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Article

DNA Damage Regulates Senescence-Associated Extracellular Vesicle Release via the Ceramide Pathway to Prevent Excessive Inflammatory Responses

1
Project for Cellular Senescence, The Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan
2
Graduate School of Science and Engineering, Ibaraki University, Mito, Ibaraki 310-8512, Japan
3
Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012, Japan
4
Advanced Research & Development Programs for Medical Innovation (PRIME), Japan Agency for Medical Research and Development (AMED), Chiyoda-ku, Tokyo 104-0004, Japan
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(10), 3720; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103720
Received: 29 April 2020 / Revised: 15 May 2020 / Accepted: 19 May 2020 / Published: 25 May 2020
(This article belongs to the Special Issue Recognition of DNA Lesions)
DNA damage, caused by various oncogenic stresses, can induce cell death or cellular senescence as an important tumor suppressor mechanism. Senescent cells display the features of a senescence-associated secretory phenotype (SASP), secreting inflammatory proteins into surrounding tissues, and contributing to various age-related pathologies. In addition to this inflammatory protein secretion, the release of extracellular vesicles (EVs) is also upregulated in senescent cells. However, the molecular mechanism underlying this phenomenon remains unclear. Here, we show that DNA damage activates the ceramide synthetic pathway, via the downregulation of sphingomyelin synthase 2 (SMS2) and the upregulation of neutral sphingomyelinase 2 (nSMase2), leading to an increase in senescence-associated EV (SA-EV) biogenesis. The EV biogenesis pathway, together with the autophagy-mediated degradation pathway, functions to block apoptosis by removing cytoplasmic DNA fragments derived from chromosomal DNA or bacterial infections. Our data suggest that this SA-EV pathway may play a prominent role in cellular homeostasis, particularly in senescent cells. In summary, DNA damage provokes SA-EV release by activating the ceramide pathway to protect cells from excessive inflammatory responses. View Full-Text
Keywords: DNA damage; extracellular vesicle (EV); exosome; ceramide pathway; cellular senescence; senescence-associated secretory phenotype (SASP); senescence-associated extracellular vesicle (SA-EV); autophagy; bacterial infection; Bacillus Calmette–Guérin (BCG) DNA damage; extracellular vesicle (EV); exosome; ceramide pathway; cellular senescence; senescence-associated secretory phenotype (SASP); senescence-associated extracellular vesicle (SA-EV); autophagy; bacterial infection; Bacillus Calmette–Guérin (BCG)
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MDPI and ACS Style

Hitomi, K.; Okada, R.; Loo, T.M.; Miyata, K.; Nakamura, A.J.; Takahashi, A. DNA Damage Regulates Senescence-Associated Extracellular Vesicle Release via the Ceramide Pathway to Prevent Excessive Inflammatory Responses. Int. J. Mol. Sci. 2020, 21, 3720. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103720

AMA Style

Hitomi K, Okada R, Loo TM, Miyata K, Nakamura AJ, Takahashi A. DNA Damage Regulates Senescence-Associated Extracellular Vesicle Release via the Ceramide Pathway to Prevent Excessive Inflammatory Responses. International Journal of Molecular Sciences. 2020; 21(10):3720. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103720

Chicago/Turabian Style

Hitomi, Kazuhiro, Ryo Okada, Tze M. Loo, Kenichi Miyata, Asako J. Nakamura, and Akiko Takahashi. 2020. "DNA Damage Regulates Senescence-Associated Extracellular Vesicle Release via the Ceramide Pathway to Prevent Excessive Inflammatory Responses" International Journal of Molecular Sciences 21, no. 10: 3720. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103720

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