Research for poly(ADP-ribosylation) as a potential cancer therapeutic target

• Project/Area Number: 22300343
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Clinical oncology
• Research Institution: National Cancer Center Japan
• Principal Investigator: MASUTANI MITSUKO 独立行政法人国立がん研究センター, その他部局等, その他 (60238904)
• Co-Investigator(Renkei-kenkyūsha): OKAYASU Ryuichi 放射線医学総合研究所, 放射線防護研究センター, Senior Researcher (50356135) ; FUJIMORI Hiroaki 国立がん研究センター研究所, 創薬臨床研究分野, 研究員 (00590043)
• Project Period (FY): 2010-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000); Fiscal Year 2014: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2013: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2012: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2011: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2010: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
• Keywords: PARP / PARG / NAD / gamma-irradiation / cancer / PARP1 / DNMT3b / knockdown / gamma irradiation / 放射線 / アルキル化剤 / 合成致死 / epigenetic

Outline of Final Research Achievements

Poly(ADP-ribosylation) reaction is catalyzed by poly(ADP-ribose) polymerase, PARP-1, PARP-2, PARP-3 and other PARP family proteins and is involved in DNA repair response, chromatin regulation, and cell death. We analyzed the sensitivity restricting genes for PARP inhibitors and their mechanisms. We also analyzed the effects of PARP inhibitors on epigenome regulation. Poly(ADP-ribose) glycohydrolase (PARG )is a major enzyme for poly(ADP-ribose) degradation and participates in DNA damage response. We studied the possibility of PARG inhibitors as a cancer therapeutic agent using biochemical strategies.

