is imperative that DNA damage in these regions is repaired accurately to protect the genomic information. Previous studies have reported that an accurate DNA repair pathway is activated when DNA damage occurs in the transcribed genomic regions. However, scientists did not know how cells recognize the importance of genomic information and activate the accurate repair pathway.

In this study, the research group of Research Associate Takaaki Yasuhara, graduate student Reona Kato and Professor Kiyoshi Miyagawa at the Graduate School of Medicine, the University of Tokyo, and Lecturer Atsushi Shibata at the Graduate School of Medicine, Gunma University, revealed that R-loops, a special structure consisting of DNA and RNA, are formed when breaks in DNA’s double strand are induced in the transcribed genomic regions. Moreover, recognition of R-loops by the protein Rad52 promotes the activation of the accurate repair pathway, or homologous recombination repair, a mechanism designated as Transcription-Associated Homologous Recombination Repair (TA-HRR). Furthermore, the researchers demonstrated that inhibiting TA-HRR significantly increased interchromatid fusions, a precursor of genomic abnormalities frequently observed in cancer, suggesting that TA-HRR is critical for suppressing cancer development.

These findings represent an inherent mechanism by which human cells suppress cancer growth. Detailed understanding of these kinds of protection mechanisms in human cells and how the collapse of these mechanisms leads to development of diseases may pave the way for finding a novel therapeutic target to develop new drugs.

"Seeing through our findings that cells recognize the importance of genomic regions and repair DNA damage within these regions accurately, I was really impressed how rational and sophisticated the mechanisms are in our cells," says Yasuhara. He continues, "I would like to reveal through various approaches how these wonderful mechanisms collapse, and how genomic instability and disease develop after the mechanisms' failure."

Papers

Takaaki Yasuhara, Reona Kato, Yoshihiko Hagiwara, Bunsyo Shiotani, Motohiro Yamauchi, Shinichiro Nakada, Atsushi Shibata, Kiyoshi Miyagawa, "Human Rad52 promotes XPG-mediated R-loop processing to initiate transcription-associated homologous recombination repair," Cell 175/558-570, doi:10.1016/j.cell.2018.08.056.
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