Regulation of the ubiquitin system by checkpoint kinases in response to stalled replication forks

• Project/Area Number: 19390087
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Kyoto University
• Principal Investigator: TAKATA Minoru Kyoto University, 放射線生物研究センター, 教授 (30281728)
• Co-Investigator(Kenkyū-buntansha): ISHIAI Masamichi 京都大学, 放射線生物研究センター, 准教授 (90298844) ; TOMIDA Junya 京都大学, 放射線生物研究センター, 研究員 (50511367) ; 北尾 洋之 京都大学, 放射線生物研究センター, 研究員 (30368617)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥13,780,000 (Direct Cost: ¥10,600,000、Indirect Cost: ¥3,180,000); Fiscal Year 2008: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2007: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000)
• Keywords: ファンコニ貧血 / チェックポイントキナーゼ / リン酸化 / モノユビキチン化 / DNA修復 / チェックポイント / ユビキチン化

Research Abstract

ファンコニ貧血は骨髄不全, 高発がん性, DNAクロスリンク修復欠損を特徴とする遺伝性疾患である. 本研究では DNA 損傷後誘導されるFANCI 蛋白質のリン酸化が, DNA 修復に重要なFANCD2 蛋白質モノユビキチン化の分子スイッチとして機能することを明らかにした. 現在, FANCI リン酸化が上流のコア複合体(ユビキチンE3 リガーゼ)の活性をいかなるメカニズムで制御するのか, 検討を進めている.

