| Project/Area Number |
16KK0185
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| Research Category |
Fund for the Promotion of Joint International Research (Fostering Joint International Research)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Pediatrics
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| Research Institution | University of Miyazaki |
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Principal Investigator |
Uechi Tamayo 宮崎大学, 医学部, 准教授 (10381104)
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| Project Period (FY) |
2017 – 2020
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥14,560,000 (Direct Cost: ¥11,200,000、Indirect Cost: ¥3,360,000)
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| Keywords | snoRNA / リボソーム / 翻訳 / RNA修飾 / 肝細胞がん / リボソームRNA / がん / 発現制御 / 分子病態学 / 高次生命科学 |
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| Outline of Final Research Achievements |
Ribosomes are macromolecular complexes that are composed of ribosomal proteins and RNAs. H/ACA small nucleolar RNAs (snoRNAs) are responsible for converting hundreds of specific uridine residues to pseudouridine within the RNAs and are found altered expression in numerous cancers. We found that loss of SNORA24 gene in mice expressing RASG12V promoted the development of liver cancer resembling human steatohepatitic hepatocellular carcinoma, and are associated with poor survival. These findings suggest that snoRNA-guided chemical modifications may play important roles in safeguarding against oncogenic insult. At the molecular level, using single-molecule FRET analysis, we find that such ribosomes exhibit perturbations in aminoacyl-transfer RNA selection and altered dynamics within the pre-translocation ribosome complex. These data should provide a fundamental clue to molecular mechanisms of the mRNA-specific translation controls and pathogenesis of the diseases with mutated ribosomes.
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| Academic Significance and Societal Importance of the Research Achievements |
ヒトのリボソームは79種類のタンパク質と4種類のRNAで構成され、RNAは約200箇所で化学修飾を受ける複雑な構造体である。タンパク質や修飾の翻訳における役割は未解明であるが、様々な先天性疾患やがんとの関連が示唆されている。しかし、ほぼすべての細胞に存在するリボソームの異常がなぜ特定の疾患を引き起こすのか不明である。本研究では、RNA修飾の翻訳における役割を初めて示した。また、リボソームにmRNA特異的な翻訳調節機構が備わっていることを示唆し、疾患発症の分子メカニズムを解明する手がかりとなる。
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