Defining the molecular mechanism of the cell cycle-specific regulation of chromosome end fusion at dysfunctional telomeres

• Project/Area Number: 25440080
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cell biology
• Research Institution: Gunma University
• Principal Investigator: Konishi Akimitsu 群馬大学, 大学院医学系研究科, 講師 (50381877)
• Project Period (FY): 2013-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: テロメア / 染色体不安定化 / DNA損傷反応 / DNA修復 / 細胞周期 / 染色体末端融合 / 細胞癌化 / クロマチン

Outline of Final Research Achievements

In this study, we aimed to elucidate the molecular mechanism of the cell cycle-specific regulation of chromosome end fusion leading to the cell carcinogenesis. We revealed that chromatin ubiquitination at the end of chromosomes induced by telomere dysfunction was largely diminished in S/G2 cell cycle phase. As a result, the recruitment of 53BP1, which is an essential factor for chromosome end fusion, is suppressed in S/G2 phase. We also elucidated that TRF2, the central factor for telomere protection, directly binds to the chromatin (core histone) to stabilize the chromosome ends.

Research Products

• [Int'l Joint Research] The Rockefeller University(米国)
• [Int'l Joint Research] The Scripps Research Institute(米国)
• [Journal Article] TRF2 Protein Interacts with Core Histones to Stabilize Chromosome Ends. (2016)
  • Author(s): Konishi A, Izumi T, Shimizu S
  • Journal Title: J Biol Chem. Volume: 291(39) Issue: 39 Pages: 20798-810
  • DOI: 10.1074/jbc.m116.719021
  • Peer Reviewed / Open Access
• [Journal Article] Autophagy controls centrosome number by degrading Cep63. (2016)
  • Author(s): Watanabe Y, Honda S, Konishi A, Satoko Arakawa S, Murohashi M, Yamaguchi H, Torii S, Tanabe M, Tanaka S, Warabi E, Shimizu S.
  • Journal Title: Nature Communications Volume: 7 Issue: 1 Pages: 13508-13508
  • DOI: 10.1038/ncomms13508
  • NAID: 120007129257
  • Peer Reviewed / Open Access
• [Journal Article] Enzymatic characterization of recombinant rat DDHD2: a soluble diacylglycerol lipase. (2016)
  • Author(s): Araki M, Ohshima N, Aso C, Konishi A, Obinata H, Tatei K, Izumi T.
  • Journal Title: J. Biochem. Volume: 160 Issue: 5 Pages: 269-279
  • DOI: 10.1093/jb/mvw034
  • NAID: 40021012775
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Protein purification and cloning of diacylglycerol lipase from rat brain. (2016)
  • Author(s): Aso C, Araki M, Ohshima N, Tatei K, Hirano T, Obinata H, Kishi M, Kishimoto K, Konishi A, Goto F, Sugimoto H, Izumi T.
  • Journal Title: J. Biochem. Volume: 159 Issue: 6 Pages: 585-597
  • DOI: 10.1093/jb/mvw002
  • NAID: 40020869378
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] TRF2はコアヒストンとの直接結合によりテロメアのループ構造を維持する (2017)
  • Author(s): 小西 昭充、和泉 孝志、清水 重臣
  • Organizer: 第34回染色体ワークショップ
  • Place of Presentation: 松島
  • Year and Date: 2017-01-12
• [Presentation] オートファジーによるCep63の分解を介した中心体数の制御 (2016)
  • Author(s): 本田 真也, 渡辺 雄一郎, 小西 昭充, 室橋 道子, 荒川 聡子, 山口 啓史, 清水 重臣
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-11-30
• [Presentation] Cell cycle-dependent regulation of DNA damage response at dysfunctional telomeres (2016)
  • Author(s): Hiraku Suzuki, Anastasie Tshilela Kadiombo, Akimitsu Konishi, Takashi Izumi
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-11-30
• [Presentation] Cell Cycle-Dependent Regulation of DNA Damage Response and DNA Repair at Dysfunctional Telomeres (2016)
  • Author(s): Akimitsu Konishi
