Molecular mechanism of genomic DNA fragmentation and secretion
| Project/Area Number |
17K19618
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| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Tumor biology and related fields
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| Research Institution | Japanese Foundation for Cancer Research |
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Principal Investigator |
Takahashi Akiko 公益財団法人がん研究会, がん研究所 細胞老化プロジェクト, プロジェクトリーダー (60380052)
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| Research Collaborator |
LOO tze mun
OKADA ryo
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| Project Period (FY) |
2017-06-30 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2018: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2017: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
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| Keywords | 細胞老化 / DNA分解酵素 / 核酸センサー / 自然免疫応答 / SASP / ゲノムDNA / cfDNA / cell free DNA |
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| Outline of Final Research Achievements |
Cellular senescence is the state of essentially irreversible cell cycle arrest that can be induced by a variety of potentially oncogenic stimuli. On the other hand, cellular senescence also causes secretion of various inflammatory factors. This phenotype is senescence-associated secretory phenotype (SASP), which contributes to many aspects of physiology and disease. 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 cytoplasmic DNA sensors, provoking SASP through activation of the innate immune response. Here we demonstrated that cytoplasmic DNA accumulation causes the secretion of cfDNA from senescent cells.
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| Academic Significance and Societal Importance of the Research Achievements |
細胞老化は重要ながん抑制機構であるが、老化した細胞がSASP因子を分泌することでさまざまな加齢性疾患を引き起こしてしまう副作用があることが明らかとなっている。私たちは本研究から、加齢に伴い体内に蓄積した老化細胞では核の構造的異常が高頻度で観察されること、また細胞質DNA分解酵素の発現低下により細胞質にDNA断片が蓄積し自然免疫応答を引き起こすことでSASPを誘導することを見出した。さらにこれらのゲノム断片はcfDNAとして細胞外へ分泌しており、このcfDNAが周囲の組織や遠隔臓器に取り込まれることで加齢に伴う慢性炎症や自己免疫疾患の発症に関与している可能性が示唆された。
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Report
(3 results)
Research Products
(24 results)
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[Journal Article] Downregulation of cytoplasmic DNases is implicated in cytoplasmic DNA accumulation and SASP in senescent cells2018
Author(s)
Takahashi A, Loo TM, Okada R, Kamachi F, Watanabe Y, Wakita M, Watanabe S, Kawamoto S, Miyata K, Barber GN, Ohtani N, Hara E
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Journal Title
Nature Communications
Volume: 9
Issue: 1
Pages: 1249-1249
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Exosomes maintain cellular homeostasis by excreting harmful DNA from cells2017
Author(s)
Takahashi, A., Okada, R., Nagao, K., Kawamata, Y., Hanyu, A., Yoshimoto, S., Takasugi, M., Watanabe, S., Kanemaki, M.T., Obuse, C. & Hara, E.
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Journal Title
Nature Communications
Volume: -
Issue: 1
Pages: 15287-15287
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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