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DNA損傷時のユビキチンリガーゼRNF126による転写制御メカニズムの解明

Research Project

Project/Area Number 20K12157
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 63020:Radiation influence-related
Research InstitutionTohoku University

Principal Investigator

石田 典子  東北大学, 東北メディカル・メガバンク機構, 助教 (10361073)

Co-Investigator(Kenkyū-buntansha) 中川 直  山陽小野田市立山口東京理科大学, 薬学部, 講師 (30707013)
Project Period (FY) 2020-04-01 – 2025-03-31
Project Status Granted (Fiscal Year 2023)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Keywordsユビキチンリガーゼ / タンパク分解 / ユビキチン化 / 転写制御 / 転写 / ヒストンシャペロン
Outline of Research at the Start

1. RNF126依存的なNAP1L1のユビキチン化およびタンパク分解: siRNA、RNF126 KOマウス初代細胞等を用いて調べる。
2. NAP1L1と結合する転写因子および転写複合体解析:細胞増殖関連の転写因子や転写複合体とNAP1L1の結合を確認する。また、NAP1L1のタンパク分解やガンマ線照射による、転写因子のクロマチン結合や下流遺伝子の発現量に与える影響を調べる。
3. 細胞周期およびDNA損傷特異的なNAP1L1タンパク分解とクロマチン構造変換を介した転写制御:siRNA、RNF126KOマウス初代細胞等を用いてmRNA発現量やChIP解析を行う。

Outline of Annual Research Achievements

DNA損傷時にDNA損傷修復と転写制御がユビキチン依存性タンパク質分解を介して協調的に制御されていることを示すことが本研究の目標であり、代表者らがDNA修復因子Ku80のユビキチンリガーゼとして発見した、RNF126によるヒストンシャペロンNAP1L1のタンパク分解を介した、DNA損傷におけるクロマチン構造変換と転写制御メカニズムを明らかにしたい。 代表者らはこれまでにNAP1のカウンターパートであるNAP1L1がユビキチンリガーゼRNF126と結合し、ユビキチン化されてタンパク質分解を受けることを発見した。細胞株を用い、野生型やユビキチン化活性を欠損した変異体RNF126の過剰発現やsiRNAによるRNF126のノックダウン細胞を解析した結果、RNF126は細胞周期 のG2初期にNAP1L1の分解を促すことで、増殖に重要な転写因子E2F-1のクロマチンへの結合量と転写活性を負に制御しているのではないかと考えられた。E2F-1は NAP1, NAP2と結合し、コアクチベーターp300/CBPと転写複合体を形成して働くことがこれまでに報告されており、RNF126はNAP1L1のタンパク質分解を介してクロ マチン構造を変化させ、転写複合体アセンブリーを制御しているという仮設が考えられた。この仮説を検証するために、NAP1L1のタンパク質発現量を調べて細胞 周期を通じて一定であること、またS期のみ核局在を示す結果を得た。しかし、ガンマ線照射時にはNAP1L1の発現量低下が確認された。DNA損傷時には、S期でも NAP1L1が分解を受けて機能を停止すると考えられ、生化学的手法を用いて解析を進めている。 マイクロアレイを用いたmRNA発現量の解析を行い、RNF126-RNAi処理細胞、RNF126 の野生型やCS変異体の過剰発現細胞についてRNAを抽出しマイクロアレイの解析結果を検討し、ついかじっけんを実施中である。

Current Status of Research Progress
Current Status of Research Progress

4: Progress in research has been delayed.

Reason

代表者が所属する東北メディカル・メガバンク機構バイオバンク部門は、コホート研究等における検体の受入・処理・保管管理等が主な業務であることに加えて、昨年度より第3期に入り教職員の減少が生じて研究に充てる時間が減少しているため、今年度の予定遅延の一因となっている。また、当初立てた 仮説を検証する生化学実験が遅延している状況である。

Strategy for Future Research Activity

今後の研究について、1年間の期間延長申請が承認されたため、仮説を検証する生化学実験の見直しを行う。

Report

(4 results)
  • 2023 Research-status Report
  • 2022 Research-status Report
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (17 results)

All 2023 2022 2021 2020

All Journal Article (16 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 16 results,  Open Access: 11 results) Presentation (1 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Detection and Correction of Sample Misidentifications in a Biobank Using the MassARRAY System and Genomic Information2023

    • Author(s)
      Kudo Hisaaki、Ishida Noriko、Nobukuni Takahiro、Aoki Yuichi、Saito Sakae、Nishijima Ichiko、Terakawa Takahiro、Yamamoto Masayuki、Minegishi Naoko、Yamashita Riu、Kumada Kazuki
    • Journal Title

