| Project/Area Number |
18K06961
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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 49010:Pathological biochemistry-related
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| Research Institution | Kyushu University |
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Principal Investigator |
Unoki Motoko 九州大学, 生体防御医学研究所, 准教授 (30525374)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | ICF症候群 / DNAメチル化 / クロマチンリモデリング / 染色体不安定性 / ペリセントロメア / DNA修復 / 非相同末端結合 / DNA複製 / CDCA7 / HELLS / Rループ / DNA損傷 / 染色体安定性 / エピジェネティクス / NHEJ / DNA損傷修復 |
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| Outline of Final Research Achievements |
ICF syndrome is a rare recessive disorder which shows DNA hypomethylation at pericentromeric repeats. In this study, we found that CDCA7 and HELLS, which are mutated in ICF patients, make a protein complex, and facilitate non-homologous end-joining repair of DNA double-strand breaks (DSBs) and the accumulation of proteins on nascent DNA, including the DNMT1/UHRF1 maintenance DNA methylation complex as well as proteins involved in the resolution or prevention of R-loops. Consistent with the hypomethylation state of pericentromeric repeats, the transcription and DSBs caused by aberrant R-loop formation were increased in CDCA7 and HELLS knockout cells. Hence, we propose that hypomethylation due to inefficient DNMT1/UHRF1 recruitment at pericentromeric repeats by defects in the CDCA7/HELLS complex could induce centromeric/pericentromeric instability via ectopic expression and pathological R-loop formation, which may explain a part of the molecular pathogenesis of ICF syndrome.
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| Academic Significance and Societal Importance of the Research Achievements |
ICF症候群は稀な遺伝病ではあるが、本研究を通してCDCA7/HELLS複合体がエピジェネティック制御機構及びDNA損傷修復機構への関与を介して染色体の安定性を維持する機構の大枠を明らかにすることができた。この結果は両機構間のクロストークが染色体安定性の維持すなわちゲノムインテグリティの維持に重要であることを示唆しており、これは学術的に重要な発見である。また本研究成果は、ゲノムインテグリティの破綻に起因する癌などその他の疾患の理解及び治療法開発に繋がる可能性があり、社会的にも重要な発見である。
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