Research Products

• [Journal Article] The Fanconi anemia pathway : Insights from somatic cell genetics using DT40 cell line. Invited review. (2009)
  • Author(s): Takata M, Ishiai M, Kitao H
  • Journal Title: Mutation Research Fanconi anemia special Issue (in press)
  • Peer Reviewed
• [Journal Article] Regulation of histone H4 acetylation by transcription factor E2A in Ig gene conversion (2008)
  • Author(s): Kitao H, Kimura M, Yamamoto K, Seo H, Namikoshi K, Agata Y, Ohta K, Takata M.
  • Journal Title: Int Immunol 20(2) Pages: 277-84
  • NAID: 10021239538
• [Journal Article] FANCG promotes formation of a newly identified protein complex containing BRCA2, FANCD2 and XRCC3 (2008)
  • Author(s): Wilson JB, Yamamoto K, Marriott AS, Hussain S, Sung P, Hoatlin ME, Mathew CG, Takata M, Thompson LH, Kupfer GM, Jones NJ.
  • Journal Title: Oncogene 27(26) Pages: 3641-52
• [Journal Article] Induction of lung adenocarcinoma in transgenic mice expressing activated EGFR driven by the SP-C promoter (2008)
  • Author(s): Ohashi K, Rai K, Fujiwara Y, Osawa M, Hirano S, Takata K, Kondo E, Yoshino T, Takata M, Tanimoto M, Kiura K.
  • Journal Title: Cancer Sci. 99(9) Pages: 1747-53
  • NAID: 10024010760
• [Journal Article] KU70/80,DNA-PKcs, and Artemis are essential for the rapid induction of apoptosis after massive DSB formation (2008)
  • Author(s): Abe T, Ishiai M, Hosono Y, Yoshimura A, Tada S, Adachi N, Koyama H, Takata M, Takeda S, Enomoto T, Seki M.
  • Journal Title: Cell Signal 20(11) Pages: 1978-85
• [Journal Article] FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway (2008)
  • Author(s): Ishiai M, Kitao H, Smogorzewska A, Tomida J, Kinomura A, Uchida E, Saberi A, Kinoshita E, Kinoshita Kikuta E, Koike T, Tashiro S, Elledge SJ, Takata M.
  • Journal Title: Nat Struct Mol Biol 15(11) Pages: 1138-46
• [Journal Article] KU70/80, DNA-PKcs, and Artemis are essential for the rapidinduction of apoptosisi after massive DSB formation (2008)
  • Author(s): Abe T, et al
  • Journal Title: Cell Signal. 20 Pages: 1978-1985
  • Peer Reviewed
• [Journal Article] Enhancement of radiation induced cell death in chicken B Iymphocytes by waithaferin A. (2008)
  • Author(s): Uma Devi P, Takata M, et al
  • Journal Title: Indian J Exp Biol. 46 Pages: 437-42
  • Peer Reviewed
• [Journal Article] FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway. (2008)
  • Author(s): Ishiai M, Kitao H, Elledge SJ, Takata M., et al
  • Journal Title: Nat Struct Mol Biol. 15 Pages: 1138-46
  • Peer Reviewed
• [Journal Article] Current topics in DNA double-strand break repair. (2008)
  • Author(s): Kobayashi J, et. al.
  • Journal Title: J Radiat Res (Tokyo) 49 Pages: 93-103
  • Peer Reviewed
• [Journal Article] FANCG promotes formation of a newly identified protein complex containing BRCA2, FANCD2 and XRCC3. (2008)
  • Author(s): Wilson JB, et. al.
  • Journal Title: Oncogene (epub ahead of print)
  • Peer Reviewed
• [Journal Article] Regulation of histone H4 acetylation by transcription factor E2A in Ig gene conversion. (2008)
  • Author(s): Kitao H, et. al.
  • Journal Title: Int Immunology 20 Pages: 277-84
  • Peer Reviewed
• [Journal Article] Emergence of Epidermal Growth Factor Receptor T790M Mutation during Chronic Exposure to Gefitinib in a Non Small Cell Lung Cancer Cell Line (2007)
  • Author(s): Ogino A, Kitao H, Hirano S, Uchida A, Ishiai M, Kozuki T, Takigawa N, Takata M, Kiura K, Tanimoto M
  • Journal Title: Cancer Res. 67(16) Pages: 7807-14
• [Journal Article] Epidermal growth factor receptor mutation status and adjuvant chemotherapy with uracil tegafur for adenocarcinoma of the lung (2007)
  • Author(s): Suehisa H, Toyooka S, Hotta K, Uchida A, Soh J, Fujiwara Y, Matsuo K, Ouchida M, Takata M, Kiura K, Date H.
  • Journal Title: J Clin Oncol 25(25) Pages: 3952-7
  • NAID: 130004903139
• [Journal Article] Subcellular distribution of human RDM1 protein isoforms and their nucleolar accumulation in response to heat shock and proteotoxic stress (2007)
  • Author(s): Messaoudi L, Yang YG, Kinomura A, Stavreva DA, Yan G, Bortolin-Cavaille ML, Arakawa H, Buerstedde JM, Hainaut P, Cavaille J, Takata M, Van Dyck E.
  • Journal Title: Nucleic Acids Res. 35(19) Pages: 6571-6587
• [Journal Article] Cells deficient in the FANC/BRCA pathway are hypersensitive to plasma levels of formaldehyde (2007)
  • Author(s): Ridpath JR, Nakamura A, Tano K, Luke AM, Sonoda E, Arakawa H, Buerstedde JM, Gillespie DA, Sale JE, Yamazoe M, Bishop DK, Takata M, Takeda S, Watanabe M, Swenberg JA, Nakamura J.
  • Journal Title: Cancer Res. 67(23) Pages: 11117-22
