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Regulation of DNA repair pathway choice and gene editing by DNA repair machinery

Research Project

Project/Area Number 26241014
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Risk sciences of radiation and chemicals
Research InstitutionOsaka University

Principal Investigator

Nakada Shinichiro  大阪大学, 医学系研究科, 特命教授 (70548528)

Co-Investigator(Kenkyū-buntansha) 逆井 良  金沢医科大学, 医学部, 講師 (10549950)
寺尾 由里  大阪大学, 医学部, 技術職員 (80466846)
Project Period (FY) 2014-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥40,690,000 (Direct Cost: ¥31,300,000、Indirect Cost: ¥9,390,000)
Fiscal Year 2017: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000)
Fiscal Year 2016: ¥8,970,000 (Direct Cost: ¥6,900,000、Indirect Cost: ¥2,070,000)
Fiscal Year 2015: ¥8,970,000 (Direct Cost: ¥6,900,000、Indirect Cost: ¥2,070,000)
Fiscal Year 2014: ¥14,820,000 (Direct Cost: ¥11,400,000、Indirect Cost: ¥3,420,000)
KeywordsDNA修復 / 相同組換え / ゲノム編集 / 合成致死 / DNA損傷応答 / 相同組み換え / PARP阻害剤 / ユビキチン / DNA損傷
Outline of Final Research Achievements

DNA double-strand breaks (DSBs) are deleterious DNA damage. DSBs are repaired by two major DNA repair pathways: Non Homologous End Joining and Homologous Recombination (HR). RNF8 has been known as a molecule that promotes NHEJ and suppresses HR. In this research, we revealed that RNF8 promotes HR in BRCA1-negative cells. 2. DSBs are utilized for gene editing technology. However, DSBs can induce gene mutations during gene editing with DSBs. We have developed DSB-free new gene editing methods and revealed molecular mechanisms working in the gene editing technology.

Academic Significance and Societal Importance of the Research Achievements

BRCA1欠損癌はHR機能不全によりPARP阻害剤による治療が奏功すると知られている。しかし、中にはBRCA1非依存的なHRの回復によりPARP阻害剤抵抗性となるものがある。この様な細胞においてRNF8がHRを促進していることを明らかにした。これは、PARP阻害剤抵抗性を克服するための重要な分子生物学的な基盤と考えられる。DNA2本鎖切断を用いずにゲノムの編集を可能としたことにより、疾患遺伝子の変異を安全に修正する技術の基盤を開発した。さらなる発展により、遺伝性疾患の細胞治療の開発につながる可能性がある。

Report

(5 results)
  • 2018 Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • 2015 Annual Research Report
  • 2014 Annual Research Report
  • Research Products

    (41 results)

All 2018 2017 2016 2015 2014 Other

All Int'l Joint Research (2 results) Journal Article (10 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 10 results,  Open Access: 10 results,  Acknowledgement Compliant: 2 results) Presentation (21 results) (of which Int'l Joint Research: 5 results,  Invited: 13 results) Remarks (6 results) Patent(Industrial Property Rights) (2 results)

  • [Int'l Joint Research] University of Nebraska Medical Center(米国)

    • Related Report
      2017 Annual Research Report
  • [Int'l Joint Research] ネブラスカ大学(米国)

    • Related Report
      2016 Annual Research Report
  • [Journal Article] Precise and Efficient Nucleotide Substitution near Genomic Nick via Non-Canonical Homology- Directed Repair.2018

    • Author(s)
      Nakajima K, Zhou Y, Tomita A, Hirade Y, Gurumurthy CB, Nakada S
    • Journal Title

      Genome Res.

