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Formation and repair mechanisms of radiation-induced DNA-protein cross-links

Research Project

Project/Area Number 18H03374
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 63020:Radiation influence-related
Research InstitutionHiroshima University

Principal Investigator

IDE Hiroshi  広島大学, 統合生命科学研究科(理), 教授 (30223126)

Co-Investigator(Kenkyū-buntansha) 平山 亮一  国立研究開発法人量子科学技術研究開発機構, 放射線医学総合研究所 重粒子線治療研究部, 主任研究員(定常) (90435701)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2020: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2019: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2018: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Keywords放射線 / DNA損傷 / 修復機構
Outline of Final Research Achievements

DNA molecules that carry the genetic information of the cell are constantly associated with various proteins. DNA-associated proteins are covalently trapped in DNA to form DNA-protein cross-links (DPCs) when cells are irradiated with ionizing radiation or treated with other DNA-damaging agents. However, little is known about the amount of DPC damage resulting from the exposure to ionizing radiation and other DNA-damaging agents. Furthermore, how DPC damage is repaired in cells remains largely elusive. In the present study, we irradiated cells with X-rays and analyzed the proteins involved in DPCs. The possible mechanisms of DPC formation are discussed. We also used cells that were deficient in tyrosyl-DNA phosphodiesterases (TDP) 1 and 2 together with other enzymes, and elucidated the roles of these enzymes in the repair of DPCs that contained the cleavage complex of topoisomerases 1 and 2 (TOP1cc and TOP2cc).

Academic Significance and Societal Importance of the Research Achievements

DNA-タンパク質架橋(DPC)は,放射線,紫外線,ホルムアルデヒドなどの変異原物質で誘発される主要なDNA損傷の一つである。本研究により,DPCの生成機構と修復機構の一端が明らかになった。DNA損傷は,発がんや老化の原因となることが知られていることから,DPC形成に起因する発がんおよび老化機構の解明につながると予想される。また,カンプトテシンやエトポシドなどの抗がん剤は,DPCを形成することによりがん細胞を死滅させる。DPC修復に関わる酵素を標的とした阻害剤を分子設計することにより,効果の高いがん治療が可能となるとなる。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • Research Products

    (17 results)

All 2020 2019 2018 Other

All Journal Article (5 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 5 results,  Open Access: 4 results) Presentation (11 results) (of which Int'l Joint Research: 2 results,  Invited: 1 results) Remarks (1 results)

  • [Journal Article] Tyrosyl-DNA phosphodiesterase 2 (TDP2) repairs topoisomerase 1 DNA-protein crosslinks and 3′-blocking lesions in the absence of tyrosyl-DNA phosphodiesterase 1 (TDP1)2020

    • Author(s)
      Tsuda Masataka、Kitamasu Kaito、Kumagai Chiho、Sugiyama Kazuya、Nakano Toshiaki、Ide Hiroshi
    • Journal Title

      DNA Repair

      Volume: - Pages: 102849-102849

    • DOI

      10.1016/j.dnarep.2020.102849

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Participation of TDP1 in the repair of formaldehyde-induced DNA-protein cross-links in chicken DT40 cells2020

    • Author(s)
      Toshiaki Nakano, Mahmoud I. Shoulkamy, Masataka Tsuda, Hiroyuki Sasanuma, Kouji Hirota, Minoru Takata, Shin-ichiro Masunaga, Shunichi Takeda, Hiroshi Ide, Tadayoshi Bessho, Keizo Tano
    • Journal Title

      PLOS ONE

      Volume: 15 Issue: 6 Pages: 0234859-0234859

    • DOI

      10.1371/journal.pone.0234859

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Direct observation of damage clustering in irradiated DNA with atomic force microscopy2020

    • Author(s)
      Xu Xu, Toshiaki Nakano, Masataka Tsuda, Ryota Kanamoto,Ryoichi Hirayama, Akiko Uzawa and Hiroshi Ide
    • Journal Title

