Molecular mechanisms of severe genomic instability induced by embedded ribonucleotides
| Project/Area Number |
19K12339
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 63030:Chemical substance influence on environment-related
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| Research Institution | Chiba University |
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Principal Investigator |
Sassa Akira 千葉大学, 大学院理学研究院, 准教授 (10738347)
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| Project Period (FY) |
2019-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
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| Keywords | DNA損傷 / ゲノム不安定性 / DNA修復 / 突然変異 / RNA前駆体 / リボヌクレオチド / ゲノム |
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| Outline of Research at the Start |
細胞内のリボヌクレオチドは、エネルギー産生の基質やRNA前駆体として必須である一方で、DNA複製中にDNA前駆体と間違われてゲノムに取り込まれることがある。その頻度は、細胞あたり実に100万分子にもなり、適切に除去されなければ極めて深刻な神経変性疾患や発がんの引き金になると言われている。本研究は、リボヌクレオチドによってゲノムにいかなる異常が、どの様な機構を介して引き起こされるかを問い、リボヌクレオチドの蓄積による疾患の発症機構を紐解く。
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| Outline of Final Research Achievements |
Ribonucleoside triphosphate is essential as the substrate for energy production and RNA synthesis. However, it can also be incorporated into the genome during DNA replication. In this study, we focused on genomic instability induced by the accumulation of ribonucleotides and its underlying mechanisms. First, we newly identified that nucleotide excision repair has an activity to excise an oxidized ribonucleotide embedded into DNA, which suppresses ribonucleotide-induced mutagenesis in cells. Second, we revealed that Tyrosyl-DNA phosphodiesterases TDP1 and TDP2 are involved in the ribonucleotide-induced mutagenesis in cells.
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| Academic Significance and Societal Importance of the Research Achievements |
DNA中に取り込まれたリボヌクレオチドはDNA複製の妨害や染色体異常を引き起こし、深刻な神経変性疾患の発症や細胞のがん化につながることが報告されている。本研究において示唆されたゲノム不安定化の抑制及び誘発のメカニズムは、疾患発症の仕組みを明らかにするための分子基盤になると共に、治療法の開発につながる重要な知見となり得る。
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Report
(5 results)
Research Products
(50 results)
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[Journal Article] Follow-up genotoxicity assessment of Ames-positive/equivocal chemicals using the improved thymidine kinase gene mutation assay in DNA repair-deficient human TK6 cells2021
Author(s)
A. Sassa, T. Fukuda, A. Ukai, M. Nakamura, R. Sato, S. Fujiwara, K. Hirota, S. Takeda, K.I. Sugiyama, M. Honma, M. Yasui
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Journal Title
Mutagenesis
Volume: 36
Issue: 5
Pages: 331-338
DOI
Related Report
Peer Reviewed
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[Presentation] Alternate processing pathways of a single ribonucleotide incorporated into DNA and its consequences in human cells2019
Author(s)
Akira Sassa, Haruto Tada, Ayuna Takeishi, Kaho Harada, Kazuma Nakatani, Masataka Tsuda, Hiroyuki Sasanuma, Shunichi Takeda, Kaoru Sugasawa, Manabu Yasui, Masamitsu Honma, Kiyoe Ura
Organizer
The Joint Meeting of The 6th Asian Congress on Environmental Mutagens and the 48th Annual Meeting of the Japanese Environmental Mutagen Society
Related Report
Int'l Joint Research
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