Structural basis for DNA methylation maintenance regulated by replication factors.

• Project/Area Number: 18H02392
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 43020:Structural biochemistry-related
• Research Institution: Yokohama City University
• Principal Investigator: Arita Kyohei 横浜市立大学, 生命医科学研究科, 教授 (40549648)
• Co-Investigator(Kenkyū-buntansha): 西山 敦哉 東京大学, 医科学研究所, 准教授 (50378840)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000); Fiscal Year 2020: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
• Keywords: DNAメチル化 / 複製因子 / ユビキチン化 / 構造生物学 / クロマチン / DNA複製 / UHRF1 / LIG1 / リン酸化 / 分子動力学計算 / DNA維持メチル化 / DNMT1 / ユビキチン / エピジェネティクス

Outline of Final Research Achievements

DNA methylation defines the gene expression patterns in the differentiated cells. Importantly, DNA methylation patterns in the cells are faithfully inherited to the next generation through the individual’s life. In this study, we performed the structural biology of the proteins that are involved in the DNA methylation maintenance. We found the novel mechanism of DNA methylation maintenance: replication coupled DNA methylation maintenance, which is distinct from the previous mechanism.

Academic Significance and Societal Importance of the Research Achievements

DNA維持メチル化は複雑な過程を経て正確に継承される。これにより細胞のがん化などが防がれる。このDNAメチル化が維持される新しい機構を本研究では発見したので、基礎生物学研究の発展とその理解に貢献した。また、がんの薬剤開発に向けた予備的な研究も開始し一定の結果も得られたので、今後の研究の進展により医薬開発などの産業面への波及も考えられる。