      Nucleic Acids Research

      Volume: 48(3) Issue: 3 Pages: e18-e18

    • DOI

      10.1093/nar/gkz1159

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Repair of trapped topoisomerase II covalent cleavage complexes: Novel proteasome-independent mechanisms2019

    • Author(s)
      Masataka Tsuda, Kaito Kitamasu, Seiji Hosokawa, Toshiaki Nakano, Hiroshi Ide
    • Journal Title

      Nucleosides, Nucleotides & Nucleic Acids

      Volume: - Issue: 1-3 Pages: 1-15

    • DOI

      10.1080/15257770.2019.1674332

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] DNA-protein cross-links: Formidable challenges to maintaining genome integrity2018

    • Author(s)
      Hiroshi Ide, Toshiaki Nakano, Amir Salem, Mahmoud Shoulkamy
    • Journal Title

      DNA Repair

      Volume: 71 Pages: 190-197

    • DOI

      10.1016/j.dnarep.2018.08.024

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] 酸化剤よるDNA-タンパク質クロスリンク損傷生成2020

    • Author(s)
      井出博,中野敏彰,津田雅貴,瀬畑敬文,久保山政弥
    • Organizer
      日本放射線影響学会第63回大会
    • Related Report
      2020 Annual Research Report
  • [Presentation] チロシル-DNA-ホスホジエステラーゼが関与する新規なDNA二本鎖切断修復経路2020

    • Author(s)
      津田雅貴,北舛海斗,山本あかね,中野敏彰,井出博
    • Organizer
      日本放射線影響学会第63回大会
    • Related Report
      2020 Annual Research Report
  • [Presentation] チロシル-DNA ホスホジエステラーゼ2(TDP2)はDNAにトラップされたトポイソメラーゼ1を修復する2020

    • Author(s)
      津田雅貴,北舛海斗,中野敏彰,井出博
    • Organizer
      第49回日本環境変異原学会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 放射線が誘発するDNA-タンパク質クロスリンク損傷の定量2019

    • Author(s)
      井出博,中野敏彰,津田雅貴,平山亮一, 鵜澤玲子
    • Organizer
      日本放射線影響学会第62回大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] DNAにトラップされたトポイソメラーゼ2の除去機構2019

    • Author(s)
      津田雅貴, 北舛海斗, 中野敏彰, 井出博
    • Organizer
      6th Asian Congress on Environmental Mutagens (ACEM)
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 過酸化物によるゲノム損傷―DNA-タンパク質クロスリンク形成2019

    • Author(s)
      徐徐, 瀬畑敬文, 久保山政弥, 津田雅貴, 中野敏彰, 井出博
    • Organizer
      第42回分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] チロシルDNAホスホジエステラーゼ2 (TDP2)によるDNA切断端に共有結合したトポイソメラーゼ2の修復機構2019

    • Author(s)
      津田雅貴, 北舛海斗, 中野敏彰, 笹沼博之, 武田俊一, 井出博
    • Organizer
      第42回分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Direct observation of damage clustering in irradiated DNA2018

    • Author(s)
      Hiroshi Ide
    • Organizer
      15th International workshop on radiation damage to DNA
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 抗ガン治療薬シタラビン(Ara-C)の作用機序の解明2018

    • Author(s)
      津田雅貴,井出博,武田俊一,廣田耕志
    • Organizer
      日本放射線影響学会第61回大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 原子間力顕微鏡を用いた放射線誘発DNA損傷の解析2018

    • Author(s)
      金本僚太,徐徐,松坂智幸,中野敏彰,平山亮一,鵜澤玲子,井出博
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 脊椎動物細胞における DNA-タンパク質クロスリンク損傷修復へのTDP1, TDP2遺伝子産物の関与2018

    • Author(s)
      藤池春奈,Mahmoud Shoulkamy,Amir Salem,津田雅貴,笹沼博之,増永慎一郎,武田俊一,井出博,田野 恵三
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
  • [Remarks] 遺伝子化学研究室

    • URL

      https://genechem.hiroshima-u.ac.jp

    • Related Report
      2020 Annual Research Report

URL: 

Published: 2018-04-23   Modified: 2022-01-27  

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