Molecular mechanisms of control of recombination by dynamics of RAD51/DMC1-DNA complexes
| Project/Area Number |
19H00981
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Medium-sized Section 43:Biology at molecular to cellular levels, and related fields
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| Research Institution | Osaka University |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥45,760,000 (Direct Cost: ¥35,200,000、Indirect Cost: ¥10,560,000)
Fiscal Year 2021: ¥12,350,000 (Direct Cost: ¥9,500,000、Indirect Cost: ¥2,850,000)
Fiscal Year 2020: ¥14,040,000 (Direct Cost: ¥10,800,000、Indirect Cost: ¥3,240,000)
Fiscal Year 2019: ¥19,370,000 (Direct Cost: ¥14,900,000、Indirect Cost: ¥4,470,000)
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| Keywords | 相同組換え / ゲノム安定化 / 減数分裂 / DNA２重鎖切断修復 / RAD51 / DMC1 / 染色体 / ゲノム編集 / 生殖細胞 / DNA修復 |
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| Outline of Research at the Start |
DNA相同鎖検索反応に関わる２つのRecAホモログRAD51, DMC1の一本鎖DNA複合体形成の動的に制御を介した、相同組換えのパートナー選択に代表される組換え径路の選択や特異性の産出の仕組みの分子基盤を統合的に理解することを目指す。特にヒトRAD51-DNA複合体をRAD51メディエーターとアンチリコンビナーゼに制御する因子に焦点を当て、生化学的、構造生物学的に解析することに加え、ヒト細胞とマウス個体レベルの組換え反応の解析する。また、減数分裂期特有の、相同染色体間での組換えパートナー選択の仕組みの解明のために、出芽酵母の減数分裂型Dmc1の集合を助ける因子群の構造、生化学的解析も実施する
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| Outline of Final Research Achievements |
Homologous recombination is essential for the maintenance of genome stability and creation of genome diversity. RAD51 assembly on single-stranded (ss)DNAs is a crucial step in the homology search and strand exchange in the recombination. The formation of the RAD51 filament is promoted by various positive factors and regulated by negative regulators. However, the mechanisms of control of RAD51 filament dynamics by these factors remain largely unknown. In this study, we report a new role of the human FIGNL1, AAA+ ATPase, as a novel regulator of RAD51 assembly/disassembly. Persistent RAD51 assembly in FIGNL1-depleted human cells suggests its role in the disassembly of RAD51 filaments as a negative regulator. Fignl1 conditional knock-out shows defective meiotic recombination, indicating a positive role in the recombination. Taken together, our data suggest that FIGNL1 plays dual roles in RAD51-filament formation.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究成果は相同組換えのブレーキ役のタンパク質・遺伝子(FIGNL1)の新しい機能を愛からにしました。この因子を生殖細胞で失うと、配偶子を形成できなくなります。このタンパク質の機能を明らかにすることで、生体内でのDNA同士の交換反応である相同組換えを適切に制御する新しいメカニズムを解明しました。相同組換えの機能不全による不妊や異数体病の原因解明や診断・治療方法の開発につながることが期待できます。また、今回発見した組換え因子を人工的に制御することで、ゲノム編集の最適化など幅広い応用が可能であると考えられます。
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Report
(5 results)
Research Products
(43 results)
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[Journal Article] Enhanced processivity of Dnmt1 by monoubiquitinated histone H32020
Author(s)
Y. Mishima, L. Brueckner, S. Takahashi, T. Kawakami, J. Otani, A. Shinohara, K. Takeshita, R. G. Garvilles, M. Watanabe, N. Sakai, H. Takeshima, C. Nachtegael, A. Nishiyama, M. Nakanishi, K. Arita, K. Nakashima, H. Hojo, I. Suetake
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Journal Title
Genes Cells
Volume: 25
Issue: 1
Pages: 22-32
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Toward Global Standardization of Conducting Fair Investigations of Allegations of Research Misconducts2020
Author(s)
Nouchi R, Aihara H, Arie F, Asashima M, Daida H, Fudano J, Fujiwara Y, Fushiki S, Geller RJ, Hatano K, Homma T, Kimura M, Kuroki T, Miki K, Morita I, Nitta K, Shinohara A, Siomi MC, Yoshida M, Ichikawa I
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Journal Title
Accountability in Research: Policies and Quality Assurance
Volume: in press
Issue: 6
Pages: 327-346
DOI
Related Report
Peer Reviewed
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[Journal Article] Srs2 helicase prevents the formation of aberrant DNA damage during late prophase I of yeast meiosis2019
Author(s)
Sasanuma, H., Sabhan, H.M.S., Furihata, Y., Challa, K., Palmer, L. Gasser, S.M., Shinohara, M., and A. Shinohara
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Journal Title
Chromosoma
Volume: 128
Issue: 3
Pages: 453-471
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] A. Shinohara, Human RAD51 paralogue, SWSAP1, fosters RAD51 filament by regulating the anti-recombinase, FIGNL1 AAA+ ATPase.2019
Author(s)
Matsuzaki, K., Kondo, S., Ishikawa, T., and A. Shinohara,
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Journal Title
Nature Communications
Volume: 10
Issue: 1
Pages: 1407-1407
DOI
Related Report
Peer Reviewed / Open Access
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