Analysis of the mechanism of cell sensitivity against anti-cancer drug caused by ubiquitination-dependent DNA-PK activation

• Project/Area Number: 15K16127
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Risk sciences of radiation and chemicals
• Research Institution: Kanazawa Medical University
• Principal Investigator: SAKASAI Ryo 金沢医科大学, 医学部, 助教 (10549950)
• Research Collaborator: SHIBATA Atsushi 群馬大学, 大学院医学系研究科・大学院研究教育支援センター, 研究講師 (30707633)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: DNA二本鎖切断 / 非相同末端連結 / 相同組換え修復 / 相同組換え

Outline of Final Research Achievements

Anti-cancer drug camptothecin (CPT) causes DNA double-strand break (DSB) containing a single-DNA end that is referred to as one-ended DSB. Given that contribution of non-homologous end joining (NHEJ) to the repair of one-ended DSBs are considered to sensitize cells to CPT, it is important to reveal the mechanism of NHEJ contribution to the repair of one-ended DSBs for consideration of CPT efficacy in the chemotherapy.
Several researches suggested that UbcH5 is involved in the appearance of chromosome aberrations and CPT-resistance via NHEJ. SIAH1 was also identified as E3 ubiquitin ligase that is involved in NHEJ activation, but it has showed different phenotypes from UbcH5 so far.

Research Products

• [Journal Article] Replication stress induces accumulation of FANCD2 at central region of large fragile genes. (2018)
  • Author(s): Okamoto Y, Iwasaki WM, Kugou K, Takahashi KK, Oda A, Sato K, Kobayashi W, Kawai H, Sakasai R, Takaori-Kondo A, Yamamoto T, Kanemaki MT, Taoka M, Isobe T, Kurumizaka H, Innan H, Ohta K, Ishiai M, Takata M.
  • Journal Title: Nucleic Acids Res. Volume: 46(6) Issue: 6 Pages: 2932-2944
  • DOI: 10.1093/nar/gky058
  • NAID: 120006488604
  • Peer Reviewed / Open Access
• [Journal Article] Caspase-mediated cleavage of X-ray repair cross-complementing group 4 promotes apoptosis by enhancing nuclear translocation of caspase- activated DNase (2018)
  • Author(s): 1.Sunatani Y, Kamdar RP, Sharma MK, Matsui T, Sakasai R, Hashimoto M, Ishigaki Y, Matsumoto Y, Iwabuchi K
  • Journal Title: Exp Cell Res Volume: 362 Issue: 2 Pages: 450-460
  • DOI: 10.1016/j.yexcr.2017.12.009
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Aquarius is required for proper CtIP expression and homologous recombination repair (2017)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] The distinctive cellular responses to DNA strand breaks caused by a DNA topoisomerase I poison in conjunction with DNA replication and RNA transcription (2015)
  • Author(s): Sakasai R, Iwabuchi K.
  • Journal Title: Genes & Genetic Systems Volume: 90 Issue: 4 Pages: 187-194
  • DOI: 10.1266/ggs.15-00023
  • NAID: 130005118395
  • ISSN: 1341-7568, 1880-5779
  • Peer Reviewed
• [Presentation] ユビキチン化因子UBE2E2によるDNAトポイソメラーゼIIの制御 (2017)
  • Author(s): 逆井良、砂谷優実、松井理、岩淵邦芳
  • Organizer: 第24回DNA複製・組換え・修復ワークショップ
• [Presentation] Analysis of repair pathway for one-ended DNA double-strand breaks (2017)
  • Author(s): Ryo Sakasai, Yumi Sunatani, Tadashi Matsui, Kuniyoshi Iwabuchi
  • Organizer: 日本放射線影響学会第60回大会
• [Presentation] PARP inhibition disrupts repair of one-ended DNA double-strand breaks (2017)
  • Author(s): Ryo Sakasai, Kuniyoshi Iwabuchi
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] RNAヘリカーゼAquariusはDNA-RNAハイブリッドを解消して相同組換え修復を促進する (2016)
  • Author(s): 逆井良 磯野真由 若杉光夫 橋本光正 砂谷優実 松井理 柴田淳史 松永司 岩淵邦芳
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市西区）
  • Year and Date: 2016-11-30
• [Presentation] RNAヘリカーゼAquariusはR-loopを解消して相同組換え修復を促進する (2016)
  • Author(s): 逆井良 磯野真由 若杉光夫 橋本光正 砂谷優実 松井理 柴田淳史 松永司 岩淵邦芳
  • Organizer: 日本放射線影響学会第59回大会
  • Place of Presentation: ＪＭＳアステールプラザ（広島県広島市）
  • Year and Date: 2016-10-26
  • Invited
• [Presentation] Topoisomerase II switching is regulated by ubiquitination (2016)
  • Author(s): Sakasai R, Sunatani Y, Matsui T, Iwabuchi K
  • Organizer: Gordon Research Conference, DNA Topoisomerase in Biology & Medicine
  • Place of Presentation: メーン州 米国
  • Year and Date: 2016-08-07
  • Int'l Joint Research
• [Presentation] Ubiquitin-dependent activation of DNA-PKcs leads to chromosomal aberration in response to one-ended DNA double strand breaks (2015)
  • Author(s): Ryo Sakasai, Yumi Sunatani, Tadashi Matsui, Mitsumasa Hashimoto, Kuniyoshi Iwabuchi
  • Organizer: ICRR2015
  • Place of Presentation: 京都国際会館（京都府京都市）
  • Year and Date: 2015-05-25
  • Int'l Joint Research
• [Remarks] 金沢医科大学 医学部 生化学I
  • URL: https://kmu-bc1.jimdo.com/
• [Remarks] Iwabuchi Lab 金沢医科大学 生化学I
  • URL: http://kmu-bc1.jimdo.com