      Volume: 28 Issue: 2 Pages: 223-230

    • DOI

      10.1101/gr.226027.117

    • Related Report
      2017 Annual Research Report 2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Structural insights into two distinct binding modules for Lys63-linked polyubiquitin chains in RNF1682018

    • Author(s)
      Takahashi Tomio S.、Hirade Yoshihiro、Toma Aya、Sato Yusuke、Yamagata Atsushi、Goto-Ito Sakurako、Tomita Akiko、Nakada Shinichiro、Fukai Shuya
    • Journal Title

      Nature Communications

      Volume: 9 Issue: 1 Pages: 170-170

    • DOI

      10.1038/s41467-017-02345-y

    • Related Report
      2017 Annual Research Report 2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] T315I mutation of BCR-ABL1 into human Philadelphia chromosome-positive leukemia cell lines by homologous recombination using the CRISPR/Cas9 system2018

    • Author(s)
      Tamai Minori、Inukai Takeshi、Kojika Satoru、Abe Masako、Kagami Keiko、Harama Daisuke、Shinohara Tamao、Watanabe Atsushi、Oshiro Hiroko、Akahane Koshi、Goi Kumiko、Sugihara Eiji、Nakada Shinichiro、Sugita Kanji
    • Journal Title

      Scientific Reports

      Volume: 8 Issue: 1 Pages: 9966-9966

    • DOI

      10.1038/s41598-018-27767-6

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Human Rad52 Promotes XPG-Mediated R-loop Processing to Initiate Transcription-Associated Homologous Recombination Repair2018

    • Author(s)
      Yasuhara Takaaki、Kato Reona、Hagiwara Yoshihiko、Shiotani Bunsyo、Yamauchi Motohiro、Nakada Shinichiro、Shibata Atsushi、Miyagawa Kiyoshi
    • Journal Title

      Cell

      Volume: 175 Issue: 2 Pages: 558-570

    • DOI

      10.1016/j.cell.2018.08.056

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] BRCA1 ensures genome integrity by eliminating estrogen-induced pathological topoisomerase II-DNA complexes2018

    • Author(s)
      Sasanuma Hiroyuki、Tsuda Masataka、Morimoto Suguru、Saha Liton Kumar、Rahman Md Maminur、Kiyooka Yusuke、Fujiike Haruna、Cherniack Andrew D.、Itou Junji、Callen Moreu Elsa、Toi Masakazu、Nakada Shinichiro、Tanaka Hisashi、Tsutsui Ken、Yamada Shintaro、Nussenzweig Andre、Takeda Shunichi
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 115 Issue: 45

    • DOI

      10.1073/pnas.1803177115

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Novel polyubiquitin imaging system, PolyUb-FC, reveals that K33-linked polyubiquitin is recruited by p62/SQSTM1.2017

    • Author(s)
      Yoichi Nibe, Shigeru Oshima, Masanori Kobayashi, Chiaki Maeyashiki, Yu Matsuzawa, Kana Otsubo, Hiroki Matsuda, Emi Aonuma, Yasuhiro Nemoto, Takashi Nagaishi, Ryuichi Okamoto, Kiichiro Tsuchiya, Tetsuya Nakamura, Shinichiro Nakada, Mamoru Watanabe
    • Journal Title

      Autophagy.

      Volume: 22 Issue: 2 Pages: 1-43

    • DOI

      10.1080/15548627.2017.1407889

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] RFWD3-Mediated Ubiquitination Promotes Timely Removal of Both RPA and RAD51 from DNA Damage Sites to Facilitate Homologous Recombination2017

    • Author(s)
      Inano Shojiro、Sato Koichi、Katsuki Yoko、Kobayashi Wataru、Tanaka Hiroki、Nakajima Kazuhiro、Nakada Shinichiro、Miyoshi Hiroyuki、Knies Kerstin、Takaori-Kondo Akifumi、Schindler Detlev、Ishiai Masamichi、Kurumizaka Hitoshi、Takata Minoru
    • Journal Title

      Molecular Cell

      Volume: 66 Issue: 5 Pages: 622-634

    • DOI

      10.1016/j.molcel.2017.04.022

    • Related Report
      2017 Annual Research Report 2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Aquarius is required for proper CtIP expression and homologous recombination repair2017

    • Author(s)
      2.Sakasai R, Isono M, Wakasugi M, Hashimoto M, Sunatani Y, Matsui T, Shibata A, Matsunaga T, Iwabuchi K
    • Journal Title

      Sci Rep

      Volume: 7 Issue: 1 Pages: 1-11

    • DOI

      10.1038/s41598-017-13695-4

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] BRCA1 directs the repair pathway to homologous recombination by promoting 53BP1 dephosphorylation2017

