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A functional deficiency of TERA/VCP/p97 contributes to impaired DNA repair in multiple polyglutamine diseases

Author

Listed:
  • Kyota Fujita

    (Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan)

  • Yoko Nakamura

    (Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan)

  • Tsutomu Oka

    (Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan)

  • Hikaru Ito

    (Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan)

  • Takuya Tamura

    (Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan)

  • Kazuhiko Tagawa

    (Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan)

  • Toshikazu Sasabe

    (Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan)

  • Asuka Katsuta

    (Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
    Faculty of Science, Toho University, 2-2-1 Miyama, Funabashi 274-8510, Japan)

  • Kazumi Motoki

    (Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan)

  • Hiroki Shiwaku

    (Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan)

  • Masaki Sone

    (Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
    Faculty of Science, Toho University, 2-2-1 Miyama, Funabashi 274-8510, Japan)

  • Chisato Yoshida

    (Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan)

  • Masahisa Katsuno

    (Graduate School of Medicine, Nagoya University, 65, Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan)

  • Yoshinobu Eishi

    (Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan)

  • Miho Murata

    (National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashimachi, Kodaira 187-8551, Japan)

  • J. Paul Taylor

    (St. Jude Children’s Research Hospital)

  • Erich E. Wanker

    (Max-Delbrück Center for Molecular Medicine)

  • Kazuteru Kono

    (Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan)

  • Satoshi Tashiro

    (Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan)

  • Gen Sobue

    (Graduate School of Medicine, Nagoya University, 65, Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan)

  • Albert R. La Spada

    (Cellular and Molecular Medicine, and Neurosciences, and the Institute for Genomic Medicine, University of California, San Diego)

  • Hitoshi Okazawa

    (Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan)

Abstract

It is hypothesized that a common underlying mechanism links multiple neurodegenerative disorders. Here we show that transitional endoplasmic reticulum ATPase (TERA)/valosin-containing protein (VCP)/p97 directly binds to multiple polyglutamine disease proteins (huntingtin, ataxin-1, ataxin-7 and androgen receptor) via polyglutamine sequence. Although normal and mutant polyglutamine proteins interact with TERA/VCP/p97, only mutant proteins affect dynamism of TERA/VCP/p97. Among multiple functions of TERA/VCP/p97, we reveal that functional defect of TERA/VCP/p97 in DNA double-stranded break repair is critical for the pathology of neurons in which TERA/VCP/p97 is located dominantly in the nucleus in vivo. Mutant polyglutamine proteins impair accumulation of TERA/VCP/p97 and interaction of related double-stranded break repair proteins, finally causing the increase of unrepaired double-stranded break. Consistently, the recovery of lifespan in polyglutamine disease fly models by TERA/VCP/p97 corresponds well to the improvement of double-stranded break in neurons. Taken together, our results provide a novel common pathomechanism in multiple polyglutamine diseases that is mediated by DNA repair function of TERA/VCP/p97.

Suggested Citation

  • Kyota Fujita & Yoko Nakamura & Tsutomu Oka & Hikaru Ito & Takuya Tamura & Kazuhiko Tagawa & Toshikazu Sasabe & Asuka Katsuta & Kazumi Motoki & Hiroki Shiwaku & Masaki Sone & Chisato Yoshida & Masahisa, 2013. "A functional deficiency of TERA/VCP/p97 contributes to impaired DNA repair in multiple polyglutamine diseases," Nature Communications, Nature, vol. 4(1), pages 1-13, October.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms2828
    DOI: 10.1038/ncomms2828
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    Cited by:

    1. Xiaocen Jin & Hikari Tanaka & Meihua Jin & Kyota Fujita & Hidenori Homma & Maiko Inotsume & Huang Yong & Kenichi Umeda & Noriyuki Kodera & Toshio Ando & Hitoshi Okazawa, 2023. "PQBP5/NOL10 maintains and anchors the nucleolus under physiological and osmotic stress conditions," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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