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Regulatory mechanisms of CtIP nuclease during DNA crosslink repair

Research Project

Project/Area Number 24310042
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypePartial Multi-year Fund
Section一般
Research Field Risk sciences of radiation/Chemicals
Research InstitutionKyoto University

Principal Investigator

TAKATA Minoru  京都大学, 放射線生物研究センター, 教授 (30281728)

Co-Investigator(Kenkyū-buntansha) UNNO Junya  京都大学, 放射線生物研究センター, 研究員 (50614153)
KATSUKI Yoko  京都大学, 放射線生物研究センター, 研究員 (00645377)
Project Period (FY) 2012-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥15,600,000 (Direct Cost: ¥12,000,000、Indirect Cost: ¥3,600,000)
Fiscal Year 2014: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2013: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2012: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
KeywordsFanconi貧血 / FANCD2 / CtIP / ユビキチン化 / DNAクロスリンク損傷 / DNA損傷修復 / ファンコニ貧血 / end resection / クロスリンク修復 / モノユビキチン化 / Fanconi anemia / DNA損傷応答 / DNA修復 / チェックポイント
Outline of Final Research Achievements

The Fanconi anemia (FA) pathway is critically involved in the maintenance of hematopoietic stem cells and the suppression of carcinogenesis. A key FA protein, FANCD2, is monoubiquitinated and accumulates in chromatin in response to DNA interstrand crosslinks (ICLs), where it coordinates DNA repair through mechanisms that are still poorly understood. Here we report that CtIP protein is a direct interactor of FANCD2. A region spanning amino acids 166 to 273 of CtIP, and monoubiquitination of FANCD2, were both essential for the FANCD2-CtIP interaction and MMC-induced CtIP foci. Remarkably, both FANCD2 and CtIP were critical for MMC-induced RPA2 hyperphosphorylation, an event that accompanies end resection of double strand breaks. Collectively, our results reveal a role of monoubiquitinated FANCD2 in end resection, anchoring CtIP to chromatin during ICL repair.

Report

(4 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Annual Research Report
  • 2012 Annual Research Report
  • Research Products

    (32 results)

All 2014 2013 2012 Other

All Journal Article (16 results) (of which Peer Reviewed: 16 results,  Open Access: 6 results,  Acknowledgement Compliant: 3 results) Presentation (14 results) (of which Invited: 6 results) Remarks (2 results)

  • [Journal Article] Defective FANCI Binding by a Fanconi Anemia-Related FANCD2 Mutant.2014

    • Author(s)
      Sato K, Ishiai M, Takata M, Kurumizaka H.
    • Journal Title

      PLoS One

      Volume: 9 Issue: 12 Pages: e114752-e114752

    • DOI

      10.1371/journal.pone.0114752

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] The Trp53-Trp53inp1-Tnfrsf10b Pathway Regulates the Radiation Response of Mouse Spermatogonial Stem Cells.2014

    • Author(s)
      Kei Ishii, Masamichi Ishiai, Hiroko Morimoto, Mito Kanatsu-Shinohara, Ohtsura Niwa, Minoru Takata, and Takashi Shinohara.
    • Journal Title

      Stem Cell Reports.

      Volume: 3 Issue: 4 Pages: 676-89

    • DOI

      10.1016/j.stemcr.2014.08.006

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Expression and purification of human FANCI and FANCD2 using Escherichia coli cells.2014

    • Author(s)
      Daisuke Takahashi, Koichi Sato, Mayo Shimomuki, Minoru Takata, Hitoshi Kurumizaka
    • Journal Title

      Protein Expression and Purification

      Volume: 103 Pages: 8-15

    • DOI

      10.1016/j.pep.2014.08.012

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Modularized functions of the Fanconi anemia core complex.2014

    • Author(s)
      Huang Y, Leung JW, Lowery M, Matsushita N, Wang Y, Shen X, Huong D, Takata M, Chen J, Li L.
    • Journal Title

      Cell Rep.

