The roles of R-loop structure in DNA damage signaling and genome

• Project/Area Number: 18K18191
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 63020:Radiation influence-related
• Research Institution: The University of Tokyo
• Principal Investigator: Yasuhara Takaaki 東京大学, 大学院医学系研究科(医学部), 助教 (90757056)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Discontinued (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: R-loop構造 / DNA二重鎖切断 / DNA損傷シグナリング / DNA修復

Outline of Final Research Achievements

In this study, we revealed that R-loops, a special structure consisting of DNA and RNA, are formed when DNA double-strand breaks are induced in the transcribed genomic regions. Moreover, recognition of R-loops by 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, we 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 development. 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 target to develop new drugs.

Academic Significance and Societal Importance of the Research Achievements

今回明らかになった転写共役型相同組換え修復のメカニズムは、ゲノム異常を原因として生じるがんなどの疾患を防ぐために細胞が保持している防御機構の一つであり、それらの破綻は疾患の発症と密接に関連していることが示唆された。このようなメカニズムの解明によって将来的には、疾患を予防したり、治療したりする手法の開発につながると考えられる。

Research Products

• [Int'l Joint Research] マサチューセッツ総合病院(米国)
• [Int'l Joint Research] オックスフォード大学(英国)
• [Int'l Joint Research] マサチューセッツ総合病院(米国)
• [Int'l Joint Research] オックスフォード大学(英国)
• [Int'l Joint Research] マサチューセッツ総合病院(米国)
• [Int'l Joint Research] オックスフォード大学(英国)
• [Journal Article] RNF8 promotes high linear energy transfer carbon-ion-induced DNA double-stranded break repair in serum-starved human cells (2020)
  • Author(s): Nakajima Nakako Izumi、Yamauchi Motohiro、Kakoti Sangeeta、Cuihua Liu、Kato Reona、Permata Tiara Bunga Mayang、Iijima Moito、Yajima Hirohiko、Yasuhara Takaaki、Yamada Shigeru、Hasegawa Sumitaka、Shibata Atsushi
  • Journal Title: DNA Repair Volume: 91-92 Pages: 102872-102872
  • DOI: 10.1016/j.dnarep.2020.102872
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] p53 deficiency augments nucleolar instability after ionizing irradiation. (2019)
  • Author(s): Kakoti, S., Yamauchi, M., Gu, W., Kato, R., Yasuhara, T., Hagiwara, Y., Laskar, S., Oike, T., Sato, H., Held, KD., Nakano, T., and Shibata, A.
  • Journal Title: Oncology Reports Volume: 42 Pages: 2293-2302
  • DOI: 10.3892/or.2019.7341
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The role of R-loops in transcription-associated DNA double-strand break repair (2019)
  • Author(s): Kato Reona、Miyagawa Kiyoshi、Yasuhara Takaaki
  • Journal Title: Molecular & Cellular Oncology Volume: 6 Issue: 1 Pages: 1542244-1542244
  • DOI: 10.1080/23723556.2018.1542244
  • Peer Reviewed
• [Journal Article] Elucidation of the Mechanism Regulating Transcription Associated Dna Double Strand Break Repair and Its Pathway (2019)
  • Author(s): Shibata Atsushi、Yasuhara Takaaki
  • Journal Title: Impact Volume: 2019 Issue: 3 Pages: 50-51
  • DOI: 10.21820/23987073.2019.3.50
• [Journal Article] Base excision repair regulates PD-L1 expression in cancer cells (2019)
  • Author(s): Permata, MBT, Hagiwara, Y., Sato, H., Yasuhara, T., Oike, T., Gondhowiardjo, S., Held, KD, Nakano, T., and Shibata, A.
  • Journal Title: Oncogene Volume: 印刷中 Issue: 23 Pages: 4452-4466
  • DOI: 10.1038/s41388-019-0733-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Human Rad52 Promotes XPG-Mediated R-loop Processing to Initiate Transcription-Associated Homologous Recombination Repair (2018)
  • Author(s): Yasuhara Takaaki、Kato Reona、Hagiwara Yoshihiko、Shiotani Bunsyo、Yamauchi Motohiro、Nakada Shinichiro、Shibata Atsushi、Miyagawa Kiyoshi
  • Journal Title: Cell Volume: 175 Issue: 2 Pages: 558-570
  • DOI: 10.1016/j.cell.2018.08.056
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] RNA転写とDNA二重鎖切断修復のクロストーク (2019)
  • Author(s): 安原崇哲
  • Organizer: 第42回日本分子生物学会年会
  • Invited
• [Presentation] Rad52 promotes XPG-mediated R-loop processing to initiate transcription-associated homologous recombination repair (2019)
  • Author(s): Takaaki Yasuhara、Kato Reona、Shibata Atsushi、Miyagawa Kiyoshi
  • Organizer: Keystone Symposia - Genomic Instability and DNA Repair
  • Int'l Joint Research
• [Presentation] Rad52 promotes XPG-mediated R-loop processing to initiate transcription-associated homologous recombination repair (2018)
  • Author(s): Takaaki Yasuhara、Kato Reona、Shibata Atsushi、Miyagawa Kiyoshi
  • Organizer: Abcam meeting - Mechanisms of Recombination 2018
  • Int'l Joint Research
• [Remarks] 東京大学大学院医学系研究科 プレスリリース
  • URL: http://www.m.u-tokyo.ac.jp/news/admin/release_20180921.pdf
• [Remarks] UTokyo Research 日本語版
  • URL: https://www.u-tokyo.ac.jp/focus/ja/articles/z0508_00107.html
• [Remarks] UTokyo Research English
  • URL: https://www.u-tokyo.ac.jp/focus/en/articles/z0508_00108.html