Mechanism of genomic DNA damage response mediated by acetylation of non-histone proteins

• Project/Area Number: 26281026
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Risk sciences of radiation and chemicals
• Research Institution: National Institutes for Quantum and Radiological Science and Technology
• Principal Investigator: YASUDA Takeshi 国立研究開発法人量子科学技術研究開発機構, 放射線医学総合研究所 放射線障害治療研究部, 主任研究員(定常) (60332269)
• Co-Investigator(Kenkyū-buntansha): 増本 博司 長崎大学, 医歯薬学総合研究科(医学系), 講師 (80423151) ; 荻 朋男 名古屋大学, 環境医学研究所, 教授 (80508317) ; 小原 千寿香 (逸見千寿香 / 小原 千寿香(逸見千寿香)) 国立研究開発法人量子科学技術研究開発機構, 緊急被ばく医療研究センター, 研究員 (90415977)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000); Fiscal Year 2016: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2015: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2014: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
• Keywords: DNA損傷応答 / アセチル化 / 脱アセチル化 / DNA相同組換え / RAD52 / p300 / CBP / RAD51 / DNA修復 / 相同組換え / ゲノム編集 / アポトーシス / 放射線 / 細胞死

Outline of Final Research Achievements

We newly identified several non-histone proteins involved in DNA damage response, which are acetylated by p300 and CBP histone acetyltransferases in vitro. Among the identified acetylated proteins, we showed that p300/CBP acetylate RAD52, a human homologous recombination (HR) DNA repair protein, at DNA double strand break (DSB) sites. We identified 13 acetylation sites in RAD52. We revealed that non-acetylated RAD52 initially accumulates at DSB sites, but dissociates prematurely from them. In the absence of RAD52 acetylation, RAD51, which plays a central role in HR, also dissociates prematurely from DSB sites, and hence HR is impaired. Furthermore, we demonstrated that the acetylation of RAD52 is linked to ATM signaling. Our findings clarify the importance of RAD52 acetylation in HR.