    • Author(s)
      Mayu Isono, Atsuko Niimi, Takahiro Oike, Yoshihiko Hagiwara, Hiro Sato, Ryota Sekine, Yukari Yoshida, Shin-Ya Isobe, Chikashi Obuse, Ryotaro Nishi, Elena Petricci, Shinichiro Nakada, Takashi Nakano, Atsushi Shibata
    • Journal Title

      Cell Reports

      Volume: 18 Issue: 2 Pages: 520-532

    • DOI

      10.1016/j.celrep.2016.12.042

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Opposing roles of RNF8/RNF168 and deubiquitinating enzymes in ubiquitination-dependent DNA double-strand break response signaling and DNA-repair pathway choice.2016

    • Author(s)
      Nakada S.
    • Journal Title

      J Radiat Res.

      Volume: 未定 Issue: S1 Pages: i33-i40

    • DOI

      10.1093/jrr/rrw027

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] DNA2本鎖切断を作らず、ニックでゲノム編集を誘導する2018

    • Author(s)
      中田慎一郎
    • Organizer
      ゲノム編集学会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] ニックにより誘導するIndel発生が少ないゲノム編集2018

    • Author(s)
      中田慎一郎
    • Organizer
      日本核酸医薬学会生物セッション第2回サテライトシンポジウム
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] ニックを用いた正確なゲノム編集法 (SNGD法)2018

    • Author(s)
      中田慎一郎
    • Organizer
      日本遺伝子細胞治療学会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] Precise gene editing by a combination of single nicks in the target gene and donor plasmid.2018

    • Author(s)
      Shinichiro Nakada, Kazuhiro Nakajima, Yue Zhou, Akiko Tomita, Yoshihiro Hirade.
    • Organizer
      Gordon Research Conference
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ニックによる正確で効率のよいゲノム編集法では 非古典的なHDRが利用されている2017

    • Author(s)
      中田慎一郎
    • Organizer
      ゲノム編集学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Repair pathways for one-ended DNA double-strand breaks caused by camptothecin.2017

    • Author(s)
      Sakasai R, Sunatani Y, Matsui T, Iwabuchi K.
    • Organizer
      Gordon Research Conference
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Single Nicking of a Target Gene and Donor Plasmid Enables Precise and Efficient Nucleotide Substitution by Non-Canonical Homology-Directed Repair2017

    • Author(s)
      Shinichiro Nakada
    • Organizer
      US-Japan DNA repair meeting
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] ニックによる正確で効率のよいゲノム編集法では 非古典的なHDRが利用されている2017

    • Author(s)
      中田慎一郎
    • Organizer
      分子生物学会
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] 非典型的なhomology directed repairによりDNA2本鎖切 を起こさずにゲノム編集が可能である2017

    • Author(s)
      中嶋裕宏、周越、中田慎一郎
    • Organizer
      ゲノム編集学会
    • Related Report
      2016 Annual Research Report
  • [Presentation] ニックを入れたドナープラスミドを用いて標的遺伝子上の1つのニックから高効率かつ安全な塩基置換を行う2016

    • Author(s)
      中田慎一郎
    • Organizer
      分子生物学会
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Choice of DNA double-strand break repair pathway by E3 ubiquitin ligase RNF8.2016

    • Author(s)
      Shinichiro Nakada
    • Organizer
      日本癌学会
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] RNF8 regulates sensitivity of BRCA153BP1 knockout cells to DNA cross-linking agents2016

    • Author(s)
      Kiyoko Kato, Shinichiro Nakada
    • Organizer
      Fanconi Anemia Symposium
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 相同組換え修復過程におけるユビキチン化の関与2015

    • Author(s)
      中田慎一郎
    • Organizer
      第38回日本分子生物学会年会・第88回日本生化学会合同大会
    • Place of Presentation
      神戸ポートアイランド
    • Year and Date
      2015-12-01
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] DNA Damage-induced Ubiquitination Affects DNA Repair Pathway Choice.2015

    • Author(s)
      Shinichiro Nakada
    • Organizer
      15th International Congress of Radiation Research
    • Place of Presentation
      京都国際会議場
    • Year and Date
      2015-05-25
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Multiple Ubiquitination Pathways suppress RAD51 recruitment through facilitating RPA S4/S8 phosphorylation2015