      Volume: 7 Issue: 6 Pages: 1849-57

    • DOI

      10.1016/j.celrep.2014.04.029

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] FANCD2 Binds CtIP and Regulates DNA-End Resection during DNA Interstrand Crosslink Repair.2014

    • Author(s)
      Unno J
    • Journal Title

      Cell Rep.

      Volume: 7 Issue: 4 Pages: 1039-1047

    • DOI

      10.1016/j.celrep.2014.04.005

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Tumor suppressor RecQL5 controls recombination induced by DNA crosslinking agents2014

    • Author(s)
      Yoshifumi Hosono, Takuya Abe, Masamichi Ishiai, M. Nurul Islam, Hiroshi Arakawa, Weidong Wang, Shunichi Takeda, Yutaka Ishii, Minoru Takata, Masayuki Seki, Takemi Enomoto
    • Journal Title

      Biochimica et Biophysica Acta-Molecular Cell Research

      Volume: 1843 Issue: 5 Pages: 1002-1012

    • DOI

      10.1016/j.bbamcr.2014.01.005

    • Related Report
      2014 Annual Research Report 2013 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A novel interplay between the Fanconi anemia core complex and ATR-ATRIP kinase during DNA cross-link repair2013

    • Author(s)
      J Tomida, A Itaya, T Shigechi, J Unno, E Uchida, M Ikura, Y Masuda, S Matsuda J Adachi, M Kobayashi, AR Meetei, Y Maehara, K Yamamoto K Kamiya, A Matsuura, T Matsuda. T Ikura, M Ishiai, M Takata
    • Journal Title

      Nucleic Acids Research

      Volume: VOL. 41 Issue: 14 Pages: 6930-6941

    • DOI

      10.1093/nar/gkt467

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Variant ALDH2 is associated with accelerated progression of bone marrow failure in Japanese Fanconi anemia patients.2013

    • Author(s)
      Hira A, Yoshida K
    • Journal Title

      Blood

      Volume: 122 Issue: 18 Pages: 3206-3209

    • DOI

      10.1182/blood-2013-06-507962

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Vandetanib is effective in EGFR-mutant lung cancer cells with PTEN deficiency.2013

    • Author(s)
      Takeda H, Takigawa N, Ohashi K, Minami D, Kataoka I, Ichihara E, Ochi N, Tanimoto M, Kiura K.
    • Journal Title

      Mol Cancer Res

      Volume: 319 Issue: 2 Pages: 417-423

    • DOI

      10.1158/1541-7786.mcr-12-0401

    • NAID

      120005359097

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] NBS1 directly activates ATR independently of MRE11 and TOPBP1.2013

    • Author(s)
      Kobayashi M, Hayashi N, Takata M, Yamamoto K.
    • Journal Title

      Genes Cells.

      Volume: 18 Issue: 3 Pages: 238-46

    • DOI

      10.1111/gtc.12031

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] DNA robustly stimulates FANCD2 monoubiquitylation in the complex with FANCI2012

    • Author(s)
      Koichi Sato. Kazue Toda, Masamichi Ishiai, Minora Takata, Hitoshi Kurumizaka
    • Journal Title

      Nucleic Acids Research

      Volume: 40 Issue: 10 Pages: 4553-4561

    • DOI

      10.1093/nar/gks053

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Matched sibling donor stem cell transplantation for Fanconi anemia patients with T-cell somatic mosaicism2012

    • Author(s)
      Yabe M, Shimizu T, Morimoto T, Koike T, Takakura H, Tsukamoto H, Muroi K, Oshima K, Asami K, Takata M, Yamashita T, Kato S, Yabe H
    • Journal Title

      Pediatric Transplant

      Volume: (印刷中) Issue: 4 Pages: 340-345

    • DOI

      10.1111/j.1399-3046.2012.01669.x

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Histone chaperone activity of Fanconi anemia proteins, FANCD2 and FANCI, is required for DNA crosslink repair2012

