Molecular mechanism linking pre-rRNA processing and nucleolar stress response

• Project/Area Number: 18K06640
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Meiji Pharmaceutical University
• Principal Investigator: Nagahama Masami 明治薬科大学, 薬学部, 教授 (60281169)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: リボソーム生合成 / 核小体ストレス / RNAエキソソーム / rRNAプロセシング / AAA ATPase / PICT1 / MTR4 / NVL / NVL2 / rRNA / 核小体 / p53

Outline of Final Research Achievements

In yeast cells, Nop53 functions as an adaptor for recruiting RNA helicase MTR4 to its appropriate RNA substrate during ribosome biogenesis. In human cells, PICT1 seems to be a functionally homologous protein for Nop53.　In this study, we demonstrated that PICT1 is involved in both the pre-rRNA processing and regulating tumor suppressor p53, thereby linking ribosome biogenesis to cell growth regulation.

Academic Significance and Societal Importance of the Research Achievements

本研究は、リボソーム構築の過程においてrRNAプロセシングの異常を監視し、核小体ストレス応答により細胞増殖が制御される機構について、NVL2、MTR4-ExosomeおよびPICT1の機能を明らかにしたものである。PICT1は、がん抑制因子p53を安定化し、細胞増殖およびアポトーシスを制御する。また、臨床分野では、様々ながんの予後規定因子として注目されている。したがって、この研究成果は、新たな抗がん剤を開発するための学術基盤として重要である。

