Mechanisms underlying the p53-nucleosome interaction

• Project/Area Number: 17K15043
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Genome biology
• Research Institution: The University of Tokyo (2018); Waseda University (2017)
• Principal Investigator: Arimura Yasuhiro 東京大学, 定量生命科学研究所, 特任助教 (80754697)
• Research Collaborator: NISHIMURA Masahiro
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: クロマチン / p53 / 転写因子 / がん / ヌクレオソーム / ヌクレオーム / ゲノム機能発現

Outline of Final Research Achievements

In eukaryotic cells, DNA binds with histones and forms nucleosome. p53, the principal tumor repressor, can bind to the nucleosome and recognize the target DNA sequence on the nucleosome. In this project, we found that the N terminal region of p53 facilitates p53-nucleosome binding and this region directly binds to the histone. These findings contribute to understanding the mechanism that represses the tumor via p53-nucleosome interaction.

Academic Significance and Societal Importance of the Research Achievements

p53は、代表的ながん抑制タンパク質であり、がん患者の4割以上がp53遺伝子に変異を有する。p53は、特定のDNA配列を認識して結合し、近傍領域にコードされた遺伝子の転写を活性化する「転写因子」とよばれるグループのタンパク質であるが、ヌクレオソームを形成しているDNA配列を認識可能であるという点において、一般的な転写因子とは異なる性質を有する。本研究ではこの性質の理解を目指して研究を行った。本研究の成果は、p53が、がん抑制の最上流で働くメカニズムを理解する上で重要な知見である。これらの知見は将来的には、がん抑制メカニズムの理解や、がんに対する治療法の確立につながる。

Research Products

• [Journal Article] The CENP-A centromere targeting domain facilitates H4K20 monomethylation in the nucleosome by structural polymorphism. (2019)
  • Author(s): Arimura Y, Tachiwana H, Takagi H, Hori T, Kimura H, Fukagawa T, Kurumizaka H
  • Journal Title: Nature Commun. Volume: 10 Issue: 1 Pages: 576-576
  • DOI: 10.1038/s41467-019-08314-x
  • Peer Reviewed / Open Access
• [Journal Article] Cancer-associated mutations of histones H2B, H3.1 and H2A.Z.1 affect the structure and stability of the nucleosome (2018)
  • Author(s): Arimura Yasuhiro、Ikura Masae、Fujita Risa、Noda Mamiko、Kobayashi Wataru、Horikoshi Naoki、Sun Jiying、Shi Lin、Kusakabe Masayuki、Harata Masahiko、Ohkawa Yasuyuki、Tashiro Satoshi、Kimura Hiroshi、Ikura Tsuyoshi、Kurumizaka Hitoshi
  • Journal Title: Nucleic Acids Research Volume: - Pages: 10007-10018
  • DOI: 10.1093/nar/gky661
  • NAID: 120006545208
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Methods for Preparing Nucleosomes Containing Histone Variants (2018)
  • Author(s): Kujirai Tomoya、Arimura Yasuhiro、Fujita Risa、Horikoshi Naoki、Machida Shinichi、Kurumizaka Hitoshi
  • Journal Title: Methods Mol Biol. Volume: 1832 Pages: 3-20
  • DOI: 10.1007/978-1-4939-8663-7_1
  • ISBN: 9781493986620, 9781493986637
  • Peer Reviewed
• [Journal Article] Association of M18BP1/KNL2 with CENP-A Nucleosome Is Essential for Centromere Formation in Non-mammalian Vertebrates (2017)
  • Author(s): Tetsuya Hori, Wei-Hao Shang, Masatoshi Hara, Mariko Ariyoshi, Yasuhiro Arimura, Risa Fujita, Hitoshi Kurumizaka, Tatsuo Fukagawa
  • Journal Title: Developmental Cell Volume: 42 Issue: 2 Pages: 181-189
  • DOI: 10.1016/j.devcel.2017.06.019
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Synthetic Posttranslational Modifications: Chemical Catalyst-Driven Regioselective Histone Acylation of Native Chromatin (2017)
  • Author(s): Amamoto Yoshifumi、Aoi Yuki、Nagashima Nozomu、Suto Hiroki、Yoshidome Daisuke、Arimura Yasuhiro、Osakabe Akihisa、Kato Daiki、Kurumizaka Hitoshi、Kawashima Shigehiro A.、Yamatsugu Kenzo、Kanai Motomu
  • Journal Title: Journal of the American Chemical Society Volume: 139 Issue: 22 Pages: 7568-7576
  • DOI: 10.1021/jacs.7b02138
  • Peer Reviewed
• [Journal Article] Crystal structure of the overlapping dinucleosome composed of hexasome and octasome (2017)
  • Author(s): Daiki Kato, Akihisa Osakabe, Yasuhiro Arimura, Yuka Mizukami, Naoki Horikoshi, Kazumi Saikusa, Satoko Akashi, Yoshifumi Nishimura, Sam-Yong Park, Jumpei Nogami, Kazumitsu Maehara, Yasuyuki Ohkawa, Atsushi Matsumoto, Hidetoshi Kono, Rintaro Inoue, Masaaki Sugiyama, Hitoshi Kurumizaka
  • Journal Title: Science Volume: 356 Issue: 6334 Pages: 205-208
  • DOI: 10.1126/science.aak9867
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Crystal Structure and Characterization of Novel Human Histone H3 Variants, H3.6, H3.7, and H3.8 (2017)
  • Author(s): Taguchi H, Xie Y, Horikoshi N, Maehara K, Harada A, Nogami J, Sato K, Arimura Y, Osakabe A, Kujirai T, Iwasaki T, Semba Y, Tachibana T, Kimura H, Ohkawa Y, Kurumizaka H.
  • Journal Title: Biochemistry Volume: 56 Issue: 16 Pages: 2184-2196
  • DOI: 10.1021/acs.biochem.6b01098
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 失敗から学ぶヌクレオソーム構造・機能解析 (2018)
  • Author(s): 有村泰宏
  • Organizer: 第５回ヒストンバリアント研究会
  • Invited
• [Presentation] Chromatin Remodeler or Histone Chaperone Independent Histone Exchange Activity of Histone Variant H2A.B (2017)
  • Author(s): Arimura, Y., Kato, D., Yajima, N. and Kurumizaka, H.
  • Organizer: EMBO Conference: The Nucleosome: From Atoms to Genomes
  • Int'l Joint Research
• [Presentation] 試験管内再構成ヌクレオソームを用いた転写因子p53の機能解析 (2017)
  • Author(s): 有村泰宏，西村正宏, 胡桃坂仁志
  • Organizer: ConBio2017
  • Invited
• [Presentation] 第35回染色体ワークショップ・第16回核ダイナミクス研究会 (2017)
  • Author(s): 転写因子p53のヒストンとの相互作用
  • Organizer: グリーンホテル三ヶ根
• [Book] あなたのタンパク質精製、大丈夫ですか？ (2018)
  • Author(s): 胡桃坂 仁志、有村 泰宏
  • Total Pages: 186
  • Publisher: 羊土社
  • ISBN: 9784758122382