Research Products

• [Int'l Joint Research] サセックス大学(英国)
• [Int'l Joint Research] コロラド州立大学(米国)
• [Int'l Joint Research] University of Sussex(英国)
• [Int'l Joint Research]
• [Journal Article] Structural Basis of Homology-Directed DNA Repair Mediated by RAD52 (2018)
  • Author(s): Saotome, M., Saito, K., Yasuda, T., Ohtomo, H., Sugiyama, S., Nishimura, Y., Kurumizaka, H., Kagawa, W.
  • Journal Title: iScience Volume: 3 Pages: 50-62
  • DOI: 10.1016/j.isci.2018.04.005
  • Peer Reviewed / Open Access
• [Journal Article] Novel function of HATs and HDACs in homologous recombination through acetylation of human RAD52 at double-strand break sites (2018)
  • Author(s): Yasuda Takeshi、Kagawa Wataru、Tajima Katsushi
  • Journal Title: PLOS Genetics Volume: 14 Issue: 3 Pages: 1007277-1007277
  • DOI: 10.1371/journal.pgen.1007277
  • NAID: 120006459820
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Fra1 enhances the radioresistance of colon cancer cells to Xray or Cion radiation (2018)
  • Author(s): Endo, S., Fujita, M., Yamada, S., Imadome, K., Nakayama, F., Isozaki, T., Yasuda, T., Imai, T., Matsubara, H.
  • Journal Title: Oncol Rep Volume: 39 Pages: 1112-1118
  • DOI: 10.3892/or.2018.6223
  • Peer Reviewed / Open Access
• [Journal Article] Strong radioprotective FGF1 signaling down-regulates proliferative and metastatic capabilities of the angiosarcoma cell line, ISOS-1, through the dual inhibition of EGFR and VEGFR pathways (2017)
  • Author(s): Miura, T., Fujita, M., Kawano, M., Imadome, K., Yasuda, T., Nishihara, S., Imamura, T., Masuzawa, M., Imai, T., Nakayama, F.
  • Journal Title: Clin Transl Radiat Oncol Volume: 7 Pages: 83-90
  • DOI: 10.1016/j.ctro.2017.10.006
  • Peer Reviewed / Open Access
• [Journal Article] Xeroderma pigmentosum group C protein interacts with histones: regulation by acetylated states of histone H3. (2017)
  • Author(s): Kakumu E
  • Journal Title: Genes Cells. Volume: 3 Issue: 3 Pages: 310-327
  • DOI: 10.1111/gtc.12479
  • Peer Reviewed / Open Access
• [Journal Article] Intra- and extracellular plasminogen activator inhibitor-1 regulate effect of vitronectin against radiation-induced endothelial cell death (2016)
  • Author(s): Hazawa M, Yasuda T, Saotome-Nakamura A, Tomiyama K, Obara C, Gotoh T, Tajima K
  • Journal Title: Vascular Pharmacology Volume: 87 Pages: 150-158
  • DOI: 10.1016/j.vph.2016.09.006
  • Peer Reviewed
• [Journal Article] Differentiation and Molecular Properties of Mesenchymal Stem Cells Derived from Murine Induced Pluripotent Stem Cells Derived on Gelatin or Collagen (2016)
  • Author(s): Obara C, Takizawa K, Tomiyama K, Hazawa M, Saotome-Nakamura A, Gotoh T, Yasuda T, Tajima K
  • Journal Title: Stem cells international Volume: - Issue: 1 Pages: 9013089-9013089
  • DOI: 10.1155/2016/9013089
  • Peer Reviewed / Open Access
• [Journal Article] Nontoxic concentration of DNA-PK inhibitor NU7441 radio-sensitizes lung tumor cells with little effect on DSB repair. (2016)
  • Author(s): Shigeaki Sunada, Hideki Kanai, Younghyun Lee, Takeshi Yasuda, Hirokazu Hirakawa, Cuihua Liu, Akira Fujimori, Mitsuru Uesaka, Ryuichi Okayasu
  • Journal Title: Cancer Science Volume: 107 Issue: 9 Pages: 1250-1255
  • DOI: 10.1111/cas.12998
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] FGF18 Signaling in the Hair Cycle Resting Phase Determines Radioresistance of Hair Follicles by Arresting Hair Cycling (2016)
  • Author(s): Kawano, M., Umeda, S., Yasuda T, Fujita, M., Ishikawa, A., Imamura, T., Imai, T., Nakayama, F
  • Journal Title: Advances in Radiation Oncology Volume: 1 Issue: 3 Pages: 170-181
  • DOI: 10.1016/j.adro.2016.05.004
  • Peer Reviewed / Open Access
• [Journal Article] Characteristics of three-dimensional prospectively isolated mouse bone marrow mesenchymal stem/stromal cell aggregates on nanoculture plates (2016)
  • Author(s): Chizuka Obara, Ken-ichi Tomiyama, Kazuya Takizawa, Rafiqul Islam, Takeshi Yasuda, Takaya Goto, & Katsushi Tajima
  • Journal Title: Cell Tissue Res Volume: 0 Issue: 1 Pages: 0-0
