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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 蔡明道(Ming-Daw Tsai) | |
dc.contributor.author | Hsiang-Chun Su | en |
dc.contributor.author | 蘇香君 | zh_TW |
dc.date.accessioned | 2021-06-17T04:38:20Z | - |
dc.date.available | 2024-08-01 | |
dc.date.copyright | 2020-08-28 | |
dc.date.issued | 2020 | |
dc.date.submitted | 2020-08-20 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/70783 | - |
dc.description.abstract | DNA損傷反應(DDR)是藉由傳遞DNA雙股斷裂(DSB)訊號來調控DNA修復、細胞週期停滯和細胞凋亡等細胞機制以維持基因組穩定性。哺乳類動物DDR途徑是由Mre11-NBS1-Rad50(MRN complex)複合蛋白所啟動,用以辨識斷裂的DNA末端並激活ATM,活化的ATM使組蛋白H2AX磷酸化(H2AX)。以DNA損傷檢查點的媒介蛋白MDC1充當訊號樞紐,通過串聯的BRCT來擷取H2AX信號,並通過磷酸化的SDTD片段放大MRN-ATM訊號。DDR訊號若是傳遞失敗可能會導致增加輻射和放射模擬藥物所誘導的殺傷力,因此可作為癌症治療中的有效治療目標。 在這項研究中,我們的目的在於探討DDR途徑中的多種蛋白質-蛋白質之間的相互作用是否能作為癌症治療的潛在標靶。我們的研究結果顯示,異位表達的MDC1(MDC1-SDTD)的磷酸化SDTD片段增強了癌細胞對X射線照射的敏感性。從機制上講,MDC1-SDTD干擾了MRN信號傳遞,導致延遲了H2AX和ATM聚集點的形成並延長了聚集點存在的時間,隨後在X射線照射下導致了G1檢查點的細胞週期停滯。進一步的分析還表明,MDC1-SDTD不僅減弱了DSB誘導的MDC1聚集,甚至也減弱了非同源末端連接因子Ku70/80的聚集,從而導致在DSB時染色體畸變增加,DSB修復受到阻礙,染色質過早鬆弛和細胞凋亡增強。整體來說,我們的研究結果顯示MDC1-SDTD是未來癌症治療的潛在藥物標靶。 | zh_TW |
dc.description.abstract | DNA damage response (DDR) maintains genomic stability by transducing signals of DNA double-strand break (DSB) to cellular machineries including DNA repair, cell cycle checkpoint, and apoptosis. Mammalian DDR pathway is initiated by the Mre11-NBS1-Rad50 (MRN) sensor complex to recognize broken DNA ends and activate ATM for the phosphorylation of histone H2AX (H2AX). The mediator of damage checkpoint MDC1 functions as a signaling hub to mediate the signal of H2AX through the interaction between tandem BRCT domains of MDC1 and H2AX, which subsequently amplifies the MRN-ATM signal through the interaction between phosphorylated SDTD motif and NBS1. Failure in transmitting the DDR signaling may cause radiation- and radiomimetic drug-induced cell death which seems a potent therapeutic target in cancer management. In this study, we aim to examine such potency by targeting multiple protein-protein interactions in DDR pathway. Our results showed that ectopic expression of the phosphorylated SDTD motif of MDC1 (MDC1-SDTD) enhanced cell sensitivity to x-ray irradiation in cancer cells. Mechanistically, MDC1-SDTD interfered with MRN signaling upon x-ray irradiation, which led to the delayed formation and prolonged resolution of H2AX and ATM foci, and subsequently caused the arrested cell cycle progression at G1 checkpoint. Further analyses also indicate that MDC1-SDTD not only attenuated the DSB-induced recruitment of MDC1 but also non-homologous end-joining factors Ku70/80, which results in chromosomal aberration, impaired DSB repair, premature chromatin relaxation, and cell apoptosis. These results collectively suggest that MDC1-SDTD is a potential drug target for cancer therapy. | en |
dc.description.provenance | Made available in DSpace on 2021-06-17T04:38:20Z (GMT). No. of bitstreams: 1 U0001-2008202015563700.pdf: 19412664 bytes, checksum: b76b087a03b161c8483f53894220f8ed (MD5) Previous issue date: 2020 | en |
