Analysis of DNA-damage-tolerance mechanisms that facilitate restart of stalled DNA replication

• Project/Area Number: 25340030
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Risk sciences of radiation and chemicals
• Research Institution: Kyoto University
• Principal Investigator: MOTEGI AKIRA 京都大学, 医学研究科, 助教 (80452332)
• Co-Investigator(Renkei-kenkyūsha): MASUTANI MITSUKO 長崎大学, 大学院医歯薬総合研究科, 教授 (60238904)
• Project Period (FY): 2013-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: DNA損傷トレランス / 複製後修復 / 組換え修復 / ユビキチン / 相同組換え / DNA修復

Outline of Final Research Achievements

In this study, we showed that simultaneous genetic disruption of the ubiquitin ligase SHPRH and FANC, one of core factors in the Fanconi Anemia (FA) pathway, substantially rescued hypersensitivity towards cisplatin, an inter-strand cross-linking (ICL) agent. This observation suggests that SHPRH-dependent pathway antagonizes to the FA pathway. We also showed that PARP-1 prohibits resection in in vitro extract assay and that low expression of CtIP nuclease in breast cancer correlates with poor prognosis and hypersensitivity towards PARP inhibitors.

Research Products

• [Journal Article] Loss of CtIP disturbs homologous recombination repair and sensitizes breast cancer cells to PARP inhibitors. (2016)
  • Author(s): Wang J, Ding Q, Fujimori H, Motegi A, Miki Y, Masutani M.
  • Journal Title: Oncotarget. Volume: 7 Issue: 7 Pages: 7701-7714
  • DOI: 10.18632/oncotarget.6715
  • NAID: 120005820856
  • Peer Reviewed / Open Access
• [Journal Article] Rad18 and Rnf8 facilitate homologous recombination by two distinct mechanisms, promoting Rad51 focus formation and suppressing the toxic effect of nonhomologous end-joining (2015)
  • Author(s): Michael Schmid, Akira Motegi (ほか総計106名、代表者は前から63番目)
  • Journal Title: Cytogenet. Genome Res. Volume: 145 Issue: 2 Pages: 78-179
  • DOI: 10.1159/000430927
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Rad18 and Rnf8 facilitate homologous recombination by two distinct mechanisms, promoting Rad51 focus formation and suppressing the toxic effect of nonhomologous end-joining (2015)
  • Author(s): Shunsuke Kobayashi, Yohei Kasaishi, Shinichiro Nakada, Tokiyo Takagi, Saho Era, Akira Motegi, Roland K. Chiu, Shunichi Takeda, and Kouji Hirota
  • Journal Title: Oncogene Volume: 34 Issue: 33 Pages: 4403-4411
  • DOI: 10.1038/onc.2014.371
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Multiple genetic manipulations of DT40 cell line (2014)
  • Author(s): Akira Motegi, Minoru Takata
  • Journal Title: Methods in Molecular Biology Volume: 1114 Pages: 25-35
  • DOI: 10.1007/978-1-62703-761-7_3
  • ISBN: 9781627037600, 9781627037617
• [Presentation] CtIP is a novel biomarker for predicting the sensitivity of breast cancers to PARP inhibitors (2016)
  • Author(s): Akira Motegi,Junhui Wang, Hiroaki Fujimori, Yoshio Miki, and Mitsuko Masutani
  • Organizer: The 2nd RBC-CEA Joint Workshop
  • Place of Presentation: 京都大学 (京都市)
  • Year and Date: 2016-04-11
• [Presentation] PARP-1 and PARG promote genomic integrity by regulating resection of DNA double-strand breaks (2015)
  • Author(s): Akira Motegi,Junhui Wang, Hiroaki Fujimori, Yoshio Miki, and Mitsuko Masutani
  • Organizer: 第38回日本分子生物学会年会、第88回日本生化学会合同大会
  • Place of Presentation: 神戸市
  • Year and Date: 2015-12-01
  • Invited
• [Presentation] PARP-1 and PARG regulate 53BP1 to control DNA end resection (2015)
  • Author(s): Junhui Wang, Akira Motegi, Hiroaki Fujimori, Yoshio Miki, and Mitsuko Masutani
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋市
  • Year and Date: 2015-10-08
• [Presentation] PARP-1 and PARG are both required for the regulation of 53BP1 after IR (2014)
  • Author(s): Junhui Wang, Akira Motegi, Hiroaki Fujimori, Yoshio Miki, and Mitsuko Masutani
  • Organizer: The 73rd Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Yokohama, Japan
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] PARP-1 suppresses the end-resection of 5'- and 3'-blocked termini of double-strand DNA breaks by CtIP (2013)
  • Author(s): Junhui Wang, Akira Motegi, HIroaki Fujimori, Yoshio Miki, Mitsuko Masutani
  • Organizer: The 72nd Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Yokohama, Japan
• [Remarks] 京都大学教育研究活動データベース
  • URL: https://kyouindb.iimc.kyoto-u.ac.jp/j/mI6jZ