Research Products

• [Journal Article] Design and synthesis of phenolic hydrazide hydrazones as potent poly(ADP-ribose) glycohydrolase (PARG) inhibitors. (2014)
  • Author(s): Islam R, Koizumi F, Kodera Y, Inoue K, Okawara T, Masutani M.
  • Journal Title: Bioorg Med Chem Lett. Volume: 15 Pages: 3802-3806
  • Peer Reviewed
• [Journal Article] ADP-ribosyltransferases Parp1 and Parp7 safeguard pluripotency of ES cells. (2014)
  • Author(s): Roper SJ, Chrysanthou S, Senner CE, Sienerth A, Gnan S, Murray A, Masutani M, Latos P, Hemberger M.
  • Journal Title: Nucleic Acids Res. Volume: 42 Issue: 14 Pages: 8914-8927
  • DOI: 10.1093/nar/gku591
  • Peer Reviewed
• [Journal Article] The H19 induction triggers trophoblast lineage commitment in mouse ES cells. (2013)
  • Author(s): Fujimori H, Mukai H, Murakami Y, Hemberger M, Hippo Y, Masutani M.
  • Journal Title: Biochem Biophys Res Commun. Volume: 436 Issue: 2 Pages: 313-318
  • DOI: 10.1016/j.bbrc.2013.05.100
  • Peer Reviewed
• [Journal Article] Poly(ADP-ribosylation) in carcinogenesis. (2013)
  • Author(s): Masutani M, Fujimori H.
  • Journal Title: Molecular Aspects of Medicine Volume: 34 Issue: 6 Pages: 1202-1216
  • DOI: 10.1016/j.mam.2013.05.003
  • Peer Reviewed
• [Journal Article] Poly(ADP-ribosylation) regulates chromatin organization through histone H3 modification and DNA methylation of the first cell cycle of mouse embryos. (2013)
  • Author(s): Osada T, Ryden AM, Masutani M.
  • Journal Title: Biochem Biophys Res Commun. Volume: 434 Issue: 1 Pages: 15-21
  • DOI: 10.1016/j.bbrc.2013.03.074
  • Peer Reviewed
• [Journal Article] The Arf/p53 protein module, which induces apoptosis, down-regulates histone H2AX to allow normal cells to survive in the presence of anti-cancer drugs. (2013)
  • Author(s): Yuko Atsumi, Aki lnase, Eiji Sugihara, Ryo Sakasai, Hiroaki Fujimori, Hirobumi Teraoka, Hideyuki Saya, Masamoto Kanno, Fumio Tashiro, Hitoshi Nakagami, Mitsuko Masutani, Ken-ichi Yoshioka
  • Journal Title: The Journal of Biological Chemistry Volume: 288巻 Issue: 19 Pages: 13269-13277
  • DOI: 10.1074/jbc.m112.402560
  • Peer Reviewed
• [Journal Article] Parg Deficiency Confers Radio-sensitization through Enhanced Cell Death in Mouse ES Cells Exposed to Various Forms of Ionizing Radiation. (2013)
  • Author(s): Shirai H, Fujimori H, Gunji A, Maeda D, Hirai T, Poetsch AR, Harada H, Yoshida T, Sasai K, Okayasu R, Masutani M.
  • Journal Title: Biochem Biophys Res Commun. Volume: Epub ahead of print Issue: 1 Pages: 100-106
  • DOI: 10.1016/j.bbrc.2013.04.048
  • Peer Reviewed
• [Journal Article] PARP阻害剤: がん治療における合成致死と増感剤としての役割 (2013)
  • Author(s): 平井崇久、笹井啓資、益谷 美都子
  • Journal Title: 放射線生物研究 Radiation Biology Research Communications Volume: 48 Pages: 52-65
  • NAID: 40019645305
  • Peer Reviewed
• [Journal Article] Radiosensitization effect of PARP inhibitor in cells exposed to low and High LET radiation (2012)
  • Author(s): Hirai, et al
  • Journal Title: Cancer Science Volume: (In press)
  • Peer Reviewed
• [Presentation] PARP-1は、Dnmt3 promoterの制御因子として機能する (2014)
  • Author(s): 藤森浩彰、向井大晃、平井崇久、原田博美、工藤祐子、村上康文、渡邉昌俊、益谷美都子
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都市
  • Year and Date: 2014-10-15
• [Presentation] 創薬の基盤としてのADP-リボシル化の生化学 (2014)
  • Author(s): 益谷美都子、藤森浩彰、原田博美、光畑元晴、高村 岳樹
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都市
  • Year and Date: 2014-10-15
  • Invited
• [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, Mitsuko Masutani
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜市
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Poly(ADP-ribose) formation/metabolism after DNA damage (DNA 損傷後のpoly(ADP-ribose)の動態の検討 (2013)
  • Author(s): Hiromi Harada, Miyuki Hozumi, Hiroaki Fujimori, Takahisa Hirai, Soichiro Saito, Yasufumi Murakami, Mitsuko Masutani
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: 神奈川県 横浜市 パシフィコ横浜
• [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: 第72回日本癌学会学術総会
  • Place of Presentation: 神奈川県 横浜市 パシフィコ横浜
• [Presentation] Biological radiosensitization by PARP inhibitors (2013)
  • Author(s): Mitsuko Masutani, Takahisa Hirai, Hiroaki Fujimori, Souichiro Saito, Teiji Nishio, Ryuichi Okayasu, Akira Fujimori, Keisuke Sasai
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 神奈川県 横浜市 パシフィコ横浜
  • Invited
• [Presentation] PARG機能阻害によるがん細胞株におけるアルキル化剤に対する致死感受性亢進 (2012)
  • Author(s): 白井秀徳 藤森浩彰 岡島泰久 益谷美都子
  • Organizer: 第16回日本がん分子標的治療学会学術集会
  • Place of Presentation: 北九州市
• [Presentation] Radio-sensitization by Parg deficiency in mouse ES cells exposed to low and high LET radiation. (2012)
  • Author(s): Hidenori Shirai, Takahisa Hirai, Keisuke Sasai2 Ryuichi Okayasu, Mitsuko Masutani
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌市
• [Presentation] PARG機能阻害によるがん細胞株におけるアルキル化剤に対する致死感受性亢進 (2012)
  • Author(s): 藤森浩彰、向井大晃、村上康文、益谷美都子
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡市
• [Presentation] PARP阻害剤の抗がん剤としての作用機構 (2011)
  • Author(s): 益谷美都子, 他3名
  • Organizer: 第15回学術集会日本がん分子標的治療学会学術集会
  • Place of Presentation: 東京(招待講演)
  • Year and Date: 2011-06-24
• [Presentation] PARPの機能と抗がん剤としてのPARP阻害剤の作用機序 (2011)
  • Author(s): 益谷美都子
  • Organizer: 遺伝医学合同学術集会2011シンポジウム
  • Place of Presentation: 京都(招待講演)
  • Year and Date: 2011-06-17
• [Presentation] Radiosensitization effect of PARP inhibitor in cells exposed to low and high LET radiation (2011)
  • Author(s): Hirai, et al
  • Organizer: ASTRO 53^<rd> Annual Meeting
  • Place of Presentation: Miami, Florida, USA
• [Book] PARP Inhibitors for Cancer Therapy Cancer Drug Discovery and Development (2015)
  • Author(s): Junhui Wang, Akira Sato, Hiroaki Fujimori, Yoshio Miki, Mitsuko Masutani
  • Publisher: Springer, New York