2023 Fiscal Year Final Research Report
Defects in a novel nucleotide excision repair factor leading to genomic instability in congenital dyskeratosis cells
| Project/Area Number |
20K07308
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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 48040:Medical biochemistry-related
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| Research Institution | Hamamatsu University School of Medicine |
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Principal Investigator |
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| Project Period (FY) |
2020-04-01 – 2024-03-31
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| Keywords | テロメラーゼ / 先天性角化症 / XPF / PRMT4 |
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| Outline of Final Research Achievements |
We found that the same telomerase complex factors are required for the removal of CPDs. We suspected an association with telomerase-mediated NER because XPF/ERCC1, a core factor of the nucleotide excision repair machinery (NER), is localised in the telomere region, but the regulation of XPF/ERCC1 activity is not known. We found that the arginine methyltransferase, PRMT4/CARM1, is required for the maintenance of XPF function. So far, it has been shown that methylation by PRMT4 affects the localisation of XPF-ERCC1 at sites of DNA damage and nuclease activity, which is largely due to changes in the binding capacity of XPF to ERCC1.
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| Free Research Field |
DNA損傷修復
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| Academic Significance and Societal Importance of the Research Achievements |
テロメア領域に生じたCPDが既知のNERによって修復されるのかわかっていない。我々はNERの進行にテロメラーゼのサブユニットTERT, TERC, DKCが必要とされることを明らかにした。これらテロメラーゼサブユニットの欠損は先天性角化症(DC)の原因となる。我々はテロメアに局在するNER因子ERCC1/XPFの機能制御にPRMT4が必要であることを見出した。XPFの活性はNERやICL repairに必須のヌクレアーゼであるとともにcisplatinなど抗癌剤に対する抵抗性に関わることが明らかにされており本研究の成果からDCに対する治療標的創出や薬剤耐性の軽減に寄与することが期待される。
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