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Unraveling the regulation of fidelity in DNA replication and homology-directed repair

Research Project

Project/Area Number 20H03186
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 43010:Molecular biology-related
Research InstitutionKyushu University

Principal Investigator

Takahashi Tatsuro  九州大学, 理学研究院, 教授 (50452420)

Project Period (FY) 2020-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2023: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Keywordsミスマッチ修復 / ツメガエル卵抽出液 / 相同組換え / ゲノム安定性 / DNA二重鎖切断修復 / DNA二重鎖切断損傷修復 / 相同性依存的修復 / DNA二重鎖切断損傷
Outline of Research at the Start

遺伝情報物質であるDNAは、複製や組換えによって維持、再編、安定継承される。一方、これらの反応の誤りによって、DNA二重鎖の塩基対ミスマッチが生じることがあり、それらは変異や染色体不安定性の原因となる。またDNAはクロマチン構造に巻き取られているため、上記反応は全てクロマチン上で起こる。本研究ではミスマッチ形成に応答し、複製、組換えを正確に達成する反応の分子メカニズムを、特にクロマチン上での機能に焦点をあてて解析する。

Outline of Final Research Achievements

The mismatch repair system handles both DNA biosynthesis and recombination errors to increase the fidelity in DNA replication and recombination. While these reactions are triggered by the same mismatch sensors, the downstream events are highly diverged. Importantly, the molecular mechanism of recombination regulation by the mismatch repair system remains ambiguous, and the pathway-choice mechanism of the two pathways is also poorly understood. In this study, we established biochemical model systems that recapitulate the regulation of recombination using Xenopus egg nucleoplasmic extracts and purified proteins. Using these systems, we identified factors that affect the fidelity of recombination. These results contribute to the basic understanding of genome maintenance.

Academic Significance and Societal Importance of the Research Achievements

ゲノムの安定性は、がんなどのゲノム安定性疾患や、老化の背景として重要である。本研究で取り扱うミスマッチ応答機構は重要ながん抑制機構として知られ、この機構の破綻は孤発性および遺伝性発がんの原因のひとつとなっている。本研究の成果は、ミスマッチ応答機構の動作原理の理解を進めるもので、基礎科学としてのゲノム安定性、ゲノム品質管理の理解に貢献する。また、本研究成果は、ゲノム安定性維持機構の解明を通じて、発がんや老化の理解にも貢献する。

Report

(5 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • Research Products

    (33 results)

All 2024 2023 2022 2021 2020 Other

All Int'l Joint Research (2 results) Journal Article (4 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 4 results,  Open Access: 4 results) Presentation (26 results) (of which Int'l Joint Research: 5 results,  Invited: 6 results) Remarks (1 results)

  • [Int'l Joint Research] University of Dundee(英国)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] University of Queensland(オーストラリア)

    • Related Report
      2023 Annual Research Report
  • [Journal Article] The Atad5 RFC-like complex is the major unloader of proliferating cell nuclear antigen in Xenopus egg extracts2024

    • Author(s)
      Kawasoe Yoshitaka、Shimokawa Sakiko、Gillespie Peter J.、Blow J. Julian、Tsurimoto Toshiki、Takahashi Tatsuro S.
    • Journal Title

      Journal of Biological Chemistry

      Volume: 300 Issue: 1 Pages: 105588-105588

    • DOI

      10.1016/j.jbc.2023.105588

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Resection of DNA double-strand breaks activates Mre11-Rad50-Nbs1- and Rad9-Hus1-Rad1-dependent mechanisms that redundantly promote ATR checkpoint activation and end processing in Xenopus egg extracts2024

    • Author(s)
      Tatsukawa Kensuke、Sakamoto Reihi、Kawasoe Yoshitaka、Kubota Yumiko、Tsurimoto Toshiki、Takahashi Tatsuro S.、Ohashi Eiji
    • Journal Title

      Nucleic Acids Research

      Volume: 52 Issue: 6 Pages: 3146-3163

    • DOI

      10.1093/nar/gkae082

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The termination of UHRF1-dependent PAF15 ubiquitin signaling is regulated by USP7 and ATAD52023

