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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 冀宏源 | |
| dc.contributor.author | Chih-Ying Lee | en |
| dc.contributor.author | 李致瑩 | zh_TW |
| dc.date.accessioned | 2021-06-17T04:28:59Z | - |
| dc.date.available | 2023-08-21 | |
| dc.date.copyright | 2018-08-21 | |
| dc.date.issued | 2018 | |
| dc.date.submitted | 2018-08-13 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/70474 | - |
| dc.description.abstract | 存在細胞中的小分子是如何影響DNA基因體的完整性，一直是研究癌症生物學裡很有趣的課題。和正常細胞相比，多胺小分子在許多種類的癌細胞裡會被大量製造，來維持癌細胞的存活及快速增生，使得多胺小分子被認為影響腫瘤發展的過程。在此博士論文裡，我們團隊證明了多胺尚未被研究發現的新穎功能：參與雙股DNA斷裂修補機制。並且我們的研究結果顯示，多胺只會專一性的促進同源重組反應(homologous recombination)所催化的DNA雙股斷裂修補，而不影響DNA雙股斷裂修補中的另一種修補機制：非同源重組端接合(non-homologous DNA end-joining)。藉由生化特性分析，證明了多胺可大幅刺激同源重組酶(recombinase) RAD51蛋白的DNA股交換活性，更進一步研究顯示，此刺激機轉源自於多胺分子可提高同源重組酶RAD51蛋白在進行同源搜尋(homology search)尋找同源的修補模板DNA時，增加其捕獲雙股DNA的碰撞反應，而利用了動物實驗分析，我們也證明了多胺分子在活體細胞內對於DNA雙股斷裂的修補扮演著重要的角色。我們的研究經由深入探討後提供了一重要的發現：多胺分子可利用調控同源重組修補反應來維持基因體的穩定性。 | zh_TW |
| dc.description.abstract | How naturally occurring cellular small chemicals impact upon genome integrity is of great interests in cancer biology. Many cancers synthesize elevated levels of polyamines to sustain cell growth and proliferation, thus implicating these compounds in tumorigenesis. Here, we document a novel function of polyamines in DNA double-strand break (DSB) repair. Specifically, we show that polyamines facilitate homologous recombination-mediated DSB repair without affecting non-homologous DNA end-joining. Biochemical reconstitution and functional analyses demonstrate that polyamines significantly enhance the DNA strand exchange activity of RAD51. The stimulatory effect of polyamines by RAD51 stems from the enhancement of duplex DNA capture in the DNA homology search process. We also reveal the importance of polyamines to DSB repair in an animal model. Our findings thus furnish valuable insights into the role of polyamines in genome maintenance via homology-directed DNA repair. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T04:28:59Z (GMT). No. of bitstreams: 1 ntu-107-F01b46001-1.pdf: 4391344 bytes, checksum: fd9d5b275a4a5b9c0564cd7d8fd81fc1 (MD5) Previous issue date: 2018 | en |
| dc.description.tableofcontents | 論文口試委員會審訂書 1
誌謝 2 中文摘要 3 ABSTRACT 4 CHAPTER 1: INTRODUCTION 8 1-1 Role of polyamines in cells 8 1-2 Polyamines and cancer 9 1-3 DNA double-strand break repair 10 1-4 Homologous recombination 11 1-5 Aim of the study 13 CHAPTER 2: MATERIALS AND METHODS 14 2-1 Cell culture and reagents 14 2-2 Plasmids 14 2-3 Plasmid and siRNA transfection 15 2-4 Comet assay 15 2-5 Cell-cycle analysis 16 2-6 Measurement of intracellular polyamines 16 2-7 Homologous recombination assay 18 2-8 Non-homologous end-joining assay 19 2-9 Antibodies 19 2-10 Immunoblotting analysis 20 2-11 Immunofluorescence staining 21 2-12 Cell viability Assay 22 2-13 DNA substrates 22 2-14 Recombinant proteins 24 2-15 DNA stand exchange assay 24 2-16 D-loop assay 25 2-17 Exonuclease I protection assay 25 2-18 Duplex DNA capture assay 26 2-19 Synaptic complex assay 27 2-20 Animals 28 2-21 Statistics 29 CHAPTER 3: RESULTS 30 3-1 DSB repair requires polyamines 30 3-2 Polyamines regulate HR efficiency 30 3-3 Polyamines influence RAD51 activity 32 3-4 Polyamines enhance DNA strand exchange 32 3-5 Polyamines promote dsDNA capture by RAD51 33 3-6 Synthetic polyamine analogs lack activity 36 3-7 Implication for polyamines function in DSB repair in vivo 36 CHAPTER 4: DISCUSSION 38 4-1 Conclusion 38 4-2 The role of polyamines in DNA damage response 39 4-3 The distinct function of polyamines from BRCA2 40 4-4 Polyamines facilitate duplex DNA capture and homology search during homologous recombination 42 4-5 The specific action of polyamines in DNA repair 43 4-6 Future directions 44 FIGURES 46 REFERENCE 69 | |
| dc.language.iso | en | |
| dc.title | 多胺參與DNA雙股斷裂修復中的作用機制 | zh_TW |
| dc.title | The mechanistic role of polyamines in DNA double-strand break repair | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 106-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 張智芬,詹迺立,林頌然,郭靜穎 | |
| dc.subject.keyword | 同源重組,DNA 雙股斷裂修補,多胺,同源搜尋, | zh_TW |
| dc.subject.keyword | Homologous recombination,DNA double-strand break repair,Polyamines,Homology search, | en |
| dc.relation.page | 74 | |
| dc.identifier.doi | 10.6342/NTU201803192 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2018-08-13 | |
| 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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