• [Journal Article] Deubiquitination of FANCD2 Is Required for DNA Crosslink Repair (2007)
  • Author(s): Oestergaard VH, Langevin F, Kuiken HJ, Pace P, Niedzwiedz W, Simpson LJ, Ohzeki M, Takata M, Sale JE, Patel KJ.
  • Journal Title: Mol Cell 28(5) Pages: 798-809
• [Journal Article] Subcellular distribution of human RDM1 protein isoforms and their nucleolar accumulation in response to heat shock and proteotoxic stress (2007)
  • Author(s): Messaoudi L, et. al.
  • Journal Title: Nucleic Acids Res 35 Pages: 6571-6587
  • Peer Reviewed
• [Journal Article] Deubiquitination of FANCD2 Is Required for DNA Crosslink Repair. (2007)
  • Author(s): Oestergaard VH, et. al.
  • Journal Title: Mol Cell 28 Pages: 798-809
  • Peer Reviewed
• [Journal Article] Cells deficient in the FANC/BRCA pathway are hypersensitive to plasma levels of formaldehyde. (2007)
  • Author(s): Ridpath JR, et. al.
  • Journal Title: Cancer Res 67 Pages: 11117-22
  • Peer Reviewed
• [Presentation] Monoubiquitination and phosphorylation dependent activation of the Fanconi anemia pathway, Recent Development in DNA Repair Studies (2009)
  • Author(s): Minoru Takata
  • Organizer: The 3rd International Open Laboratory Workshop
  • Place of Presentation: 放射線総合医学研究所千葉県
  • Year and Date: 2009-02-27
• [Presentation] 「ファンコニ貧血経路によるゲノム安定化メカニズム」「生き物はどのようにして放射線に立ち向かうか-DNA損傷応答と適応応答-」 (2008)
  • Author(s): 高田穣(招待講演)
  • Organizer: 第3回放射線防護研究センターシンポジウム(放射線総合医学研究所)
  • Place of Presentation: 千葉県
  • Year and Date: 2008-12-16
• [Presentation] ファンコニ貧血経路によるゲノム安定化メカニズム (2008)
  • Author(s): 高田穣
  • Organizer: 第3回放射線防護研究センターシンポジウム
  • Place of Presentation: 千葉県放射線総合医学研究所
  • Year and Date: 2008-12-16
• [Presentation] ゲノムの安定性維持メカニズムとファンコニ貧血 (2008)
  • Author(s): 高田穣
  • Organizer: 第101回小児血液腫瘍懇話会
  • Place of Presentation: 東京都
  • Year and Date: 2008-07-18
• [Presentation] Frequent Loss of the Immunogolobulin Heavy Chain Gene Occurs in FANCJ deficient DT40 Cell Line (2008)
  • Author(s): H. Kitao, I. Nada, A. Kinomura, M. Takata
  • Organizer: Nineteenth Annual Fanconi Anemia Research Fund Scientific Symposium
  • Place of Presentation: Chicago
• [Presentation] Role of FANCI protein and its phosphorylation for the Fanconi anemia pathway function (2008)
  • Author(s): M. Takata, H. Kitao, A. kinomura, A. Smogorzewska, S. J. Elledge, M. Ishiai
  • Organizer: Nineteenth Annual Fanconi Anemia Research Fund Scientific Symposium
  • Place of Presentation: Chicago
• [Presentation] FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway. Symposium : "DNA repair network deficiency and carcinogenesis" (2008)
  • Author(s): Ishiai M, Kitao H, Takata M.
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋市, 神戸
• [Presentation] ファンコニ貧血経路の制御とFANCI タンパク質のリン酸化メカニズム (2008)
  • Author(s): 冨田純也、内田亜希子、北尾洋之、木下英司、内田恵美、小林昌彦、山本健一、小池透、石合正道、高田穣
  • Organizer: 第31回日本分子生物学会年会、第81回日本生化学会大会合同大会
  • Place of Presentation: 神戸市
• [Presentation] ファンコニ貧血経路の活性化制御とFANCIタンパク質のリン酸化メカニズム (2008)
  • Author(s): 冨田純也、内田亜希子、北尾洋之、木下英司、内田恵美、小林昌彦、山本健一、小池透、石合正道、高田穣
  • Organizer: 日本放射線影響学会第51回大会
  • Place of Presentation: 北九州市
• [Presentation] FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway Symposium. (2008)
  • Author(s): Ishiai M, Kitao H, Takata M
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋市
• [Presentation] Role of Fanci protein and its phosphorylation for the Fanconia anemia pathway function (2007)
  • Author(s): Minoru Takata
  • Organizer: Nineteenth Annual Fanconia Anemia Research Fund Sceintific Symposium
  • Place of Presentation: The westin Michigan Avenue, Chicago, Il, U.S.A
  • Year and Date: 2007-10-10
• [Presentation] ファンコニ貧血コア複合体によるモノユビキチン化とDNAクロスリンク修復制御 (2007)
  • Author(s): 高田穣、北尾洋之、木野村愛子、石合正道
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜市
• [Presentation] FancD2/FancI complex regulates crosslink repair in the Fanconi anemia pathway. "Chromosome and Genome Stability and Instability" (2007)
  • Author(s): M.Takata
  • Organizer: Chromosome Cycle International Symposium
  • Place of Presentation: Osaka
• [Presentation] ファンコニ貧血コア複合体によるFANCD2/FANCI複合体のモノユビキチン化と相同組換え修復。ワークショップ 放射線DNA損傷修復機構研究の最前線 (2007)
  • Author(s): 高田穣、北尾洋之、木野村愛子、石合正道
  • Organizer: 放射線影響学会6第50回大会
  • Place of Presentation: 幕張メッセ
• [Presentation] FANCJ 遺伝子欠損DT40細胞株で起こる免疫グロブリン重鎖遺伝子でのゲノム欠失 (2007)
  • Author(s): 北尾洋之、ナンダインドラジット、木野村愛子、シュミットマイケル、高田穣
  • Organizer: ワークショップ第30回分子生物学会第80回日本生化学会合同大会
  • Place of Presentation: 横浜市
• [Book] Fanconi anemia. A paradigmatic disease for the understanding of cancer and aging. (2007)
  • Author(s): Nanda I, et. al.
  • Total Pages: 229
  • Publisher: Karger, Switzerland
• [Remarks]
  • URL: http://www.rbc.kyoto-u.ac.jp/Late_Effect/Welcome%20.html