| Project/Area Number |
21K06015
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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 43010:Molecular biology-related
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| Research Institution | Kyoto University |
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Principal Investigator |
Begum Nasim 京都大学, 医学研究科, 特定准教授 (80362507)
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Project Status |
Completed (Fiscal Year 2023)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2022: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | CSR / AID / HNRNPU / DNA Repair / NHEJ / MED12 / R-loop / B Cells / Genomic Instability / B cell |
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| Outline of Research at the Start |
AID-induced DNA lesions in the R-loop causes recombinogenic DNA breaks in B cell genome, which oftentimes are potential source of oncogenic rearrangement This study aims to elucidate the mechanism and regulation of R-loop involved in antibody isotype switching and B cell lymphomagenesis.
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| Outline of Final Research Achievements |
During class switching in mature B cells, maintaining genomic integrity is essential due to DNA breaks and rearrangements in the antibody gene locus. This study reveals that heterogeneous ribonucleoprotein HNRNPU is pivotal in regulating R-loop dynamics and DNA repair, while MED12 controls DNA breakage and locus-specific conformation. HNRNPU interacts with DNA repair factors and binds to the Ig locus's G4 RNA/DNA structures. Loss of HNRNPU disrupts DNA repair, leading to R-loop imbalances and hindering antibody class switch processes. Conversely, MED12 loss inhibits recombination by impairing AID-induced DNA breaks and S-S synapsis, which is crucial for bringing recombining loci into proximity. Thus, HNRNPU and MED12 are critical in coordinating immune responses and maintaining genomic stability.
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| Academic Significance and Societal Importance of the Research Achievements |
The novel findings regarding the regulatory roles of HNRNPU and MED12 in recombination in B cells offer fresh perspectives on immune system functionality and linked genomic instability. These insights hold promise for the development of innovative diagnostic and therapeutic approaches in the future.
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