Mechanisms of Centrosome Aberrations Induced by DNA damage

• Project/Area Number: 21310034
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Risk sciences of radiation/Chemicals
• Research Institution: The University of Tokyo
• Principal Investigator: MIYAGAWA Kiyoshi 東京大学, 大学院・医学系・研究科, 教授 (40200133)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000); Fiscal Year 2011: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2010: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2009: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• Keywords: DNA損傷 / 中心体 / 相同組換え / 染色体不安定性 / 放射線発がん

Research Abstract

Maintenance of centrosome numbers is required for correct chromosome segregation, and radiation induces its aberrations. In order to understand their mechanisms, we investigated roles of the DNA damage response in maintenance of centrosome integrity. We found that activation of the signaling pathway mediated by ATR and Chk1 causes supernumerary centrosomes when homologous recombination repair is inhibited. Supernumerary centrosomes are frequently observed in cancer. We also found that activation of ATM is involved in centrosome aberrations when SYCE2, a cancer testis antigen, is expressed. Additionally, aneuploidy is induced by centrosome-independent mechanisms in cells defective in homologous recombination repair, indicating that multiple pathways are involved in regulation of chromosome integrity.

Research Products

• [Journal Article] Serine-threonine kinase 38 is regulated by glycogen synthase kinase-3 and modulates oxidative stress-induced cell death (2012)
  • Author(s): Atsushi Enomoto
  • Journal Title: Free Radical Biology and Medicine Volume: 52 Issue: 2 Pages: 507-515
  • DOI: 10.1016/j.freeradbiomed.2011.11.006
  • Peer Reviewed
• [Journal Article] Synaptonemal complex protein SYCP3 impairs mitotic recombination by interfering with BRCA2 (2012)
  • Author(s): Hosoya N
  • Journal Title: EMBO Rep Volume: 13 Issue: 1 Pages: 44-51
  • DOI: 10.1038/embor.2011.221
  • Peer Reviewed
• [Journal Article] Single-stranded DNA catenation mediated by human EVL and a type I topoisomerase (2010)
  • Author(s): Takaku M, Takahashi D, Machida S, Ueno H, Hosoya N, Ikawa S, Miyagawa K, Shibata T, Kurumizaka H
  • Journal Title: Nucleic Acids Res Volume: 38 Issue: 21 Pages: 7579-7586
  • DOI: 10.1093/nar/gkq630
  • Peer Reviewed
• [Journal Article] Ataxia telangiectasia mutated(ATM)-mediated DNA damage response in oxidative stress-induced vascular endothelial cell senescence (2010)
  • Author(s): Zhan H, Suzuki T, Aizawa K, Miyagawa K, Nagai R
  • Journal Title: J Biol Chem Volume: 285 Issue: 38 Pages: 29662-29670
  • DOI: 10.1074/jbc.m110.125138
  • Peer Reviewed
• [Journal Article] Ataxia telangiectasia mutated(ATM)-mediated DNA damage response in oxidative stress-induced vascular endothelial cell senescence (2010)
  • Author(s): Zhan H
  • Journal Title: J Biol Chem Volume: 385 Pages: 29662-29670
  • Peer Reviewed
• [Journal Article] The ATR-Chk1 pathway plays a role in the generation of centrosome aberrations induced by Rad51C dysfunction (2009)
  • Author(s): Katsura M, Tsuruga T, Date O, Yoshihara T, Ishida M, Tomoda Y, Okajima M, Takaku M, Kurumizaka H, Kinomura A, Mishima HK, Miyagawa K
  • Journal Title: Nucleic Acids Res Volume: 37 Issue: 12 Pages: 3959-3968
  • DOI: 10.1093/nar/gkp262
  • Peer Reviewed
• [Journal Article] Recombination activator function of the novel RAD51-and RAD51B-binding protein (2009)
  • Author(s): Takaku M, Machida S, Hosoya N, Nakayama S, Takizawa Y, Sakane I, Shibata T, Miyagawa K, Kurumizaka H
  • Journal Title: human EVL. J Biol Chem Volume: 22 Issue: 21 Pages: 14326-14336
  • DOI: 10.1074/jbc.m807715200
  • Peer Reviewed
• [Journal Article] Functional evidence for Eme1 as a marker of cisplatin resistance (2009)
  • Author(s): Tomoda Y, Katsura M, Okajima M, Hosoya N, Kohno N, Miyagawa K
  • Journal Title: Int J Cancer Volume: 124 Issue: 12 Pages: 2997-3001
  • DOI: 10.1002/ijc.24268
  • Peer Reviewed
