| Project/Area Number |
21H02400
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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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 |
CARLTON Peter 京都大学, 生命科学研究科, 准教授 (20571813)
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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 |
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2023: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Fiscal Year 2022: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2021: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
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| Keywords | 減数分裂 / C. elegans / 染色体 / 二重鎖切断 / リン酸化制御 / キナーゼ / ホスファターゼ / 線虫 / DNA二重鎖切断 / リン酸化 / 染色体ダイナミクス |
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| Outline of Research at the Start |
減数分裂において染色体が正常に分離されるためには、減数分裂前期にDNA二重鎖切断が作られ、相同染色体が繋ぎかえられることが必須である。そのためには、多すぎず、少なすぎない数の二重鎖切断がDNA切断酵素SPO-11によって作られることが重要である。我々は、DSB-1タンパク質のリン酸化制御が、切断酵素による適度なDNA切断に重要であるという現象を見つけた。本研究は、ヒトまで保存されたDSB-1タンパク質が、DNA切断量を制御するメカニズムを分子レベルで明らかにし、生殖細胞が、安全にDNAを切断することで、次世代にゲノムを継承する分子メカニズムを解明することを目指す。
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| Outline of Final Research Achievements |
We have made significant progress in understanding how programmed DNA double-strand breaks are regulated in meiotic prophase. First, we found that the phosphatase PP4 and the DNA damage kinase ATR work in opposite directions to promote and suppress double-strand breaks in C. elegans. Second, we found evidence that PP4 and ATR act through a common substrate, the protein DSB-1. DSB-1 (called Rec114 in mammals) is an essential double-strand break cofactor. DSB-1 is hyperphosphorylated in the absence of PP4; conversely, it requires ATR kinase to become phosphorylated. Third, we found that non-phosphorylatable DSB-1 is hyperactive, able to rescue double-strand break defects in PP4 mutants as well as mutants in dsb-2, a paralog of DSB-1. Our results have revealed a new facet of double-strand break initiation, and explained our previous findings in PP4 mutants, and set the stage for continued investigation into how phosphorylation of DSB-1 prevents DNA breaks from occurring.
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| Academic Significance and Societal Importance of the Research Achievements |
Our research target DSB-1 (mammalian Rec114) has been under intense investigation in the past few years, and we have used the advantages of C. elegans to understand novel features of how it both promotes and restricts double-strand break activity; our work was published in Elife (2022).
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