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Understanding mechanism of genome instability in hereditary breast cancer induced by telomere dysfunction

Research Project

Project/Area Number 17K08649
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Pathological medical chemistry
Research InstitutionGunma University

Principal Investigator

Konishi Akimitsu  群馬大学, 大学院医学系研究科, 講師 (50381877)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywordsテロメア / 染色体不安定化 / DNA損傷反応 / 細胞周期 / 乳癌 / 遺伝性乳癌 / 染色体末端融合 / DNA損傷応答 / ゲノム不安定化 / ユビキチン化 / 遺伝性乳ガン
Outline of Final Research Achievements

Breast cancer is currently the most common cancer in women, with hereditary breast cancer accounting for about 10% of the cases. Mutations in the BRCA1 gene, one of the major causative genes in hereditary breast cancer, cause genome instability. Telomeres are localized at the ends of chromosomes to play an important role in genome stabilization. In this study, we focused on telomere function to elucidate the mechanism of genome instability caused by BRCA1 abnormalities.
This study reveals a detailed molecular mechanism by which the BRCA1 complex regulates the ubiquitination of chromatin in the telomere region and represses chromosome end fusion during telomere dysfunction, which leads a genome instability.

Academic Significance and Societal Importance of the Research Achievements

遺伝性乳癌は乳癌の中でも治療に難渋するトリプルネガティブ乳癌に含まれ予後不良であり、BRCA 遺伝子に変異が存在すると70%以上という高率で遺伝性乳癌を発症することから、遺伝性乳癌の病態解明は喫緊の課題の一つである。テロメアによる染色体末端融合は、癌で高率で見られるゲノム不安定化を引き起こす原因であり、本研究で明らかになったBRCA1 複合体による染色体末端融合の分子機構に関する知見は、遺伝性乳癌の病態理解と分子標的治療法の開発につながる。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (14 results)

All 2019 2018 2017 Other

All Journal Article (2 results) (of which Peer Reviewed: 2 results,  Open Access: 2 results) Presentation (10 results) Remarks (2 results)

  • [Journal Article] Metformin activates KDM2A to reduce rRNA transcription and cell proliferation by dual regulation of AMPK activity and intracellular succinate level2019

    • Author(s)
      Tanaka Yuji、Konishi Akimitsu、Obinata Hideru、Tsuneoka Makoto
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1 Pages: 18694-18694

    • DOI

      10.1038/s41598-019-55075-0

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Dram1 regulates DNA damage-induced alternative autophagy2018

    • Author(s)
      Nagata M, Arakawa S, Yamaguchi H, Torii S, Endo H, Tsujioka M, Honda S, Nishida Y, Konishi A, Shimizu S
    • Journal Title

      Cell Stress

      Volume: 2 Issue: 3 Pages: 55-65

    • DOI

      10.15698/cst2018.03.127

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] BRCA1 complex regulates cell cycle-dependent DNA damage response at telomeres to maintain chromosome integrity2019

    • Author(s)
      小西昭充、南嶋洋司
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 早期細胞老化誘導時に起こる細胞内代謝変化への理解2019

    • Author(s)
      小西昭充
    • Organizer
      第8回DNA損傷応答ワークショップ
    • Related Report
      2019 Annual Research Report
  • [Presentation] 早期細胞老化におけるアミノ酸代謝の変調2019

    • Author(s)
      荒牧佑磨、小西昭充、南嶋洋司
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] ゲノム損傷ストレスによって誘導されるオートファジー2018

    • Author(s)
      小西昭充
    • Organizer
      第7回DNA損傷応答ワークショップ
    • Related Report
      2018 Research-status Report
  • [Presentation] Autophagy controls centrosome number by degrading Cep632018

    • Author(s)
      Yuichiro Watanabe, Akimitsu Konishi, Shinji Tanaka, Shigeomi Shimizu
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Research-status Report
  • [Presentation] 骨芽細胞様細胞MC3T3-E1におけるアクチン細胞骨格再構成を介した炎症性脂質メディエーター誘導性の骨形成制御メカニズムの解析2018

    • Author(s)
      鈴木啓、大嶋紀安、小西昭充、立井一明、佐藤精一、和泉孝志
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] メトホルミンはKDM2A依存的なrRNA転写抑制及び細胞増殖抑制を引き起こす2018

    • Author(s)
      田中祐司、小西昭充、大日方英、南雲美奈代、和泉桃佳、岡本健吾、常岡誠
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] ゲノム編集技術を用いた可視化による内在性p53蛋白ダイナミクスの一細胞解析2017

    • Author(s)
      小西昭充
    • Organizer
      DNA損傷応答ワークショップ
    • Related Report
      2017 Research-status Report
  • [Presentation] ゲノム編集技術を用いた蛍光蛋白ラベル法による内在性p53蛋白動態の1細胞解析2017

    • Author(s)
      荒牧佑磨、小西昭充、和泉孝志
    • Organizer
      染色体ワークショップ
    • Related Report
      2017 Research-status Report
  • [Presentation] ゲノム編集技術を用いた蛍光蛋白ラベル法による内在性p53蛋白動態の1細胞解析2017

    • Author(s)
      荒牧佑磨、小西昭充、和泉孝志
    • Organizer
      ConBio2017
    • Related Report
      2017 Research-status Report
  • [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

      https://tenure.showa.gunma-u.ac.jp

    • Related Report
      2019 Annual Research Report
  • [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

    • Related Report
      2018 Research-status Report 2017 Research-status Report

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Published: 2017-04-28   Modified: 2021-02-19  

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