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

Akiko Takahashi, Tze Mun Loo, Ryo Okada, Fumitaka Kamachi, Yoshihiro Watanabe, Masahiro Wakita, Sugiko Watanabe, Shimpei Kawamoto, Kenichi Miyata, Glen N. Barber, Naoko Ohtani and Eiji Hara ()
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Akiko Takahashi: Japanese Foundation for Cancer Research
Tze Mun Loo: Japanese Foundation for Cancer Research
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
Eiji Hara: Japanese Foundation for Cancer Research

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03555-8

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