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研究生: 連冠豪
Lien, Kuan-Hao
論文名稱: 以單分子螢光顯微術研究C9ORF72基因中連續六核苷酸重複序列與其轉譯產物毒性聚二肽間具專一性的交互作用
Specific interactions of tandem hexanucleotide repeats in C9ORF72 and their translational toxic polydipeptide products using single-molecule Fluorescence Microscopy
指導教授: 李以仁
Lee, I-Ren
學位類別: 碩士
Master
系所名稱: 化學系
Department of Chemistry
論文出版年: 2020
畢業學年度: 108
語文別: 中文
論文頁數: 60
中文關鍵詞: 肌萎縮性脊髓側索硬化症額顳葉失智症C9ORF72重複序列關聯非AUG轉譯單分子螢光共振能量轉移毒性聚二肽
英文關鍵詞: amyotrophic lateral sclerosis, frontotemporal dementia, C9ORF72, repeat-associated non-AUG translation, smFRET, toxic dipeptide repeats
DOI URL: http://doi.org/10.6345/NTNU202001567
論文種類: 學術論文
相關次數: 點閱:123下載:0
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  • 人類第九對染色體第72閱讀框架(C9ORF72)內含子中的GGGGCC六核苷酸序列重複擴增是最常見導致肌萎縮性脊髓側索硬化症(Amyotrophic lateral sclerosis, ALS)與額顳葉失智症(Frontotemporal dementia, FTD)的原因,正常個體中通常只具有2~23個GGGGCC重複擴增,而此二種疾病的患者卻具有上千個GGGGCC重複擴增。此類重複序列常引起重複序列關聯非AUG轉譯(Repeat associated non-AUG translation, RAN translation),可在缺少AUG起始密碼子的情況下,由有義股與反義股的全部閱讀框架轉譯出聚二肽產物。由於在無AUG啟始密碼子下易發生框架轉移(Frameshifting),因此GGGGCC可轉譯出(GA)、(GP)、(GR)三種聚二肽,而其反義股亦可轉譯出(PA)、(PR)、(GP)三種聚二肽。聚二肽中若含精氨酸(R)的具有生物毒性,為毒性聚二肽,且(GR)與(PR)皆可藉由精氨酸殘基穿透細胞膜。外源添加的(GR)、(PR)毒性聚二肽可被培養細胞吸收,引起RNA轉錄過程產生缺陷,進而導致細胞凋亡。亦有證據顯示(GR)、(PR)可進入細胞核與DNA作用造成DNA損傷。因此瞭解此二種聚二肽分子與其編碼股的交互作用成為重要的議題。
    本實驗室先前研究利用單分子螢光能量共振轉移光譜發現poly-GR可使其編碼股(GGGGCC)3形成的髮夾結構在初加入時瞬間部分解開。在本論文中我們藉由單分子螢光能量共振轉移技術發現poly-PR亦可導致其編碼股CCCCGG形成的髮夾結構瞬間部分解開,此二交互作用皆具有DNA序列專一性。為了瞭解poly-GR與(GGGGCC)3發生何種交互作用,我們利用螢光標記的(GR)25即時觀測其交互作用。我們發現螢光標記的(GR)25立即與(GGGGCC)3結合,且在數十分鐘後觀察到高亮度的螢光聚集。而由時間解析圖譜中發現總螢光強度呈階梯狀上升,發現poly-GR具特異性地聚集在(GGGGCC)3上。

