2021 Fiscal Year Final Research Report
The mechanism of NER-dependent secondary DNA damage formation and the crucial roles of the accompanying DNA damage responses in quiescent cells
| Project/Area Number |
19K12319
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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 63020:Radiation influence-related
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| Research Institution | Kanazawa University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
松永 司 金沢大学, 薬学系, 教授 (60192340)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Keywords | ヌクレオチド除去修復 / DNA損傷応答 / 二次的DNA損傷 / DNA二本鎖切断 / ssDNAギャップ |
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| Outline of Final Research Achievements |
In quiescent cells, nucleotide excision repair (NER) process generates multiple types of secondary DNA damage. However, the mechanism of secondary DNA damage formation and their biological meanings are unclear. In this study, we have examined the possible involvement of non-homologus end joining (NHEJ) in the repair of DNA double-strand break (DSB), one of the secondary DNA damages. We found that NHEJ indeed plays an important role in NER-dependent DSB repair and protects UV-induced cell death in quiescent cells. In addition, we also showed that the secondary DNA damage causes the mutations and chromosome aberrations. Furthermore, we revealed that at least two endonucleases are required for the activation of ATM as well as DNA-PKcs in the response to NER-dependent DSB. Several endonucleases may act on ssDNA gap intermediates for producing DSBs.
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| Free Research Field |
分子細胞生物学
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| Academic Significance and Societal Importance of the Research Achievements |
従来、紫外線ではDNAにゆがみを生じる塩基損傷のみが生成し、S期以外の時期では最も重篤なDSBは生じないことが定説であった。一方で我々の実験結果は、休止期の細胞では紫外線によってもDSBが生成することを示していたが、そのメカニズムが不明であった。本研究においてその生成に関与するヌクレアーゼを同定し、そのメカニズムの一端を明らかにすることができた。また、「DNA損傷に対する防御機構であるDNA修復系が、その基質となる損傷をよりリスクの高いものに変換する」という生体特有の反応が遺伝的不安定性を引き起こす要因となりうることを示し、その修復系が重要な役割を果たしていることを実証した。
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