Mechanism of targeted DNA cleavage and recombination by AID
| Project/Area Number |
16K07214
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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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| Research Field |
Medical genome science
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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) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | AID / CSR / Recombination / hnRNPK / hnRNPL / Phf5a / Samhd1 / Brd2 / BiFC / hnRNP / Serbp1 / SHM / Translocation / Chromatin regulator |
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| Outline of Final Research Achievements |
Antibody gene diversification by SHM and CSR requires AID induced DNA break and recombination at the IgH locus. How AID exerts such functions, and the genomic stability is regulated are poorly understood.
AID's N- and C-terminus played important role in monomer and dimer formation. They interacted with specific co-factors, which differentially modulated DNA break and recombination. The C-terminal AID mutant, found in HIGMII patient, was dimerization defective and reduced association of AID with CSR co-factors. Novel CSR regulatory chromatin proteins were also identified by iChIP and candidate gene knockdown. While AID-induced DNA break was facilitated by SMARCA4-SSRP1 chromatin complex, Brd2, SAMHD1, Phf5a promoted recombination. Interestingly, the dNTPase activity of SAMHD1 was found to be critical to promote DNA repair during CSR and IgH/cMyc translocation.
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| Academic Significance and Societal Importance of the Research Achievements |
A novel competitive regulatory mechanism of AID has been observed, that help explain CSR impairment in HIGMII patient. Since distinct chromatin proteins are involved in AID's DNA-break and repair regulation, they are valuable future drug target to modulate genomic recombination.
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Report
(4 results)
Research Products
(11 results)
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[Presentation] Chromatin remodeller SMARCA4 recruits topoisomerase 1 and suppresses transcription-associated genomic instability2017
Author(s)
Husain A., Begum, N.A., Taniguchi, T., Taniguchi, H., Kobayashi, M., and Honjo, T.
Organizer
International Symposium on Immune Diversity and Cancer Therapy
Place of Presentation
Kobe
Year and Date
2017-01-26
Related Report
Int'l Joint Research / Invited
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