      Biopreservation and Biobanking

      Volume: - Issue: 4 Pages: 373-382

    • DOI

      10.1089/bio.2022.0211

    • Related Report
      2023 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Whole blood transcriptome analysis for age- and gender-specific gene expression profiling in Japanese individuals2023

    • Author(s)
      Aoki YI, Taguchi K, Anzawa H, Kawashima J, Ishida N, Otuki A, Hasegawa A, Baird L, Suzuki T, Motoike IN, Ohneda K, Kumada K, Katsuoka F, Kinoshita K, Yamamoto M.
    • Journal Title

      J Biochem

      Volume: Online ahead of print. Issue: 6 Pages: 611-627

    • DOI

      10.1093/jb/mvae008

    • Related Report
      2023 Research-status Report
    • Peer Reviewed
  • [Journal Article] Neurobehavioral characteristics of mice with SETD5 mutations as models of IDD23 and KBG syndromes.2023

    • Author(s)
      Nakagawa T, Hattori S, Hosoi T, Nakayama K.
    • Journal Title

      Front Genet.

      Volume: 13 Pages: 1022339-1022339

    • DOI

      10.3389/fgene.2022.1022339

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] SPT16 ubiquitylation by DCAF14-CRL4 regulates FACT binding to histones2022

    • Author(s)
      Nakagawa T, Morohoshi A, Nagasawa Y, Nakagawa M, Hosogane M, Noda Y, Hosoi T, Nakayama K.
    • Journal Title

      Cell Reports

      Volume: 38 Issue: 12 Pages: 110541-110541

    • DOI

      10.1016/j.celrep.2022.110541

    • Related Report
      2022 Research-status Report 2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Insulin enhances gene expression of Midnolin, a novel genetic risk factor for Parkinson's disease, via ERK, PI3-kinase and multiple transcription factors in SH-SY5Y cells.2022

    • Author(s)
      Naoki Sagehashi, Yutaro Obara, Ohki Maruyama, Tadashi Nakagawa, Toru Hosoi, Kuniaki Ishii
    • Journal Title

      J. Pharmacol. Exp. Ther.

      Volume: - Issue: 2 Pages: 68-78

    • DOI

      10.1124/jpet.121.001076

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] COOH-terminal fragment of APP interacts with p62, forms an aggregate, and induces autophagic degradation in Alzheimer's cell model.2022

    • Author(s)
      Tanaka K, Kuramoto K, Nakagawa T, Nomura Y, Ozawa K, Hosoi T.
    • Journal Title

      Am J Physiol Cell Physiol.

      Volume: 323 Issue: 6 Pages: C1633-C1641

    • DOI

      10.1152/ajpcell.00003.2022

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Construction of a trio-based structural variation panel utilizing activated T lymphocytes and long-read sequencing technology.2022

    • Author(s)
      Otsuki A, Okamura Y, Ishida N, Tadaka S, Takayama J, Kumada K, Kawashima J, Taguchi K, Minegishi N, Kuriyama S, Tamiya G, Kinoshita K, Katsuoka F, Yamamoto M.
    • Journal Title

      Commun Biol.

      Volume: 5 Issue: 1 Pages: 991-991

    • DOI

      10.1038/s42003-022-03953-1

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Reduced PHOX2B stability causes axonal growth impairment in motor neurons with TARDBP mutations2021

    • Author(s)
      Mitsuzawa S, Suzuki N, Akiyama T, Ishikawa M, Sone T, Kawada J, Funayama R, Shirota M, Mitsuhashi H, Morimoto S, Ikeda K, Shijo T, Ohno A, Nakamura N, Ono H, Ono R, Osana S, Nakagawa T, Nishiyama A, Izumi R, Kaneda S, Ikeuchi Y, Nakayama K, Fujii T, Warita H, Okano H, Aoki M.
    • Journal Title

      Stem Cell Reports

      Volume: 16 Issue: 6 Pages: 1527-1541

    • DOI

      10.1016/j.stemcr.2021.04.021

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Landscape of electrophilic and inflammatory stress-mediated gene regulation in human lymphoblastoid cell lines2020

    • Author(s)
      Ishida Noriko、Aoki Yuichi、Katsuoka Fumiki、Nishijima Ichiko、Nobukuni Takahiro、Anzawa Hayato、Bin Li、Tsuda Miyuki、Kumada Kazuki、Kudo Hisaaki、Terakawa Takahiro、Otsuki Akihito、Kinoshita Kengo、Yamashita Riu、Minegishi Naoko、Yamamoto Masayuki
    • Journal Title

