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Downregulation of cytoplasmic DNases is implicated in cytoplasmic DNA accumulation and SASP in senescent cells

Author

Listed:
  • Akiko Takahashi

    (Japanese Foundation for Cancer Research
    JST)

  • Tze Mun Loo

    (Japanese Foundation for Cancer Research
    Tokyo University of Science)

  • Ryo Okada

    (Japanese Foundation for Cancer Research)

  • Fumitaka Kamachi

    (Tokyo University of Science)

  • Yoshihiro Watanabe

    (Tokyo University of Science)

  • Masahiro Wakita

    (Osaka University)

  • Sugiko Watanabe

    (Osaka University)

  • Shimpei Kawamoto

    (Osaka University)

  • Kenichi Miyata

    (Japanese Foundation for Cancer Research)

  • Glen N. Barber

    (University of Miami Miller School of Medicine)

  • Naoko Ohtani

    (Tokyo University of Science
    Osaka City University)

  • Eiji Hara

    (Japanese Foundation for Cancer Research
    Osaka University)

Abstract

Accumulating evidence indicates that the senescence-associated secretory phenotype (SASP) contributes to many aspects of physiology and disease. Thus, controlling the SASP will have tremendous impacts on our health. However, our understanding of SASP regulation is far from complete. Here, we show that cytoplasmic accumulation of nuclear DNA plays key roles in the onset of SASP. Although both DNase2 and TREX1 rapidly remove the cytoplasmic DNA fragments emanating from the nucleus in pre-senescent cells, the expression of these DNases is downregulated in senescent cells, resulting in the cytoplasmic accumulation of nuclear DNA. This causes the aberrant activation of cGAS-STING cytoplasmic DNA sensors, provoking SASP through induction of interferon-β. Notably, the blockage of this pathway prevents SASP in senescent hepatic stellate cells, accompanied by a decline of obesity-associated hepatocellular carcinoma development in mice. These findings provide valuable new insights into the roles and mechanisms of SASP and possibilities for their control.

Suggested Citation

  • Akiko Takahashi & Tze Mun Loo & Ryo Okada & Fumitaka Kamachi & Yoshihiro Watanabe & Masahiro Wakita & Sugiko Watanabe & Shimpei Kawamoto & Kenichi Miyata & Glen N. Barber & Naoko Ohtani & Eiji Hara, 2018. "Downregulation of cytoplasmic DNases is implicated in cytoplasmic DNA accumulation and SASP in senescent cells," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03555-8
    DOI: 10.1038/s41467-018-03555-8
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    Cited by:

    1. Toshiyuki Ko & Seitaro Nomura & Shintaro Yamada & Kanna Fujita & Takanori Fujita & Masahiro Satoh & Chio Oka & Manami Katoh & Masamichi Ito & Mikako Katagiri & Tatsuro Sassa & Bo Zhang & Satoshi Hatsu, 2022. "Cardiac fibroblasts regulate the development of heart failure via Htra3-TGF-β-IGFBP7 axis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Nanase Igarashi & Kenichi Miyata & Tze Mun Loo & Masatomo Chiba & Aki Hanyu & Mika Nishio & Hiroko Kawasaki & Hao Zheng & Shinya Toyokuni & Shunsuke Kon & Keiji Moriyama & Yasuyuki Fujita & Akiko Taka, 2022. "Hepatocyte growth factor derived from senescent cells attenuates cell competition-induced apical elimination of oncogenic cells," Nature Communications, Nature, vol. 13(1), pages 1-11, December.

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