  • DOI: 10.1007/s00441-016-2405-y
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Effects of carbon ion irradiation and X-ray irradiation on the ubiquitylated protein accumulation. (2016)
  • Author(s): Isozaki T, Fujita M, Yamada S, Imadome K, Shoji Y, Yasuda T, Nakayama F, Imai T, Matsubara H
  • Journal Title: International journal of oncology Volume: 印刷中 Issue: 1 Pages: 144-52
  • DOI: 10.3892/ijo.2016.3504
  • Peer Reviewed / Open Access
• [Journal Article] Mammalian Bcnt/Cfdp1, a potential epigenetic factor characterized by an acidic stretch in the disordered N-terminal and Ser250 phosphorylation in the conserved C-terminal regions (2015)
  • Author(s): Iwashita, S., Suzuki, T., Yasuda, T., Nakashima, K., Sakamoto, T., Kohno, T., Takahashi, I., Kobayashi, T., Ohno-Iwashita, Y., Imajoh-Ohmi, S., Song, S. Y., Dohmae, N.
  • Journal Title: Biosci Rep Volume: 35 Issue: 4 Pages: 1-12
  • DOI: 10.1042/bsr20150111
  • Peer Reviewed / Open Access
• [Journal Article] 放射線によるDNA 損傷と細胞応答 (2015)
  • Author(s): 安田武嗣、羽澤勝治、崔星、中山文明、田嶋克史
  • Journal Title: 医学物理 Volume: 35 Pages: 50-63
• [Journal Article] Functional regulation of the DNA damage-recognition factor DDB2 by ubiquitination and interaction with xeroderma pigmentosum group C protein. (2015)
  • Author(s): Syota Matsumoto, Eric S. Fischer, Takeshi Yasuda, Naoshi Dohmae, Shigenori Iwai, Toshio Mori, Ryotaro Nishi, Ken-ichi Yoshino, Wataru Sakai, Fumio Hanaoka, Nicolas H. Thoma, Kaoru Sugasawa
  • Journal Title: Nucleic Acids Research Volume: 3 Issue: 3 Pages: 1700-1713
  • DOI: 10.1093/nar/gkv038
  • Peer Reviewed / Open Access
• [Journal Article] Cell-permeable intrinsic cellular inhibitors of apoptosis protect and rescue intestinal epithelial cells from radiation-induced cell death. (2015)
  • Author(s): Matsuzaki-Horibuchi, S., Yasuda, T., Sakaguchi, N., Yamaguchi, Y., and Akashi, M.
  • Journal Title: J. Radiat. Res. Volume: 56 Issue: 1 Pages: 100-113
  • DOI: 10.1093/jrr/rru094
  • Peer Reviewed / Open Access
• [Journal Article] Radiation increases the cellular uptake of exosomes through CD29/CD81complex formation. (2014)
  • Author(s): Hazawa, M., Tomiyama, K., Saotome-Nakamura, A., Obara, C., Yasuda, T., Gotoh, T., Tanaka, I., Yakumaru, H., Ishihara, H., and Tajima, K.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 446 Issue: 4 Pages: 1165-1171
  • DOI: 10.1016/j.bbrc.2014.03.067
  • Peer Reviewed
• [Journal Article] Arsenite induces premature senescence via p53/p21 pathway as a result of DNA damage in human malignant glioblastoma cells. (2014)
  • Author(s): Ninomiya, Y., Cui, X., Yasuda, T., Wang, B., Yu, D., Sekine-Suzuki, E., and Nenoi, M.
  • Journal Title: BMB Reports Volume: 47 Issue: 10 Pages: 575-580
  • DOI: 10.5483/bmbrep.2014.47.10.254
  • Peer Reviewed / Open Access
• [Presentation] ヒトRAD52の脱アセチル化酵素SIRT2/SIRT3はDNA相同組換え修復に関わる (2017)
  • Author(s): 安田武嗣、滝澤和也、田嶋克史
  • Organizer: 日本放射線影響学会第60回大会
• [Presentation] 非ヒストンタンパク質のアセチル化修飾を介したDNA損傷応答 (2016)
  • Author(s): 安田 武嗣
  • Organizer: 2016年度国立遺伝学研究所 研究集会「生物ゲノム安定維持の分子機構」
  • Place of Presentation: 国立遺伝学研究所・講堂、三島市、静岡県
  • Year and Date: 2016-10-24
• [Presentation] ヒトRAD52のアセチル化を介した相同組換えにおけるアセチル化および脱アセチル化酵素の新機能の解明 (2015)
  • Author(s): 安田武嗣、香川 亘、荻 朋男、齊藤健吾、加藤宝光、鈴木健祐、藤堂 直、滝澤和也、早乙女（中邑）愛、中沢由華、Matthew D. Genet、宇井彩子、花岡文雄、菅澤 薫、岡安隆一、Penny A. Jeggo、胡桃坂仁志、田嶋克史
  • Organizer: BMB2015
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2015-12-01
  • Invited
• [Presentation] 放射線によるDNA 損傷と細胞応答 (2015)
  • Author(s): 安田武嗣、羽澤勝治、崔星、中山文明、田嶋克史
  • Organizer: 第109回 日本医学物理学会学術大会
  • Place of Presentation: 横浜
  • Year and Date: 2015-04-16 – 2015-04-19
  • Invited
• [Presentation] ヒトRAD52タンパク質のアセチル化制御 (2014)
  • Author(s): 安田武嗣、香川亘、斎藤健吾、荻朋男、花岡文雄、菅澤薫、胡桃坂仁志、田嶋克史
  • Organizer: 第37回 日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-25 – 2014-11-27
• [Remarks] プレスリリース 切れたDNAの修復に必要な新たなメカニズムを解明
  • URL: http://www.qst.go.jp/information/itemid034-004042.html
• [Remarks] Press Release
  • URL: http://www.qst.go.jp/ENG/news/itemid054-004075.html