    • Author(s)
      Koichi Sato. Masamichi Ishiai, Kazue Toda, Satoshi Furukoshi, Akihisa Osakabe, Hiroaki Tachiwana, Yoshimasa Takizawa, Wataru Kagawa, Hiroyuki Kitao, Naoshi Dohmae, Chikashi Obuse, Hiroshi Kimura, Minoru Takata, Hitoshi Kurumizaka
    • Journal Title

      The EMBO Journal

      Volume: 31 Issue: 17 Pages: 3524-3536

    • DOI

      10.1038/emboj.2012.197

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mcm8 and Mcm9 form a complex that functions in homologous recombination induced by interstrand crosslinks2012

    • Author(s)
      K. Nishimura
    • Journal Title

      Molecular Cell

      Volume: 47 Issue: 4 Pages: 511-522

    • DOI

      10.1016/j.molcel.2012.05.047

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A ubiquitin-binding protein, FAAP20, links RNF8-mediated ubiquitination to the Fanconi anemia DNA repair network.2012

    • Author(s)
      Yan Z, Guo R, Paramasivam M, Shen W, Ling C, Fox D 3rd, Wang Y, Oostra AB, Kuehl J, Lee DY, Takata M, Hoatlin ME, Schindler D, Joenje H, de Winter JP, Li L, Seidman MM, Wang W
    • Journal Title

      Mol Cell.

      Volume: 47 Issue: 1 Pages: 61-75

    • DOI

      10.1016/j.molcel.2012.05.026

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Establishment of the DNA repair-defective mutants in DT40 cells.2012

    • Author(s)
      Ishiai M, Uchida E, Takata M.
    • Journal Title

      Methods Mol Biol.

      Volume: 920 Pages: 39-49

    • DOI

      10.1007/978-1-61779-998-3_4

    • NAID

      120004996387

    • ISBN
      9781617799976, 9781617799983
    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Presentation] 日本人ファンコニ貧血患者における新規原因遺伝子UBE2Tの同定2014

    • Author(s)
      平 明日香, 吉田 健一, 佐藤 浩一, 嶋本 顕, 田原 栄俊, 胡桃坂 仁志, 小川 誠司, 高田 穣, 矢部 普正, 矢部 みはる
    • Organizer
      第37回日本分子生物学会年会 ワークショップ
    • Place of Presentation
      パシフィコ横浜
    • Year and Date
      2014-11-25 – 2014-11-27
    • Related Report
      2014 Annual Research Report
  • [Presentation] ファンコニ貧血経路とそのキータンパク質FANCD2の機能解析2014

    • Author(s)
      高田 穣, 勝木 陽子, 佐藤 浩一, 石合 正道, 胡桃坂 仁志
    • Organizer
      第37回日本分子生物学会年会 ワークショップ
    • Place of Presentation
      パシフィコ横浜
    • Year and Date
      2014-11-25 – 2014-11-27
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] UBE2T is a novel FA gene identified in Japanese Fanconi anemia patients2014

    • Author(s)
      Minoru Takata, Asuka Hira, Kenichi Yoshida, Koichi Sato, Akira Shimamoto, Hidetoshi Tahara, Hitoshi Kurumizaka, Seishi Ogawa, Hiromasa Yabe, and Miharu Yabe
    • Organizer
      The 9th 3R Symposium
    • Place of Presentation
      Gotemba Kogen Hotel
    • Year and Date
      2014-11-17 – 2014-11-21
    • Related Report
      2014 Annual Research Report
  • [Presentation] Comprehensive analysis of Japanese Fanconi anemia (FA) patients has led to the identification of an E2 enzyme UBE2T as a novel FA gene.2014

    • Author(s)
      Minoru Takata
    • Organizer
      日米修復会議
    • Place of Presentation
      エクシブ鳴門
    • Year and Date
      2014-10-29
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Infant Japanese Fanconi anemia patients with the ALDH2-AA genotype.2014

    • Author(s)
      M. Yabe, A. Hira, H, Yabe, T. Morimoto, A. Fukumura, M. Miyashita, K. Ohtsubo, K. Matsuo, M. Takata.
    • Organizer
      26th Annual Fanconi Anemia Research Fund Scientific Symposium.
    • Place of Presentation
      Bethesda MA, USA
    • Year and Date
      2014-09-18 – 2014-09-21
    • Related Report
      2014 Annual Research Report
  • [Presentation] 遺伝性DNA修復異常疾患:家族性乳がんとファンコニ貧血2014