dc.description.tableofcontents | Contents 中文摘要 I ABSTRACT IV ABBREVIATIONS VI CHAPTER 1. RESEARCH BACKGROUND 1 1.1. Overview of mammalian DNA damage response (DDR) 1 1.1.1. DNA damage 1 1.1.2. DDR pathway 3 1.1.3. Types of DNA damage and corresponding repair pathways 10 1.1.4. Cell cycle progression upon DNA damage 14 1.1.5. Chromatin relaxation (de-condensation) during DDR 15 1.2. Protein phosphorylation in the assembly of DDR complexes 16 1.2.1. Functional Mediator MDC1 in DDR 17 1.2.1.1. MDC1 N-terminal FHA domain 18 1.2.1.2. MDC1 C-terminal tandem BRCT domain 19 1.2.1.3. MDC1-SDTD repeats 19 1.2.2. Regulations of H2AX and γH2AX 20 1.2.3. Functions of MRN complex 20 1.2.4. Functions of ATM, CtIP, TopBP1, CHK2 and Ku70/80 22 1.3. Radiotherapy 23 1.4. Anti-cancer drugs induced DDR triggering apoptosis 24 CHAPTER 2. CHARACTERIZATIO OF MDC1-SDTD REPEATS FOR TARGETING DNA DAMAGE RESPONSE AND ENHANCING RADIOSENSITIZATION IN CANCER CELL LINES. 26 2.1. Materials and Methods 26 2.1.1. Cell cultures 26 2.1.2. Plasmid DNA transfection 26 2.1.3. Preparation of retrovirus based stable lines 26 2.1.4. Antibodies 27 2.1.5. Preparation of cell extract and Western blot 27 2.1.6. Clonogenic survival assay 27 2.1.7. Cell cycle assay and flow cytometry 28 2.1.8. WST-1 assay 28 2.1.9. Analyses of apoptosis and flow cytometry 29 2.1.10. Generation of DSBs by X-ray 29 2.1.11. Chemotherapy drug treatment 29 2.1.12. Laser micro-irradiation 30 2.1.13. Cell proliferation assay 30 2.1.14. Immunofluorescence assay 30 2.1.15. Immunoprecipitation 31 2.1.16. Comet assay 32 2.1.17. Karyotype analysis 32 2.1.18. In-gel digestion of MDC1-SDTD proteins for MS analysis 33 2.1.19. Mass Spectrometric Analysis and Data Processing 33 2.1.20. Statistics analysis 35 2.2. Results 36 2.2.1. Targeting protein-protein interaction (PPI) in DDR pathway sensitizes cancer cells to IR 36 2.2.2. Mass spectrometry validates constitutive phosphorylation sites of MDC1-SDTD 46 2.2.3. MDC1-SDTD interferes with the binding between NBS1 and MDC1 48 2.2.4. Ectopic expression of MDC1-SDTD obstructs DSB-induced DDR pathway 52 2.2.5. MDC1-SDTD prevents protein recruitment of MDC1 and Ku70/80 to damaged chromatin 57 2.2.6. MDC1-SDTD confers chromosome instability by incurring perturbation of DNA repair and chromatin remodeling 63 2.2.7. MDC1-SDTD alters damage-induced cell cycle checkpoints 69 2.2.8. MDC1-SDTD enhanced DNA damage-induced apoptosis 72 2.3. Discussion 77 2.3.1. Therapeutic targeting of protein-protein interactions (PPI) in treating diseases 77 2.3.2. The delayed formation of γH2AX foci formation caused by the recruitment of and MDC1 competition with MDC1-SDTD 78 2.3.3. The prolonged resolution of γH2AX foci formation and the recruitment/MDC1 competition of MDC1-SDTD 79 2.3.4. An unexpected perturbation of cell cycle checkpoints by MDC1-SDTD. 80 2.3.5. MDC1-SDTD confers synthetic lethality by sensitizing tumor cells to IR and DNA damage-based chemotherapy 81 REFERENCES 83 APPENDIX 101 | |
dc.language.iso | en | |
dc.title | 檢查點媒介蛋白MDC1磷酸化之SDTD基序靶定DNA損傷反應之抗癌特性分析 | zh_TW |
dc.title | Characterization of MDC1 pSDpTD motif in targeting DNA damage response pathway for anticancer therapy | en |
dc.type | Thesis | |
dc.date.schoolyear | 108-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 譚婉玉(Woan-Yuh Tarn),張茂山(Mau-Sun Chang),冀宏源(Hung-Yuan Chi),廖泓鈞(Hung-Jiun Liaw) | |
dc.subject.keyword | MDC1,SDTD,NBS1,DNA損傷反應,放射療法, | zh_TW |
dc.subject.keyword | MDC1,SDTD,NBS1,DNA damage response,Radiotherapy, | en |
dc.relation.page | 114 | |
dc.identifier.doi | 10.6342/NTU202004143 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2020-08-21 | |
dc.contributor.author-college | 生命科學院 | zh_TW |
dc.contributor.author-dept | 生化科學研究所 | zh_TW |
顯示於系所單位: | 生化科學研究所 |
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