    關鍵字:肌萎縮性脊髓側索硬化症、額顳葉失智症、C9ORF72、重複序列關聯非AUG轉譯、單分子螢光共振能量轉移、毒性聚二肽

    Expansion of a hexanucleotide repeat GGGGCC in an intron of chromosome 9 open reading frame 72 (C9ORF72) often causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In the C9ORF72 gene of healthy individuals, the repeat number mostly falls in between 2 and 23, while in patients sample, the repeat number goes over hundreds and even reaches thousands. Tandem DNA repeats often cause repeat-associated non-AUG (RAN) translations and produces polydipeptide repeats in the absence of an AUG start codon for both sense and antisense transcripts. Frameshifting is prone to occur during the translation in the absence of the AUG start codon and leads to translation into various polydipeptide products: GA, GP, and GR for the sense GGGGCC and PA, PR, GP for the antisense. Among them, polydipeptides containing arginine (R), poly-GR and poly-PR, carry cytotoxicity, as well as the membrane penetration capability. Exogenously added GR and PR polydipeptides can be recruited into cultured cells and induces defects in the RNA transcription process, and ultimately leads to cell apoptosis. Recently, interactions between these polydipeptides and DNA in the nucleus that lead to DNA damage have been reported. It becomes an important issue to understand the interactions between these polydipeptides and their corresponding coding nucleic acid sequences.
    Previously, our group reported that poly-GR transiently and partially opens the hairpin structure formed by its coding strand d(GGGGCC)3 by using single-molecule fluorescence energy resonance transfer (smFRET) spectroscopy. In this work, we found that poly-PR shows similar behavior when added to the hairpin formed by its coding strand d(CCCCGG)3. Both interactions show strong DNA sequence specificity. In order to further study the interactions between poly-GR and d(GGGGCC)3, we used fluorescent-labeled (GR)25 to follow the interaction dynamics in real-time. We found that the fluorescent-labeled (GR)25 immediately bound to d(GGGGCC)3. High-intensity fluorescence clusters were observed after tens of minutes. From the time-dependent fluorescence traces, we found that the total fluorescence intensity rose stepwise, which provided further evidence of the aggregation of poly-GR specifically on d(GGGGCC)3 hairpins.

    Keywords:amyotrophic lateral sclerosis, frontotemporal dementia, C9ORF72, repeat-associated non-AUG translation, smFRET, toxic dipeptide repeats

    摘要 i Abstract ii 目錄 iii 圖目錄 vi 表目錄 ix 第一章、緒論 1 1.1 肌萎縮性脊髓側索硬化症及額顳葉失智症與人類第九對染色體的變異 1 1.2 重複序列關聯非AUG轉譯 1 1.3 聚二肽對細胞之影響 3 1.3.1 聚二肽於病患組織之分佈 3 1.3.2 聚二肽之生物毒性 4 1.3.3 毒性聚二肽具細胞穿透性 4 1.3.4 毒性聚二肽誘發DNA破損 6 1.4 毒性聚二肽與其上游DNA交互作用之研究動機 6 第二章、實驗方法與儀器構造 8 2.1 實驗儀器與原理 8 2.1.1 單分子實驗技術 8 2.1.2 全內反射螢光顯微鏡 11 2.2 實驗器材與樣品製備 13 (一)載玻片與蓋玻片清洗 13 (二)載玻片與蓋玻片表面修飾 14 (三)組裝實驗玻片流道 15 2.3 DNA設計 15 (一)實驗股序列 15 (二)互補股序列 15 (三)螢光基團標記DNA 16 (四)互補股與實驗股黏合 17 (五)(GR)25C-Cy3交聯反應 18 2.4 成像緩衝液 19 (一)三重態淬滅劑 19 (二)酵素型除氧系統 19 2.5 實驗方法與數據處理 20 (一)將DNA分子固定於玻片表面 20 (二)以全內反射式顯微鏡觀測實驗樣本 21 (三)實驗數據分析 22 第三章、實驗結果與討論 26 3.1 毒性聚二肽與DNA交互作用之實驗架構 26 3.1.1 (GR30)與其編碼股d(GGGGCC)3之交互作用 27 3.1.2 (GR30)與非其編碼股之交互作用 28 3.1.3 (PR)30與其編碼股d(CCCCGG)3與之交互作用 31 3.1.4 (PR)30與非其編碼股之交互作用 33 3.2 排除酵素系統的可能影響 38 3.2.1 中性卵白素空白反應槽實驗 38 3.2.2 (GGGGCC)3反應槽實驗 39 3.3 (GR)25C-Cy3單分子實驗 40 3.3.1 實驗架構 40 3.3.2 (GR)25C-Cy3專一性測試與實驗結果 41 3.3.3 (GR)25C-Cy3聚集之時間解析 49 3.4總結 54 第四章、結論與未來展望 55 參考文獻 57

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