Research Products

• [Journal Article] Exploration of <i>Salmonella</i> effector mutant strains on MTR4 and RRP6 degradation (2020)
  • Author(s): Sun Xiaoning、Kawata Kentaro、Miki Atsuko、Wada Youichiro、Nagahama Masami、Takaya Akiko、Akimitsu Nobuyoshi
  • Journal Title: BioScience Trends Volume: 14 Issue: 4 Pages: 255-262
  • DOI: 10.5582/bst.2020.03085
  • NAID: 130007906511
  • ISSN: 1881-7815, 1881-7823
  • Year and Date: 2020-08-31
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Systematic Analysis of Targets of Pumilio-mediated mRNA Decay Reveals that PUM1 Repression by DNA Damage Activates Translesion Synthesis (2020)
  • Author(s): Toshimichi Yamada, Naoto Imamachi, Katsutoshi Imamura, Kenzui Taniue, Takeshi Kawamura, Yutaka Suzuki, Masami Nagahama, Nobuyoshi Akimitsu
  • Journal Title: Cell Reports Volume: - Issue: 5 Pages: 107542-107542
  • DOI: 10.1016/j.celrep.2020.107542
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The cellular model of albumin endocytosis uncovers link between membrane and nuclear proteins (2020)
  • Author(s): Urae Seiya、Harita Yutaka、Udagawa Tomohiro、Ode Koji L.、Nagahama Masami、Kajiho Yuko、Kanda Shoichiro、Saito Akihiko、Ueda Hiroki R.、Nangaku Masaomi、Oka Akira
  • Journal Title: Journal of Cell Science Volume: - Issue: 13
  • DOI: 10.1242/jcs.242859
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] WDR74 participates in an early cleavage of the pre-rRNA processing pathway in cooperation with the nucleolar AAA-ATPase NVL2 (2018)
  • Author(s): Hiraishi Nobuhiro、Ishida Yo-ichi、Sudo Haruka、Nagahama Masami
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 495 Issue: 1 Pages: 116-123
  • DOI: 10.1016/j.bbrc.2017.10.148
  • Peer Reviewed
• [Journal Article] Diminished nuclear RNA decay upon Salmonella infection upregulates antibacterial noncoding RNAs (2018)
  • Author(s): Imamura Katsutoshi、Takaya Akiko、Ishida Yo‐ichi、Fukuoka Yayoi、Taya Toshiki、Nakaki Ryo、Kakeda Miho、Imamachi Naoto、Sato Aiko、Yamada Toshimichi、Onoguchi‐Mizutani Rena、Akizuki Gen、Tanu Tanzina、Tao Kazuyuki、Miyao Sotaro、Suzuki Yutaka、Nagahama Masami、Yamamoto Tomoko、Jensen Torben Heick、Akimitsu Nobuyoshi
  • Journal Title: The EMBO Journal Volume: 37 Issue: 13
  • DOI: 10.15252/embj.201797723
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] がん制御因子PICT1とrRNAプロセシング複合体の相互作用による核小体ストレス応答制御 (2020)
  • Author(s): 宮尾宗太郎、齊藤佳奈子、河原康一、長浜正巳
  • Organizer: 次世代を担う若手ファーマ・バイオフォーラム2020
• [Presentation] Identification of functional targets reveals that the suppression of pumilio-mediated mRNA decay increases cell resistance to DNA damage in human cells (2019)
  • Author(s): Toshimichi Yamada, Naoto Imamachi, Katsutoshi Imamura, Takeshi Kawamura, Yutaka Suzuki, Masami Nagahama, Nobuyoshi Akimitsu
  • Organizer: mRNA Turnover: Mechanisms, Regulation and their Implication in Infectious and Age-Related Diseases
  • Int'l Joint Research
• [Presentation] がん制御因子PICT1とMTR4-Exosomeの結合およびrRNAプロセシングにおける機能 (2019)
  • Author(s): 宮尾宗太郎、齋藤佳奈子、大島廉太、上林幸拓、河原康一、長浜正巳
  • Organizer: 日本RNA学会年会
• [Presentation] 核小体AAA-ATPase NVL2と結合するスプライソソーム因子CWF19L2の機能解析 (2019)
  • Author(s): 大島廉太、三木俊二、山下文希、宮尾宗太郎、辻明彦、長浜正巳
  • Organizer: 日本RNA学会年会
• [Presentation] Systematic analysis of targets of PUMILIO (PUM)-mediated mRNA decay reveals that PUM1 regulates DNA damage response pathway (2019)
  • Author(s): Toshimichi Yamada, Naoto Imamachi, Katsutoshi Imamura, Takeshi Kawamura, Yutaka Suzuki, Masami Nagahama, Nobuyoshi Akimitsu
  • Organizer: 日本RNA学会年会
• [Presentation] Identification of functional targets reveals that the suppression of pumilio-mediated mRNA decay increases cell resistance to DNA damage in human cells (2019)
  • Author(s): Toshimichi Yamada, Naoto Imamachi, Katsutoshi Imamura, Takeshi Kawamura, Yutaka Suzuki, Masami Nagahama, Nobuyoshi Akimitsu
  • Organizer: 日本放射線影響学会大会
• [Presentation] がん制御因子PICT1とMTR4/エキソソームの相互作用およびrRNAプロセシングにおける機能解析 (2019)
  • Author(s): 宮尾宗太郎、齋藤佳奈子、河原康一、長浜正巳
  • Organizer: 次世代を担う若手ファーマ・バイオフォーラム2019
• [Presentation] Tumor regulator PICT1 interacts with MTR4/exosome and is involved in the pre-rRNA processing (2019)
  • Author(s): Sotaro Miyao, Kanako Saito, Renta Oshima, Yukihiro Kanbayashi, Kohichi Kawahara, Masami Nagahama
  • Organizer: ASCB/EMBO 2019 Meeting
  • Int'l Joint Research
• [Presentation] MTR4/Exosome-interacting proteins under control of the nucleolar AAA-ATPase NVL2 in human cells (2018)
  • Author(s): Masami Nagahama, Sotaro Miyao, Ryunosuke Nakamura, Nobuhiro Hiraishi, Koichi Kawahara, Yo-ichi Ishida
  • Organizer: International Conference on Ribosome Synthesis
  • Int'l Joint Research
• [Presentation] がん制御因子PICT1とMTR4-エキソソームの相互作用およびリボソーム生合成における機能解析 (2018)
  • Author(s): 宮尾宗太郎、河原康一、長浜正巳
  • Organizer: 次世代を担う若手ファーマ・バイオフォーラム2018
• [Presentation] 核小体ストレス応答制御タンパク質PICT1のリボソーム生合成における機能解析 (2018)
  • Author(s): 長浜正巳、宮尾宗太郎、中村龍之介、河原康一
  • Organizer: Ribosome Meeting
• [Presentation] PUM1タンパク質によるmRNA分解制御が、DNA障害後の細胞生存を促進する (2018)
  • Author(s): 山田俊理、今町直登、仲木竜、川村猛、長浜正巳、秋光信佳
  • Organizer: 日本放射線影響学会
• [Presentation] Identification of mRNAs involved in MTR4-mediated RNA decay in nucleus (2018)
  • Author(s): Han Han, Toshimichi Yamada, Yutaka Suzuki, Masami Nagahama, Nobuyoshi Akimitsu
  • Organizer: 日本分子生物学会年会
• [Presentation] MTR4-エキソソーム複合体と相互作用するTudorタンパク質SPF30の結合因子の解析 (2018)
  • Author(s): 石田洋一、濱志帆、長浜正巳
  • Organizer: 日本分子生物学会年会
• [Presentation] ヒト細胞リボソームの構築における分子リサイクリングと核小体ストレス応答 (2018)
  • Author(s): 長浜正巳
  • Organizer: 細胞でつながる研究会
  • Invited