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FANCD2 counteracts O6-methylguanine-induced mismatch repair-dependent apoptosis
https://fdc.repo.nii.ac.jp/records/2000115
https://fdc.repo.nii.ac.jp/records/20001154c0aed3d-fcc3-4b8f-9f97-b8023f75845a
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甲第353号_論文審査結果の要旨(森田祥).pdf (219 KB)
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甲第353号_論文内容の要旨(森田祥).pdf (140 KB)
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甲第353号_論文(森田祥).pdf (2.5 MB)
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| Item type | 学位論文 / Thesis or Dissertation(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2024-11-18 | |||||
| タイトル | ||||||
| タイトル | FANCD2 counteracts O6-methylguanine-induced mismatch repair-dependent apoptosis | |||||
| 言語 | en | |||||
| 言語 | ||||||
| 言語 | eng | |||||
| キーワード | ||||||
| 言語 | en | |||||
| 主題Scheme | Other | |||||
| 主題 | Mismatch repair | |||||
| キーワード | ||||||
| 言語 | en | |||||
| 主題Scheme | MeSH | |||||
| 主題 | Fanconi anemia | |||||
| キーワード | ||||||
| 言語 | en | |||||
| 主題Scheme | Other | |||||
| 主題 | DNA damage response | |||||
| キーワード | ||||||
| 言語 | en | |||||
| 主題Scheme | MeSH | |||||
| 主題 | Apoptosis | |||||
| キーワード | ||||||
| 言語 | en | |||||
| 主題Scheme | Other | |||||
| 主題 | Alkylating agent | |||||
| 資源タイプ | ||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_db06 | |||||
| 資源タイプ | doctoral thesis | |||||
| アクセス権 | ||||||
| アクセス権 | open access | |||||
| アクセス権URI | http://purl.org/coar/access_right/c_abf2 | |||||
| 著者 |
森田, 祥
× 森田, 祥× 藤兼, 亮輔× 上地, 有香× 松浦, 尚志× 日髙, 真純 |
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| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | Background: Sn1-type alkylating agents methylate the oxygen atom on guanine bases thereby producing O6-methylguanine. This modified base could pair with thymine and cytosine, resulting in the formation of O6-methylguanine/thymine mismatch during DNA replication, recognized by the mismatch repair (MMR) complex, which then initiates the DNA damage response and subsequent apoptotic processes. In our investigation of the molecular mechanisms underlying MMR-dependent apoptosis, we observed FANCD2 modification upon the activity of alkylating agent N-methyl-N-nitrosourea (MNU). This observation led us to hypothesize a relevant role for FANCD2 in the apoptosis induction process. Methods and results: We generated FANCD2 knockout cells using the CRISPR/Cas9 method in the human cervical cancer cell line HeLa MR. FANCD2-deficient cells exhibited MNU hypersensitivity. Upon MNU exposure, FANCD2 colocalized with the MMR complex. MNU-treated FANCD2 knockout cells displayed severe S phase delay followed by increased G2/M arrest and MMR-dependent apoptotic cell death. Moreover, FANCD2 knockout cells exhibited impaired CtIP and RAD51 recruitment to the damaged chromatin and DNA double-strand break accumulation, indicated by simultaneously observed increased γH2AX signal and 53BP1 foci. Conclusions: Our data suggest that FANCD2 is crucial for recruiting homologous recombination factors to the sites of the MMR-dependent replication stress to resolve the arrested replication fork and counteract O6-methylguanine-triggered MMR-dependent apoptosis. |
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| 言語 | en | |||||
| 学位名 | ||||||
| 言語 | ja | |||||
| 学位名 | 博士（歯学） | |||||
| 学位授与大学 | ||||||
| 学位授与機関識別子Scheme | kakenhi | |||||
| 学位授与機関識別子 | 37114 | |||||
| 言語 | ja | |||||
| 学位授与機関名 | 福岡歯科大学 | |||||
| 学位授与年度 | ||||||
| 内容記述 | 2024年度 | |||||
| 言語 | ja | |||||
| 学位授与年月日 | ||||||
| 学位授与年月日 | 2024-07-30 | |||||
| 報告番号 | ||||||
| 学位授与番号 | 甲第353号 | |||||
| 情報源 | ||||||
| 識別子タイプ | DOI | |||||
| 関連識別子 | https://doi.org/10.1007/s11033-024-09682-4 | |||||
| 言語 | en | |||||
| 関連名称 | Springer Nature | |||||
| 著者版フラグ | ||||||
| 出版タイプ | VoR | |||||
| 出版タイプResource | http://purl.org/coar/version/c_970fb48d4fbd8a85 | |||||