    • Author(s)
      Miyashita Ryota、Nishiyama Atsuya、Qin Weihua、Chiba Yoshie、Kori Satomi、Kato Norie、Konishi Chieko、Kumamoto Soichiro、Kozuka-Hata Hiroko、Oyama Masaaki、Kawasoe Yoshitaka、Tsurimoto Toshiki、Takahashi Tatsuro S、Leonhardt Heinrich、Arita Kyohei、Nakanishi Makoto
    • Journal Title

      eLife

      Volume: 12 Pages: 79013-79013

    • DOI

      10.7554/elife.79013

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Human DDK rescues stalled forks and counteracts checkpoint inhibition at unfired origins to complete DNA replication2021

    • Author(s)
      Jones Mathew J.K.、Gelot Camille、Munk Stephanie、Koren Amnon、Kawasoe Yoshitaka、George Kelly A.、Santos Ruth E.、Olsen Jesper V.、McCarroll Steven A.、Frattini Mark G.、Takahashi Tatsuro S.、Jallepalli Prasad V.
    • Journal Title

      Molecular Cell

      Volume: 81 Issue: 3 Pages: 426-441.e8

    • DOI

      10.1016/j.molcel.2021.01.004

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] MutSα and Smarcad1 form a mispair-activated nucleosome remodeling complex that catalyzes unidirectional nucleosome sliding2023

    • Author(s)
      Eiichiro Kanatsu, Riki Terui, Yasukazu Daigaku, Tatsuro Takahashi
    • Organizer
      The 2nd International Symposium on REPLICATION of NON GENOME ~Cutting Edge of Epigenetics~
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] An interface between strand invasion and DNA synthesis during homology-directed repair2023

    • Author(s)
      Tatsuro Takahashi
    • Organizer
      国立遺伝学研究所・研究集会「染色体安定維持研究会」
    • Related Report
      2023 Annual Research Report
  • [Presentation] Mechanistic details of the chromatin remodeling reaction associated with post-replicative DNA mismatch repair2023

    • Author(s)
      Eiichiro Kanatsu, Riki Terui, Yasukazu Daigaku, Tatsuro Takahashi
    • Organizer
      Eukaryotic DNA replication & genome maintenance
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Regulation of the fidelity of homology-directed repair in Xenopus egg extracts2023

    • Author(s)
      Yoshitaka Kawasoe, Satomi Oda, Aya Sakazume, Taisei Miyata, Tatsuro Takahashi
    • Organizer
      第96回日本生化学会大会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Regulation of the fidelity of homology-directed repair in Xenopus egg extracts2022

    • Author(s)
      高橋 達郎
    • Organizer
      国立遺伝学研究所・研究集会「染色体安定維持研究会」
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] The mechanism of a chromatin-remodeling reaction associated with replication error correction2022

    • Author(s)
      高橋 達郎
    • Organizer
      Chromosome Replication in the New Era - Old and New Questions in Life Science -
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] The mechanism of a chromatin-remodeling reaction associated with replication error correction2022

    • Author(s)
      高橋 達郎
    • Organizer
      第45回日本分子生物学会年会
    • Related Report
      2022 Annual Research Report
  • [Presentation] WernerヘリカーゼとMutLαエンドヌクレアーゼは一本鎖アニーリングの正確性を制御する2022

    • Author(s)
      河添 好孝
    • Organizer
      第95回日本生化学会大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 試験管内再構成による抗組換え反応のメカニズムの解析2022

    • Author(s)
      久持 涼子
    • Organizer
      第45回日本分子生物学会年会
    • Related Report
      2022 Annual Research Report
  • [Presentation] WernerヘリカーゼとMutLαエンドヌクレアーゼは一本鎖アニーリングの正確性を制御する2022

    • Author(s)
      河添 好孝
    • Organizer
      第45回日本分子生物学会年会
    • Related Report
      2022 Annual Research Report
  • [Presentation] ミスマッチ修復の伴うヌクレオソームリモデリングの試験管内再構成2022