Research Products

• [Int'l Joint Research] CNRS(フランス)
• [Int'l Joint Research] CNRS(フランス)
• [Int'l Joint Research] ミュンヘン大学(ドイツ)
• [Int'l Joint Research] CNRS(フランス)
• [Journal Article] Structural dynamics of double-stranded DNA with epigenome modification (2020)
  • Author(s): Furukawa Ayako、Walinda Erik、Arita Kyohei、Sugase Kenji
  • Journal Title: Nucleic Acids Research Volume: 49 Issue: 2 Pages: 1152-1162
  • DOI: 10.1093/nar/gkaa1210
  • NAID: 120006943328
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Serine 298 Phosphorylation in Linker 2 of UHRF1 Regulates Ligand-Binding Property of Its Tandem Tudor Domain (2020)
  • Author(s): Kori Satomi、Jimenji Tomohiro、Ekimoto Toru、Sato Miwa、Kusano Fumie、Oda Takashi、Unoki Motoko、Ikeguchi Mitsunori、Arita Kyohei
  • Journal Title: Journal of Molecular Biology Volume: 432 Issue: 14 Pages: 4061-4075
  • DOI: 10.1016/j.jmb.2020.05.006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Two distinct modes of DNMT1 recruitment ensure stable maintenance DNA methylation (2020)
  • Author(s): A. Nishiyama, C. Mulholland, S. Bultmann, S. Kori, A. Endo, Y. Saeki, W. Qin, C. Trummer, Y. Chiba, H. Yokoyama, S. Kumamoto, T. Kawakami, H. Hojo, G. Nagae, H. Aburatani, K. Tanaka, K. Arita, H. Leonhardt, M. Nakanishi
  • Journal Title: Nat. Commun. Volume: 11 Issue: 1 Pages: 1222-1222
  • DOI: 10.1038/s41467-020-15006-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Enhanced processivity of Dnmt1 by monoubiquitinated histone H3 (2020)
  • Author(s): Y. Mishima, L. Brueckner, S. Takahashi, T. Kawakami, J. Otani, A. Shinohara, K. Takeshita, R. G. Garvilles, M. Watanabe, N. Sakai, H. Takeshima, C. Nachtegael, A. Nishiyama, M. Nakanishi, K. Arita, K. Nakashima, H. Hojo, I. Suetake
  • Journal Title: Genes Cells Volume: 25 Issue: 1 Pages: 22-32
  • DOI: 10.1111/gtc.12732
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Structure of PCNA in complex with DNMT1 PIP box reveals the basis for the molecular mechanism of the interaction. (2019)
  • Author(s): 1.Jimenji T, Matsumura R, Kori S, Arita K.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 516 Issue: 2 Pages: 578-583
  • DOI: 10.1016/j.bbrc.2019.06.060
  • Peer Reviewed
• [Journal Article] Structure of the UHRF1 Tandem Tudor Domain Bound to a Methylated Non-histone Protein, LIG1, Reveals Rules for Binding and Regulation (2019)
  • Author(s): Kori, S. Ferry, L. Matano, S. Jimenji, T. Kodera, N. Tsusaka, T. Matsumura, R. Oda, T. Sato, M. Dohmae, N. Ando, T. Shinkai, Y. Defossez, P. A. Arita, K.
  • Journal Title: Structure Volume: 27 Issue: 3 Pages: 1-12
  • DOI: 10.1016/j.str.2018.11.012
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 構造生物学から見たDNAメチル化が複製されていく仕組み (2021)
  • Author(s): 有田恭平
  • Organizer: 第14回日本エピジェネティクス研究会年会
  • Invited
• [Presentation] The proper timing phosphorylation of Ser298 selects UHRF1-binding partners (2021)
  • Author(s): Satomi Kori, Tomohiro Jimenji, Toru Ekimoto, Laure Ferry, Shohei Matano, Miwa Sato, Fumie Kusano, Motoko Unoki, Pierre-Antoine Defossez, Mitsunori Ikeguchi, Kyohei Arita
  • Organizer: 第14回日本エピジェネティクス研究会年会
• [Presentation] Structural basis for the switching of binding partners by Ser298 phosphorylation in UHRF1 (2020)
  • Author(s): Satomi Kori, Tomohiro Jimenji, Toru Ekimoto, Miwa Sato, Fumie Kusano, Takashi Oda, Motoko Unoki, Mitsunori Ikeguchi, Kyohei Arita
  • Organizer: 第20回蛋白質科学会年会
• [Presentation] Conserved phosphorylation in UHRF1-binding partners regulates its binding to the peptide binding groove of UHRF1 TTD domain (2019)
  • Author(s): Satomi Kori, Laure Ferry, Shohei Matano, Tomohiro Jimenji, Toru Ekimoti, Takashi Oda, Pierre-Antoine Defossez, Mitsunori Ikeguchi, Kyohei Arita
  • Organizer: 16th Conference of the Asian Crystallographic Association: AsCA2019
  • Int'l Joint Research
• [Presentation] Structural basis for recognition of DNMT1 PIP box by PCNA (2019)
  • Author(s): Tomohiro Jimenji, Satomi Kori, Kyohei Arita
  • Organizer: 16th Conference of the Asian Crystallographic Association: AsCA2019
  • Int'l Joint Research
• [Presentation] A unique mechanism for multi-monoubiquitination of histone H3 by UHRF1 (2019)
  • Author(s): 松澤舜, 若月誠, 柴野歩実, 郡聡実, 古川亜矢子, 西村善文, 西山敦哉, 中西真, 有田恭平
  • Organizer: 第42回分子生物学会年会
• [Presentation] Molecular mechanism for multiple-monoubiquitination of replication factor PAF15 (2019)
  • Author(s): 柴野歩実, 松澤舜, 郡聡実, 西山敦哉, 中西真, 有田恭平
  • Organizer: 第42回分子生物学会年会
• [Presentation] Structural Study for Recognition of Ubiquitylated Histone H3 by DNA Methyltransferase (2019)
  • Author(s): Arita Kyohei, Ishiyama Satoshi, Nishiyama, Atsuya, Defossez, Pierre-Antoine, Nakanishi, Makoto
  • Organizer: ECM32 32nd European Crystallographic Meeting
  • Int'l Joint Research
• [Presentation] Crystal structure of UHRF1:LIG1 complex revealed structural change of UHRF1 and the key residues for high affinity binding (2019)
  • Author(s): Satomi Kori, Laure Ferry, Shohei Matano, Noriyuki Kodera, Takashi Oda, Pierre-Antoine Defossez,Kyohei Arita
  • Organizer: ECM32 32nd European Crystallographic Meeting
  • Int'l Joint Research
• [Presentation] Molecular mechanism for multiple-monoubiquitination of histone H3 (2019)
  • Author(s): 松澤舜, 柴野歩実, 若月誠, 郡聡実, 有田恭平
  • Organizer: 第13 回エピジェネティクス研究会年会
• [Presentation] Structural basis for the regulation of DNA methylation maintenance by replication factors (2019)
  • Author(s): 郡聡実, 治面地智宏, 又野翔平, 松村るみゑ, 横山遥、西山敦哉、中西真、佐藤衛, Pierre Defossez, 有田恭平
  • Organizer: 第13 回エピジェネティクス研究会年会
• [Presentation] マルチプルモノユビキチン化ヒストンH3が制御するDNA維持メチル化の構造基盤 (2018)
  • Author(s): 有田恭平, 石山怜, 西山敦哉, 中西真, 川上徹, 末武勲
  • Organizer: 第91 日本生化学化大会
• [Presentation] 複製因子DNA ligase 1の認識に基づいたUHRF1の構造変化の解析 (2018)
  • Author(s): 郡聡実, Laure Ferry, 治面地智宏, 又野翔平, 松村るみゑ, 古寺哲幸, 安藤敏夫, 佐藤衛, Pierre Defossez, 有田恭平
  • Organizer: 第18 回蛋白質科学会年会
• [Remarks] メチル基１つでDNAの運動性が変わることを解明
  • URL: https://www.yokohama-cu.ac.jp/news/2020/202012arita.html
• [Remarks] リン酸化によるUHRF1の結合相手の制御の仕組みを解明
  • URL: https://www.yokohama-cu.ac.jp/news/2020/202006arita.html
• [Remarks] 横浜市立大学 生命医科学研究科 構造生物学研究室 有田グループ
  • URL: http://www-mls.tsurumi.yokohama-cu.ac.jp/xtal-mls/members/kyouhei/index.html
• [Remarks] 横浜市立大学 ニュース
  • URL: https://www.yokohama-cu.ac.jp/news/2019/202003arita.html
• [Remarks] 横浜市立大学 生命医科学研究科 ニュース
  • URL: http://www.tsurumi.yokohama-cu.ac.jp/news/20190712_arita.html
• [Remarks] UHRF1とLIG1の複合体構造解析 ～阻害剤開発の基盤となる相互作用部位を同定～
  • URL: https://www.yokohama-cu.ac.jp/news/2018/201901arita.html
• [Remarks] 横浜市立大学 生命医科学研究科 構造生物学研究室 有田G ウエブサイト
  • URL: http://www-mls.tsurumi.yokohama-cu.ac.jp/xtal-mls/members/kyouhei/index.html