      Free Radical Biology and Medicine

      Volume: 161 Pages: 71-83

    • DOI

      10.1016/j.freeradbiomed.2020.09.023

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The Autism-Related Protein SETD5 Controls Neural Cell Proliferation through Epigenetic Regulation of rDNA Expression.2020

    • Author(s)
      Nakagawa T, Hattori S, Nobuta R, Kimura R, Nakagawa M, Matsumoto M, Nagasawa Y, Funayama R, Miyakawa T, Inada T, Osumi N, Nakayama KI, Nakayama K.
    • Journal Title

      iScience

      Volume: 23 Issue: 4 Pages: 101030-101030

    • DOI

      10.1016/j.isci.2020.101030

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Knockout Mouse Models Provide Insight into the Biological Functions of CRL1 Components.2020

    • Author(s)
      Nakagawa T, Nakayama K, Nakayama KI.
    • Journal Title

      Adv Exp Med Biol.

      Volume: 1217 Pages: 147-171

    • DOI

      10.1007/978-981-15-1025-0_10

    • ISBN
      9789811510243, 9789811510250
    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Identification of Dominant Transcripts in Oxidative Stress Response by a Full-Length Transcriptome Analysis2020

    • Author(s)
      Otsuki Akihito、Okamura Yasunobu、Aoki Yuichi、Ishida Noriko、Kumada Kazuki、Minegishi Naoko、Katsuoka Fumiki、Kinoshita Kengo、Yamamoto Masayuki
    • Journal Title

      Molecular and Cellular Biology

      Volume: 41 Issue: 2 Pages: 1-18

    • DOI

      10.1128/mcb.00472-20

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis.2020

    • Author(s)
      Nakamura R, Misawa K, Tohnai G, Nakatochi M, Furuhashi S, Atsuta N, Hayashi N, Yokoi D, Watanabe H, Watanabe H, Katsuno M, Izumi Y, Kanai K, Hattori N, Morita M, Taniguchi A, Kano O, Oda M, Shibuya K, Kuwabara S, Suzuki N, Aoki M, Ohta Y, Yamashita T, Abe K, Hashimoto R, Aiba I, Okada Y, Nagasaki M, Sobue G. et al.,
    • Journal Title

      Commun Biol.

      Volume: 23 Issue: 1 Pages: 526-526

    • DOI

      10.1038/s42003-020-01251-2

    • NAID

      120007178464

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] USP15 suppresses tumor immunity via deubiquitylation and inactivation of TET22020

    • Author(s)
      Chen LL, Smith MD, Lv L, Nakagawa T, Li Z, Sun SC, Brown NG, Xiong Y, Xu YP.
    • Journal Title

      Science Advances

      Volume: 6 Issue: 38 Pages: 1-13

    • DOI

      10.1126/sciadv.abc9730

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] An Amyotrophic Lateral Sclerosis-Associated Mutant of C21ORF2 Is Stabilized by NEK1-Mediated Hyperphosphorylation and the Inability to Bind FBXO32020

    • Author(s)
      Watanabe Y, Nakagawa T, Akiyama T, Nakagawa M, Suzuki N, Warita H, Aoki M, Nakayama K.
    • Journal Title

      iScience

      Volume: 23 Issue: 9 Pages: 1-15

    • DOI

      10.1016/j.isci.2020.101491

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Longitudinal plasma amino acid profiling with maternal genomic background throughout human pregnancy2020

    • Author(s)
      M Shirota, D Saigusa, R Yamashita, Y Kato, M Matsumoto, J Yamagishi, N Ishida, K Kumada, Y Oe, H Kudo, J Yokozawa, Y Kuroki, I Motoike, F Katsuoka, M Nagasaki, S Koshiba, K Nakayama, O Tanabe, J Yasuda, S Kure, K Kinoshita, H Metoki, S Kuriyama, N Yaegashi, M Yamamoto, J Sugawara
    • Journal Title

      Medical Mass Spectrometry

      Volume: 4 Pages: 36-49

    • NAID

      130007897968

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Presentation] 自閉症関連タンパク質SETD5によるrDNAのエピジェネティック制御を介した神経細胞の増殖促進2020

    • Author(s)
      中川 直、中山 啓子
    • Organizer
      第10回武田科学振興財団 薬科学シンポジウム(国際学会)
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research

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Published: 2020-04-28   Modified: 2024-12-25  

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