Application of chemical biology to a mechanistic study of human nucleotide excision repair

• Project/Area Number: 25281017
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Risk sciences of radiation and chemicals
• Research Institution: Kanazawa University
• Principal Investigator: MATSUNAGA Tsukasa 金沢大学, 薬学系, 教授 (60192340)
• Co-Investigator(Kenkyū-buntansha): INOBE Manabu 金沢大学, 薬学系, 准教授 (10312414) ; WAKASUGI Mitsuo 金沢大学, 薬学系, 助教 (80345595) ; KUNISHIMA Munetaka 金沢大学, 薬学系, 教授 (10214975) ; GOTO Kyoko 金沢大学, 薬学系, 准教授 (50180245) ; ODA Akifumi 金沢大学, 薬学系, 准教授 (50433511)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2015: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2014: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2013: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
• Keywords: ケミカルバイオロジー / 化合物ライブラリー / スクリーニング / ヌクレオチド除去修復 / 阻害剤 / 低分子化合物

Outline of Final Research Achievements

We recently identified a small-molecule inhibitor (NERi) of nucleotide excision repair in human cells, which induces proteasomal degradation of one of core NER factors, ERCC1-XPF. In this study, we have tried to uncover the detailed mechanism underlying the loss of ERCC1-XPF heterodimer after NERi treatment. We have finally identified two cellular proteins possibly involved in the proteosomal degradation of ERCC1-XPF. We have also determined a structure-activity relationship of NERi by comparing the activity of more than 100 derivatives. On the other hand, we could find no further compounds showing comparably high NER-inhibition activity with NERi after screening of another public chemical library.

