Elucidation of integrative regulation mechanisms for tankyrase-mediated miRNA biosynthesis in cancer

• Project/Area Number: 17K07186
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Japanese Foundation for Cancer Research
• Principal Investigator: Mizutani Anna 公益財団法人がん研究会, がん化学療法センター 分子生物治療研究部, 特任研究員 (30615159)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: miRNA / ポリ(ADP-リボシル)化 / がん / マイクロRNA生合成 / タンキラーゼ / 翻訳後修飾 / ポリADPリボシル化

Outline of Final Research Achievements

Tankyrases are members of poly(ADP-ribose) polymerase (PARP) family proteins. Tankyrase has multiple ankyrin repeat cluster (ARC) domains, which recognize the tankyrase-binding motifs in various proteins. Here we found that several proteins involved in microRNA (miRNA) processing have putative tankyrase-binding motifs and their functions are regulated by tankyrase. First, chemical inhibition of tankyrase PARP activity downregulated the expression levels of precursor miRNAs (pre-miRNAs) but not primary precursor miRNAs (pri-miRNAs). Sebsequent reporter assay revealed that tankyrase inhibitors or overexpression of the PARP-dead mutant tankyrase represses the pri-miRNA processing to pre-miRNA. Tankyrase ARCs bound to DGCR8 and DROSHA, which are essential components for pri-miRNA processing and have putative tankyrase-binding motifs. These observations indicate that tankyrase binds to Microprocessor, DGCR8 and DROSHA complex and modulate pri-miRNA processing to pre-miRNA.

Academic Significance and Societal Importance of the Research Achievements

本研究では、ポリ(ADP-リボシル)化と呼ばれるタンパク質の翻訳後修飾が、遺伝子発現の微調整因子であるmiRNAの産生を促進することが明らかとなった。この反応を司るタンキラーゼは、染色体末端テロメアの伸長促進やWntと呼ばれる細胞増殖シグナルの増強などを介し、がん細胞の無秩序で無制限な分裂増殖を支えることでも知られている。今回の知見から、タンキラーゼによる新たな作用点を介したがん形質制御機構の存在が示唆された。

Research Products

• [Journal Article] Tankyrase promotes primary precursor miRNA processing to precursor miRNA. (2020)
  • Author(s): Mizutani A, Seimiya H.
  • Journal Title: Biochem Biophys Res Commun Volume: 52 Issue: 4 Pages: 945-951
  • DOI: 10.1016/j.bbrc.2019.11.191
  • Peer Reviewed
• [Journal Article] RK-287107, a potent and specific tankyrase inhibitor, blocks colorectal cancer cell growth in a preclinical model. (2018)
  • Author(s): Mizutani A, Yashiroda Y, Muramatsu Y, Yoshisa H, Chikada T, Tsumura T, Okue M, Shirai F, Fukami T, Yoshida M, Seimiya H.
  • Journal Title: Cancer Science Volume: 109 Issue: 12 Pages: 4003-4014
  • DOI: 10.1111/cas.13805
  • Peer Reviewed / Open Access
• [Presentation] RK-287107, a potent and specific tankyrase inhibitor, blocks colorectal cancer cell growth in a preclinical model (2018)
  • Author(s): Anna Mizutani, Yukiko Muramatsu, Haruka Yoshida, Hiroyuki Seimiya
  • Organizer: The 77th Annual Meeting of the Japanese Cancer Association
  • Int'l Joint Research