    • Author(s)
      Nakajima K. and Nakada S.
    • Organizer
      Keystone Symposia
    • Place of Presentation
      ウィスラー カナダ
    • Year and Date
      2015-03-01 – 2015-03-06
    • Related Report
      2014 Annual Research Report
  • [Presentation] ユビキチン依存性DNA2本鎖損傷応答シグナルとDNA修復2014

    • Author(s)
      中田慎一郎
    • Organizer
      分子生物学会
    • Place of Presentation
      横浜
    • Year and Date
      2014-11-25 – 2014-11-27
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] DNA damage-induced ubiquitination affects DNA repair pathway choice2014

    • Author(s)
      Nakada S
    • Organizer
      3R symposium
    • Place of Presentation
      御殿場
    • Year and Date
      2014-11-17 – 2014-11-21
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] DNA損傷依存性ユビキチン化の精密制御による適切なDNA修復経路選択2014

    • Author(s)
      中田慎一郎
    • Organizer
      日本癌学会学術集会
    • Place of Presentation
      横浜
    • Year and Date
      2014-10-03 – 2014-10-05
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] ユビキチン化制御によるDNA2本鎖損傷修復選択機構2014

    • Author(s)
      中田慎一郎
    • Organizer
      放射線影響学会
    • Place of Presentation
      鹿児島
    • Year and Date
      2014-10-01 – 2014-10-03
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Fine-Tuning of DNA damage-induced ubiquitination supports adequate DNA repair pathway2014

    • Author(s)
      Kato K., Nakajima K. and Nakada S.
    • Organizer
      Benzon Symposium
    • Place of Presentation
      コペンハーゲン デンマーク
    • Year and Date
      2014-08-18 – 2014-08-21
    • Related Report
      2014 Annual Research Report
  • [Presentation] Fine-Tuning of DNA damage-induced ubiquitination supports adequate DNA repair pathway2014

    • Author(s)
      Kato K., Nakajima K. and Nakada S.
    • Organizer
      Gordon Research Conference
    • Place of Presentation
      香港 中国
    • Year and Date
      2014-06-06 – 2014-06-11
    • Related Report
      2014 Annual Research Report
  • [Remarks] 大阪大学 高等共創研究院・大学院医学系研究科 細胞応答制御学

    • URL

      http://www.bcr.med.osaka-u.ac.jp

    • Related Report
      2017 Annual Research Report
  • [Remarks] 遺伝子変異が発生しにくい新しいゲノム編集法を開発 ~安全な遺伝子治療に向けた新技術~

    • URL

      http://www.med.osaka-u.ac.jp/activities/results/2018year/nakada0202

    • Related Report
      2017 Annual Research Report
  • [Remarks] DNA2本鎖が切断された場所に修復タンパク質が集まる仕組み

    • URL

      http://www.med.osaka-u.ac.jp/activities/results/2018year/18-01-12

    • Related Report
      2017 Annual Research Report
  • [Remarks]

    • URL

      http://www.bcr.med.osaka-u.ac.jp

    • Related Report
      2016 Annual Research Report
  • [Remarks] 大阪大学大学院 医学系研究科 細胞応答制御学

    • URL

      http://www.bcr.med.osaka-u.ac.jp/public_html/index.html

    • Related Report
      2015 Annual Research Report
  • [Remarks] 細胞応答制御学

    • URL

      http://www.bcr.med.osaka-u.ac.jp/public_html/index.html

    • Related Report
      2014 Annual Research Report
  • [Patent(Industrial Property Rights)] ゲノム編集された細胞を製造する方法2018

    • Inventor(s)
      中田慎一郎
    • Industrial Property Rights Holder
      国立大学法人大阪大学
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2018-215588
    • Filing Date
      2018
    • Related Report
      2017 Annual Research Report
  • [Patent(Industrial Property Rights)] ゲノム編集方法2016

    • Inventor(s)
      中田慎一郎
    • Industrial Property Rights Holder
      中田慎一郎
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2016-141482
    • Filing Date
      2016
    • Related Report
      2016 Annual Research Report

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Published: 2014-04-04   Modified: 2020-03-30  

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