    • Author(s)
      高田 穣
    • Organizer
      日本家族性腫瘍学会 第17回家族性腫瘍セミナー
    • Place of Presentation
      近畿大学・東大阪キャンパス
    • Year and Date
      2014-08-24
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] ファンコニ貧血症とDNA修復メカニズム2014

    • Author(s)
      髙田 穣
    • Organizer
      第36回日本光医学・光生物学会シンポジウム
    • Place of Presentation
      大阪大学銀杏会館
    • Year and Date
      2014-07-25
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] FANCD2 in chromatin anchors CtIP and regulates DNA end resection during crosslink repair.2013

    • Author(s)
      J. Unno, A. Itaya, M. Taoka, K. Sato, J. Tomida, W. Sakai, T. Ikura, T. Isobe, H. Kurumizaka, M. Takata
    • Organizer
      25th Annual Fanconi anemia research fund Scientific Symposium
    • Place of Presentation
      Houston, Texas, USA
    • Related Report
      2013 Annual Research Report
  • [Presentation] プログレス教育講演  「ファンコニ貧血とDNAクロスリンク修復の分子機構 ー最近の進歩ー」2013

    • Author(s)
      高田 穣
    • Organizer
      日本血液学会
    • Place of Presentation
      札幌市
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] Crosstalk signaling between checkpoint and the Fanconi anemia DNA repair pathway2012

    • Author(s)
      Junya Unno, Junya Tomida, Tomoko Shigechi, Akiko l taya, and Minoru Takata
    • Organizer
      第71回日本癌学会学術総会
    • Place of Presentation
      ロイトン札幌・ホテルさっぽろ芸文館・札幌市教育文化会館(北海道)
    • Related Report
      2012 Annual Research Report
  • [Presentation] Genetic interplay between the Fanconi anemia pathway and aldehyde metabolism in humans2012

    • Author(s)
      Minoru Takata, Asuka Hira, Naoya Suzuki, Akira Niwa, Tatsutoshi Nakahata, Hiromasa Yabe, Megumu K. Saito, Keitaro Matsuo, Miharu Yabe
    • Organizer
      The 8th 3R Symposium
    • Place of Presentation
      淡路夢舞台国際会議場(兵庫県)
    • Related Report
      2012 Annual Research Report
  • [Presentation] Genetic interplay between the Fanconi anemia pathway and aldehyde metabolism in humans2012

    • Author(s)
      Minoru Takata, Asuka Hiral, Naoya Suzuki, Akira Niwa, Tatsutoshi Nakahata, Hiromasa Yabe, Megumu K. Saito, Keitaro Matsuo, Miharu Yabe
    • Organizer
      28th RBC-NIRS INTERNATIONAL SYMPOSIUM
    • Place of Presentation
      コープイン京都(京都府)
    • Related Report
      2012 Annual Research Report
  • [Presentation] Molecular pathogenesis of Fanconi anemia2012

    • Author(s)
      Minoru Takata
    • Organizer
      第54回日本小児血液・がん学会学術集会
    • Place of Presentation
      パシフィコ横浜(神奈川県)
    • Related Report
      2012 Annual Research Report
  • [Presentation] Fanconi貧血とゲノム不安定性

    • Author(s)
      高田 穣
    • Organizer
      第13回血液フォーラム21 -造血不全-
    • Place of Presentation
      東京フォーラム
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Remarks] 京都大学 放射線生物研究センター

    • URL

      http://www.rbc.kyoto-u.ac.jp

    • Related Report
      2014 Annual Research Report
  • [Remarks]

    • URL

      http://house.rbc.kyoto-u.ac.jp/Late_Effect/Japanese_site/Welcom.html

    • Related Report
      2012 Annual Research Report

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Published: 2012-04-24   Modified: 2019-07-29  

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