Research Products

• [Int'l Joint Research] University of North Carolina(米国)
• [Journal Article] Nucleotide excision repair-dependent DNA double-strand break formation and ATM signaling activation in mammalian quiescent cells (2014)
  • Author(s): Mitsuo Wakasugi, Takuma Sasaki, Megumi Matsumoto, Miyuki Nagaoka, Keiko Inoue, Manabu Inobe, Katsuyoshi Horibata, Kiyoji Tanaka, and Tsukasa Matsunaga
  • Journal Title: J. Biological Chemistry Volume: 289 Issue: 41 Pages: 28730-28737
  • DOI: 10.1074/jbc.m114.589747
  • Peer Reviewed / Open Access
• [Journal Article] Rapid proliferation of activated lymph node CD4+ T Cells is achieved by eliminating gap phases in cell cycle progression. (2014)
  • Author(s): Mishima, T., Toda, S., Ando, Y., Matsunaga, T. and Inobe, M.
  • Journal Title: Cell. Mol. Biol. Lett. Volume: 19 Issue: 4 Pages: 638-648
  • DOI: 10.2478/s11658-014-0219-z
  • Peer Reviewed / Open Access
• [Journal Article] Concanavalin A-mediated T cell proliferation is regulated by Herpes Virus Entry Mediator costimulatory molecule. (2014)
  • Author(s): Ando, Y., Yasuoka, C., Mishima, T., Ikematsu, T., Uede, T., Matsunaga, T. and Inobe, M.
  • Journal Title: In Vitro Cell. Dev. Biol.- Animal Volume: 50 Issue: 4 Pages: 313-320
  • DOI: 10.1007/s11626-013-9705-2
  • NAID: 120005349169
  • Peer Reviewed / Open Access
• [Journal Article] Proteasome inhibitors and knockdown of SMG1 cause accumulation of Upf1 and Upf2 in human cells. (2014)
  • Author(s): Zhao, X., Nogawa, A., Matsunaga, T., Takegami, T., Nakagawa, H. and Ishigaki, Y.
  • Journal Title: Int. J. Oncol. Volume: 44 Issue: 1 Pages: 222-228
  • DOI: 10.3892/ijo.2013.2149
  • Peer Reviewed
• [Journal Article] The scaffold protein JLP plays a key role in regulating ultraviolet B-induced apoptosis in mice (2014)
  • Author(s): Enkhtuya R, Sato T, Wakasugi M, Tuvshintugs B, Miyata H, Sakurai T, Matsunaga T, Yoshioka K.
  • Journal Title: Genes to Cells Volume: 19 Issue: 4 Pages: 350-358
  • DOI: 10.1111/gtc.12135
  • NAID: 120005440448
  • Peer Reviewed
• [Presentation] 最近同定された２種類のヌクレオチド除去修復阻害物質の比較検討 (2015)
  • Author(s): 福島直紀、上田将信、高森千枝、大澤琢郎、若杉光生、松永 司
  • Organizer: 日本薬学会北陸支部第127回例会
  • Place of Presentation: 富山大学
  • Year and Date: 2015-11-15
• [Presentation] ヌクレオチド除去修復因子ERCC1を分解誘導する新規化合物の抗がん剤作用増強効果 (2015)
  • Author(s): 中家裕美子、和田奈巳、西村陽平、若杉光生、猪部 学、遠藤良夫、松永 司
  • Organizer: 日本薬学会北陸支部第127回例会
  • Place of Presentation: 富山大学
  • Year and Date: 2015-11-15
• [Presentation] ヌクレオチド除去修復を阻害する低分子化合物のがん化学療法増強剤としての可能性 (2015)
  • Author(s): 松永 司、長田裕之、遠藤良夫
  • Organizer: 第19回日本がん分子標的治療学会学術集会
  • Place of Presentation: 松山全日空ホテル
  • Year and Date: 2015-06-10
• [Presentation] A small molecule inhibitor of nucleotide excision repair from chemical library screening using a newly developed cell-based immunoassay (2015)
  • Author(s): Nishinaga, M., Miyazaki, K., Takamori, C., Ohzawa, T., Wakasugi, M., Saito, T., Osada, H. and Matsunaga, T.
  • Organizer: The 15th International Congress of Radiation Research
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2015-05-25
  • Int'l Joint Research
• [Presentation] Activation of ATR and ATM signaling pathways by NER-dependent secondary damage in mammalian quiescent cells (2015)
  • Author(s): Wakasugi, M., Sasaki, T., Matsumoto, M., Nagaoka, M., Inoue, K., Inobe, M., Horibata, K., Tanaka, K. and Matsunaga, T.
  • Organizer: The 15th International Congress of Radiation Research
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2015-05-25
  • Int'l Joint Research
• [Presentation] DNA修復因子ERCC1-XPFの安定性と細胞内局在性を決定する要因の解析 (2015)
  • Author(s): 高森千枝、宮崎幸太郎、西永真理、大澤琢郎、若杉光生、松永 司
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 兵庫医療大学（神戸）
  • Year and Date: 2015-03-25 – 2015-03-28
• [Presentation] NER-dependent DSB formation activates ATM signaling pathway in mammalian quiescent cells (2015)
  • Author(s): Wakasugi, M., Sasaki, T., Nagaoka, M., Matsumoto, M., Inoue, K., Horibata, K., Tanaka, K. and Matsunaga, T.
  • Organizer: Keystone Symposia “Genomic instability and DNA repair joint with DNA replication and recombination”
  • Place of Presentation: Whistler (Canada)
  • Year and Date: 2015-03-01 – 2015-03-06
• [Presentation] 生体内の様々な細胞におけるヌクレオチド除去修復に依存した二次的DNA損傷の生成 (2014)
  • Author(s): 若杉光生、長岡美由紀、堀田侑希、松永 司
  • Organizer: 日本放射線影響学会第57回大会
  • Place of Presentation: かごしま県民交流センター（鹿児島）
  • Year and Date: 2014-10-01 – 2014-10-03
• [Presentation] シスプラチン抵抗性関連因子ERCC1を分解誘導する新規低分子化合物の同定 (2014)
  • Author(s): 松永 司、斎藤臣雄、長田裕之、遠藤良夫
  • Organizer: 第18回日本がん分子標的治療学会学術集会
  • Place of Presentation: TKPガーデンシティ仙台（仙台）
  • Year and Date: 2014-06-25 – 2014-06-27
• [Presentation] 新開発セルベースドアッセイ系を利用したヌクレオチド除去修復研究の新展開 (2013)
  • Author(s): 松永 司
  • Organizer: 日本環境変異原学会第42回大会・シンポジウム「光遺伝毒性」
  • Place of Presentation: 岡山コンベンションセンター
  • Invited
• [Presentation] 癌細胞のシスプラチン感受性を増感させるヌクレオチド除去修復阻害剤の作用機序 (2013)
  • Author(s): 松永 司、西永真理、長田裕之、若杉光生
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
• [Presentation] ヌクレオチド除去修復を阻害する低分子化合物の作用機序に関する解析 (2013)
  • Author(s): 西永真理、宮崎幸太郎、福島直紀、高森千枝、若杉光生、斎藤臣雄、長田裕之、松永 司
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド
• [Book] 光と生命の事典 (2016)
  • Author(s): 日本光生物学協会 光と生命の事典編集委員会 編
  • Total Pages: 436
  • Publisher: 朝倉書店
• [Remarks] 松永研究室｜遺伝情報制御学
  • URL: http://www.p.kanazawa-u.ac.jp/~iden/