Transcriptional regulation and DNA repair mechanism of HSF1-PARP complex by DNA damage stimulation

• Project/Area Number: 16K07256
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Molecular biology
• Research Institution: Yamaguchi University
• Principal Investigator: FUJIMOTO Mitsuaki 山口大学, 大学院医学系研究科, 准教授 (80359900)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: HSF1 / PARP1 / PARP13 / 転写 / DNA修復 / DNA damage

Outline of Final Research Achievements

Here, I show that heat shock transcription factor 1 (HSF1) interacts PARP1 through the scaffold protein PARP13. In DNA damage stimulation, inhibition of HSF1-PARP13-PARP1 complex formation caused a redistribution of PARP1 to the DNA damage site and a decrease. Furthermore, this complex formation was required to protect cells from DNA damage stress. Inhibition of complex formation. BRCA1-deficient mammary tumor cells which has a sensitive to PARP inhibitors were inhibited in cell growth formation and tumorigenesis in mice by inhibition of complex formation. These results suggest that HSF1 is involved in the stability of the genomic DNA of cancer cells, and HSF1-PARP complex acts to suppress BRCA1-deficient mammary tumorigenesis.

Academic Significance and Societal Importance of the Research Achievements

本研究で、HSF1-PARP13-PARP1複合体がDNAの安定性に関与することを明らかにした。DNAが不安定化するとDNA異常が起こり、この異常が蓄積するとがんが発症する。BRCA1遺伝子の変異で起こる乳がんはDNA修復機構に強く依存することが知られている。マウスを用いた実験から、この複合体の形成阻害がBRCA1変異乳がん細胞の腫瘍形成を顕著に抑制することを明らかにした。よって、HSF1-PARP13-PARP1複合体の解析から、乳がんなどの治療薬の開発に結びつく可能性がある。

Research Products

• [Journal Article] PARP1 promotes the human heat shock response by facilitating HSF1 binding to DNA (2018)
  • Author(s): Fujimoto Mitsuaki、Takii Ryosuke、Katiyar Arpit、Srivastava Pratibha、Nakai Akira
  • Journal Title: Molecular and Cellular Biology Volume: 38 Issue: 13
  • DOI: 10.1128/mcb.00051-18
  • Peer Reviewed
• [Journal Article] Acute HSF1 depletion induces cellular senescence through the MDM2-p53-p21 pathway in human diploid fibroblasts. (2018)
  • Author(s): Oda T, Sekimoto T, Kurashima K, Fujimoto M, Nakai A, Yamashita T.
  • Journal Title: Journal of Cell Science Volume: 印刷中 Issue: 9
  • DOI: 10.1242/jcs.210724
  • Peer Reviewed / Open Access
• [Journal Article] The HSF1-PARP13-PARP1 complex facilitates DNA repair and promotes mammary tumorigenesis (2017)
  • Author(s): Fujimoto Mitsuaki、Takii Ryosuke、Takaki Eiichi、Katiyar Arpit、Nakato Ryuichiro、Shirahige Katsuhiko、Nakai Akira
  • Journal Title: Nature Communications Volume: 8 Issue: 1 Pages: 1638-1638
  • DOI: 10.1038/s41467-017-01807-7
  • Peer Reviewed / Open Access
• [Journal Article] HSF1 and HSF3 cooperatively regulate the heat shock response in lizards (2017)
  • Author(s): Takii Ryosuke、Fujimoto Mitsuaki、Matsuura Yuki、Wu Fangxu、Oshibe Namiko、Takaki Eiichi、Katiyar Arpit、Akashi Hiroshi、Makino Takashi、Kawata Masakado、Nakai Akira
  • Journal Title: PLOS ONE Volume: 12 Issue: 7 Pages: e0180776-e0180776
  • DOI: 10.1371/journal.pone.0180776
  • Peer Reviewed / Open Access
• [Journal Article] Variations in brain defects result from cellular mosaicism in the activation of heat shock signalling (2017)
  • Author(s): Ishii Seiji、Torii Masaaki、Son Alexander I.、Rajendraprasad Meenu、Morozov Yury M.、Kawasawa Yuka Imamura、Salzberg Anna C.、Fujimoto Mitsuaki、Brennand Kristen、Nakai Akira、Mezger Valerie、Gage Fred H.、Rakic Pasko、Hashimoto-Torii Kazue
  • Journal Title: Nature Communications Volume: 8 Issue: 1 Pages: 15157-15157
  • DOI: 10.1038/ncomms15157
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A study of hearing function and histopathologic changes in the cochlea of the type 2 diabetes model Tsumura Suzuki obese diabetes mouse. (2016)
  • Author(s): Tsuda J, Sugahara K, Hori T, Kanagawa E, Takaki E, Fujimoto M, Nakai A, Yamashita H.
  • Journal Title: Acta Otolaryngology Volume: 136 Issue: 11 Pages: 1097-1106
  • DOI: 10.1080/00016489.2016.1195012
  • Peer Reviewed
• [Journal Article] Anti-TNF-α agent infliximab and splenectomy are protective against renal ischemia-reperfusion injury. (2016)
  • Author(s): Y. Nagata, M. Fujimoto, K. Nakamura, N. Isoyama, M. Matsumura, K. Fujikawa, K. Uchiyama, E. Takaki, R. Takii, A. Nakai, and H. Matsuyama.
  • Journal Title: Transplantation Volume: 100 Issue: 8 Pages: 1675-1682
  • DOI: 10.1097/tp.0000000000001222
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] 熱ショック応答とDNA修復機構 (2018)
  • Author(s): 藤本 充章
  • Organizer: 第35回日本ハイパーサーミア学会
  • Invited
• [Presentation] HSF1-PARP複合体の PAR化とリン酸化による制御 (2018)
  • Author(s): 藤本 充章
  • Organizer: 第13回 臨床ストレス応答学会
• [Presentation] HSF1-PARP複合体による熱ショック応答の調節 (2017)
  • Author(s): 藤本 充章
  • Organizer: 生命科学系学会合同年次大会
• [Presentation] HSF1の新たな機能とがん (2017)
  • Author(s): 藤本充章
  • Organizer: 第34回日本ハイパーサーミア学会
  • Invited
• [Presentation] Regulation of heat shock response by HSF1-PARP complex in mammalian cells (2017)
  • Author(s): 藤本 充章
  • Organizer: 8th International Congress on stress Responses in Biology & Medicine
  • Int'l Joint Research
• [Presentation] 熱ショック応答におけるポリADPリボシル化酵素の役割 (2016)
  • Author(s): 藤本 充章
  • Organizer: 第11回 臨床ストレス応答学会大会
  • Place of Presentation: 山口大学小串キャンパス 霜仁会館 (山口県宇部市）
• [Presentation] HSF1-PARP複合体はDNA損傷応答に関与する (2016)
  • Author(s): 藤本 充章
  • Organizer: 第89回 日本生化学会大会
  • Place of Presentation: 仙台国際センター (宮城県仙台市）
• [Remarks] 山口大学大学院医学系研究科 医化学講座
  • URL: http://ds22.cc.yamaguchi-u.ac.jp/~seika2/index-3.html