• [Journal Article] The ATR-Chk1 pathway plays a role in the generation of centrosome aberrations induced by Rad51C dysfunction (2009)
  • Author(s): Katsura M
  • Journal Title: Nucleic Acids Res 37 Pages: 3959-3968
  • Peer Reviewed
• [Journal Article] Recombination activator function of the novel RAD51-and RAD51B-binding protein, human EVL (2009)
  • Author(s): Takaku M
  • Journal Title: J Biol Chem 284 Pages: 14326-14336
  • Peer Reviewed
• [Journal Article] Functional evidence for Emel as a marker of cisplatin resistance (2009)
  • Author(s): Tomoda Y
  • Journal Title: Int J Cancer 124 Pages: 2997-3001
  • Peer Reviewed
• [Presentation] The synaptonemal complex protein SYCE2 induces chromosome instability in mitotic cells through activation of the ataxia-telangiectasia-mutated kinase (2011)
  • Author(s): Hosoya N, Miyagawa K
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市)
  • Year and Date: 2011-12-16
• [Presentation] 53BP1 nuclear foci are reduced by hypoxia in neural cells (2011)
  • Author(s): Katsura M, Aihara M, Yamagishi R, Shimazawa M, Hara H, Miyagawa K, Araie M
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(神奈川県、横浜市)
  • Year and Date: 2011-12-16
• [Presentation] Rad54B controls Numb tumor suppressor function by interacting with LNX1 (2011)
  • Author(s): Yasuhara T, Miyagawa K
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(神奈川県、横浜市)
  • Year and Date: 2011-12-14
• [Presentation] Towards a New Synthesis of Knowledge (2011)
  • Author(s): Miyagawa K
  • Organizer: 2011 Kyoto University International Forum
  • Place of Presentation: 京都大学百周年記念ホール(京都府京都市)
  • Year and Date: 2011-10-16
• [Presentation] The synaptonemal complex protein SYCE2 induces chromosome instability through activation of ATM in cancer (2011)
  • Author(s): Hosoya N, Miyagawa K
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場(愛知県名古屋市)
  • Year and Date: 2011-10-04
• [Presentation] The synaptonemal complex protein SYCE2 induces chromosome instability through activation of ATM in cancer (2011)
  • Author(s): Hosoya N
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場(愛知県 名古屋市)
  • Year and Date: 2011-10-04
• [Presentation] The DNA-dependent ATPase RAD54B maintains complex nuclear functions (2010)
  • Author(s): Miyagawa K
  • Organizer: 第33回日本分子生物学会年回
  • Place of Presentation: 神戸ポートアイランド(兵庫県神戸市)
  • Year and Date: 2010-12-10
• [Presentation] Involvement of multiple pathways in the generation of aneuploidy caused by defective homologous recombination (2010)
  • Author(s): Miyagawa K
  • Organizer: 26th Radiation Biology Center International Symposium
  • Place of Presentation: 京都テルサ(京都府京都市)
  • Year and Date: 2010-10-22
• [Presentation] Involvement of multiple pathways in the generation of aneuploidy caused by defective homologous recombination (2010)
  • Author(s): Miyagawa K
  • Organizer: 26th Radiation Biology Center International Symposium
  • Place of Presentation: Kyoto,京都テルサ
  • Year and Date: 2010-10-22
• [Presentation] DNA損傷修復の核ダイナミクス (2009)
  • Author(s): 宮川清
  • Organizer: 日本放射線影響学会第52回大会
  • Place of Presentation: 広島市南区民文化センター(広島県広島市)
  • Year and Date: 2009-11-11
• [Presentation] The ATR-Chk1 pathway plays a role in the generation of centrosome aberrations induced by Rad51C dysfunction (2009)
  • Author(s): Katsura M, Tomoda Y, Miyagawa K
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市)
  • Year and Date: 2009-10-01
• [Presentation] Disruption of the RAD52 gene results in increased radiosensitivity and aneuploidy in human cells (2009)
  • Author(s): Miyagawa K, Hosoya N
  • Organizer: The 11th International Wolfsberg Meeting on Molecular Radiation Biology/Oncology
  • Place of Presentation: Wolfsberg Castle Conference Center(Ermatingen, Switzerland)
  • Year and Date: 2009-06-27
• [Presentation] Disruption of the RAD52 gene results in increased radiosensitivity and aneuploidy in human cells (2009)
  • Author(s): Miyagawa K
  • Organizer: 11th International Wolfsberg Meeting on Molecular Radiation Biology/Oncology
  • Place of Presentation: Ermatingen, Switzerland
  • Year and Date: 2009-06-27