2022 Fiscal Year Final Research Report
Role of proofreading exonuclease activity of replicative polymerase epsilon in replication fork slowing at DNA damage
Project/Area Number |
20H04337
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Research Category |
Grant-in-Aid for Scientific Research (B)
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Allocation Type | Single-year Grants |
Section | 一般 |
Review Section |
Basic Section 63020:Radiation influence-related
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Research Institution | Tokyo Metropolitan University |
Principal Investigator |
Hirota Kouji 東京都立大学, 理学研究科, 教授 (00342840)
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Project Period (FY) |
2020-04-01 – 2023-03-31
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Keywords | DNA修復 / DNA複製 / 損傷応答 / 複製フォーク反転 / カンプトテシン |
Outline of Final Research Achievements |
Ionizing radiation causes single-strand breaks associated with the terminal bound of chemical compounds. Such damages can be induced by the topoisomerase inhibitor camptothecin. We have investigated the mechanism of cellular tolerance by the proofreading exonuclease activity of polymerase epsilon to replication arrest at single-strand break sites induced by camptothecin. We identified a novel fork reversal mechanism, the CTF18-PolE pathway, which induces fork reversal at the broken template strand, and found that this pathway acts independently of the known repair pathway pathways required for the cellular tolerance to comptothecin such as homologous recombination and TDP1-mediated repair mechanism, and simultaneous loss of these pathways results in synergistic effects. Moreover, we also found that they collaborate in the inhibition of RECAQ1 by PARP1.
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Free Research Field |
分子生物学
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Academic Significance and Societal Importance of the Research Achievements |
これまで未知であった汚い断裂末端での複製フォークの反転機構を以下のように明らかにした。ポリメラーゼεの校正エキソヌクレアーゼ活性がフォーク停止に寄与し、この制御に関わるCTF18を世界で初めて同定した。CTF18-PolE経路は既知経路の相同組換えやTDP1による除去修復機構と独立に作用し、これら経路との同時欠損はシナジー効果を生むことを見出した。CTF18-PolE経路はPARP1によるRECAQ1阻害において共同する。 上記3点の発見は基礎科学として新規制のみならず、BRCA1の標的癌治療などの医学応用にもつながる重要な知見であると考えられる。
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