  • Organizer: 10th 3R Symposium
  • Place of Presentation: Matsue
  • Year and Date: 2016-11-13
  • Int'l Joint Research
• [Presentation] テロメアにおける細胞周期依存的なDNA損傷反応・DNA修復の制御機構 (2016)
  • Author(s): 小西 昭充
  • Organizer: 第6回DNA損傷応答ワークショップ
  • Place of Presentation: 浜松
  • Year and Date: 2016-04-04
• [Presentation] Cell cycle-dependent regulation of non-homologous end joining at unprotected telomeres (2016)
  • Author(s): Kadiombo Tshilela Anastasie, Akimitsu Konishi, Takashi Izumi
  • Organizer: 第３３回染色体ワークショップ
  • Place of Presentation: 松島一の坊（宮城県宮城郡松島町）
  • Year and Date: 2016-01-12
• [Presentation] TRF2 interacts with core histones to stabilize chromosome ends (2015)
  • Author(s): Akimitsu Konishi
  • Organizer: EMBO Workshop Telomeric Chromatin and telomere fragility
  • Place of Presentation: Singapore（シンガポール）
  • Year and Date: 2015-12-07
  • Int'l Joint Research
• [Presentation] Complete sequence of human telomere DNA by single-molecule real-time sequencing technique (2015)
  • Author(s): Kaori Yauchi, Akimitsu Konishi, Takashi Izumi
  • Organizer: EMBO Workshop Telomeric Chromatin and telomere fragility
  • Place of Presentation: Singapore（シンガポール）
  • Year and Date: 2015-12-07
  • Int'l Joint Research
• [Presentation] Cell cycle-dependent regulation of non-homologous end joining at unprotected telomeres (2015)
  • Author(s): Kadiombo Tshilela Anastasie, Akimitsu Konishi, Takashi Izumi
  • Organizer: 第３８回日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド（兵庫県神戸市）
  • Year and Date: 2015-12-01
• [Presentation] Cell Cycle-Dependent Regulation of DNA Damage Response and DNA Repair at Dysfunctional Telomeres (2015)
  • Author(s): Akimitsu Konishi
  • Organizer: Cold Spring Harbor Meeting Telomere & Telomerase
  • Place of Presentation: Cold Spring Harbor, NY （米国）
  • Year and Date: 2015-04-28
  • Int'l Joint Research
• [Presentation] Cell Cycle-Dependent Regulation of DNA Damage Response and DNA Repair at Dysfunctional Telomeres. (2014)
  • Author(s): Akimitsu Konishi, Takashi Izumi, Titia de Lange
  • Organizer: 4D Nucleome
  • Place of Presentation: 広島
  • Year and Date: 2014-12-17 – 2014-12-20
• [Presentation] テロメアにおける細胞周期依存的なDNA損傷反応・DNA修復の制御機構 (2014)
  • Author(s): 小西昭充、和泉孝志、Titia de Lange
  • Organizer: 染色体ワークショップ
  • Place of Presentation: 広島
  • Year and Date: 2014-12-15 – 2014-12-17
• [Presentation] テロメアでの細胞周期依存的なDNA損傷反応・DNA修復の制御機構 (2014)
  • Author(s): 小西昭充、和泉孝志、Titia de Lange
  • Organizer: 第３７回分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] Wee1 によるDNA損傷チェックポイントの回復制御 (2013)
  • Author(s): 小西昭充、和泉孝志、清水重臣
  • Organizer: 第31回染色体ワークショップ
  • Place of Presentation: 箱根
• [Presentation] Regulation of DNA damage checkpoint termination (2013)
  • Author(s): Akimitsu Konishi, Takashi Izumi, Shigeomi Shimizu
  • Organizer: 第３６回日本分子生物学会年会
  • Place of Presentation: 神戸
• [Presentation] 細胞はどのようにしてDNA損傷から回復するのか
  • Author(s): 小西昭充
  • Organizer: 群馬大学ASRLDシンポジウム
  • Place of Presentation: 前橋
• [Remarks] 群馬大学大学院医学系研究科・代謝機能制御系器官機能制御学・生化学
  • URL: http://www.med.gunma-u.ac.jp/med-organization/bioreg/bioreg-function/123.html
• [Remarks] 群馬大学大学院医学系研究科・テニュアトラック普及推進室
  • URL: http://tenure.showa.gunma-u.ac.jp/
• [Remarks] 群馬大学大学院医学系研究科テニュアトラック普及推進室
  • URL: http://tenure.showa.gunma-u.ac.jp
• [Remarks] 群馬大学大学院医学系研究科生化学教室
  • URL: http://biochemistry.dept.med.gunma-u.ac.jp
• [Remarks] 群馬大学大学院医学系研究科テニュアトラック普及推進室
  • URL: http://tenure.showa.gunma-u.ac.jp