    • Author(s)
      金津 瑛一郎
    • Organizer
      第40回染色体ワークショップ・第21回核ダイナミクス研究会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Regulation of the fidelity of homology-directed repair in Xenopus egg extracts2022

    • Author(s)
      高橋達郎
    • Organizer
      The 11th quinquennial conference on DNA repair
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Mechanisms of mismatch-induced nucleosome remodeling during eukaryotic DNA mismatch repair2022

    • Author(s)
      金津瑛一郎
    • Organizer
      The 30th Hot Spring Harbor International Symposium Chromatin Potential in Development & Differentiation
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] MMRシステムによる相同組換え正確性制御のメカニズム2021

    • Author(s)
      高橋達郎
    • Organizer
      国立遺伝学研究所・研究集会「染色体安定維持研究会」
    • Related Report
      2021 Annual Research Report
  • [Presentation] ミスマッチ修復に伴うクロマチンリモデリング反応の試験管内再構成による解析2021

    • Author(s)
      高橋達郎
    • Organizer
      第93回日本遺伝学会年会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] MutSαとSmarcad1はミスマッチ依存的ヌクレオソームリモデリング複合体を形成する2021

    • Author(s)
      高橋達郎
    • Organizer
      第94回日本生化学会大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] WernerヘリカーゼとMutLαエンドヌクレアーゼは一本鎖アニーリングの正確性を制御する2021

    • Author(s)
      河添好孝
    • Organizer
      第26回DNA複製・組換え・修復ワークショップ
    • Related Report
      2021 Annual Research Report
  • [Presentation] ミスマッチ修復を促進するヌクレオソームリモデリングの試験管内再構成2021

    • Author(s)
      金津瑛一郎
    • Organizer
      第26回DNA複製・組換え・修復ワークショップ
    • Related Report
      2021 Annual Research Report
  • [Presentation] WernerヘリカーゼとMutLαエンドヌクレアーゼはDNA二重鎖切断修復の正確性を制御する2021

    • Author(s)
      河添好孝
    • Organizer
      第44回日本分子生物学会年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] ミスマッチ修復機構に依存したアルキル化損傷応答反応の試験管内再現による解析2021

    • Author(s)
      重信佳凜
    • Organizer
      第44回日本分子生物学会年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] クロマチンを基質としたミスマッチ修復反応の試験管内再構成に向けた解析2021

    • Author(s)
      福田翔太
    • Organizer
      第44回日本分子生物学会年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 真核生物のDNAミスマッチ修復に伴うヌクレオソームリモデリングのメカニズム2021

    • Author(s)
      金津瑛一郎
    • Organizer
      第44回日本分子生物学会年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] WernerヘリカーゼとMutLαエンドヌクレアーゼは一本鎖アニーリングの正確性を制御する2021

    • Author(s)
      河添好孝
    • Organizer
      第39回染色体ワークショップ・第20回核ダイナミクス研究会
    • Related Report
      2021 Annual Research Report
  • [Presentation] A balance between pro- and anti-recombination reactions determines the fidelity of homology-directed repair2021

    • Author(s)
      高橋 達郎
    • Organizer
      第38回染色体ワークショップ・第19回核ダイナミクス研究会
    • Related Report
      2020 Annual Research Report
  • [Presentation] The quality control mechanism of homology-directed repair in Xenopus egg extracts2020

    • Author(s)
      高橋 達郎
    • Organizer
      第43回日本分子生物学会年会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] ミスマッチ修復システムによるクロマチンリモデリングの試験管内再構成による解析2020

    • Author(s)
      高橋 達郎
    • Organizer
      日本遺伝学会第92回大会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Remarks] 研究室ウエブサイト

    • URL

      http://www.biology.kyushu-u.ac.jp/~chromosome/index.html

    • Related Report
      2023 Annual Research Report 2022 Annual Research Report 2021 Annual Research Report 2020 Annual Research Report

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Published: 2020-04-28   Modified: 2025-01-30  

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