三核苷酸重複序列 (TNR) 的擴增是造成許多遺傳性疾病的原因，而髮夾型二級結構的形成被認為是容易造成DNA滑動進而之擴張的主要原因。其中當d(CCG)n重複序列之重複次數超過200-900次時，將會導致染色體XE易脆症 (Fragile XE syndrome)，患有此疾病之病患將嚴重影響思維能力和認知功能。我們利用單分子螢光共振能量轉移 (Single-molecule fluorescence resonance energy transfer) 光譜學研究 d(CCG)n 重複序列之結構動力學，發現重複次數為10次以上之d(CCG)n序列會摺疊成兩種髮夾型二級結構，且之間有相互轉換之行為，且轉換頻率隨著重複次數的增加而增加，而我們鑑定出此一在高重複次數才出現的髮夾結構為髮夾莖的尾端不穩定所導致。由於針對三核苷酸重複序列髮夾結構的穩定具有預防及治療這些疾病的潛力。我們利用了單分子實驗觀察 d(CCG) 連續序列的不穩定與 d(CTG) 重複序列的滑動，分別測試了兩種DNA結合藥物，棘黴素 (Echinomycin) 與另一來自齊默爾曼 (Zimmerman) 團隊所研究之小分子化合物，結果顯示兩種化合物對連續序列的不穩定性皆具有顯著的抑制能力而推斷其具有良好的結合性，特別的是當混合使用兩種藥物時有著非常顯著的穩定作用，具有潛力開發成為三核苷酸重複序列相關疾病的潛力藥物。

Expansion of trinucleotide repeats (TNRs) was responsible for many genetic disorders, and the forming of the secondary structures such as hairpin is believed to be the major cause of the error-prone expansion. Among them, tandem d(CCG) repeats with over 200-900 units cause Fragile XE syndrome (FRAXE), which severely affect the thinking ability and cognitive functioning. We used single-molecule fluorescence resonance energy transfer (smFRET) spectroscopy to study structural dynamics of CCG repeats and apply the result to the drug testing. We found that d(CCG) repeats with over 10 units show transitions between two hairpin configurations and the frequency of transitions increase as repeat number increase. We identified that the hairpin configuration of the d(CCG) repeats of higher repeat numbers are due to the instability at the termini. Stabilizing TNR hairpin structures using small-molecule drugs may inhibit TNR slippage motions associated with error-prone gene expansion. Here, we tested two DNA binding drugs, Echinomycin and a small-molecule drug developed by the Zimmerman group, on our single-molecule assays of dCCG and dCTG repeats. Both of them showed good stabilization capabilities to the dynamical motions, hence, can be candidates for the TNR related diseases. Surprisingly, we found that the combination of these two small-molecule drugs has shown promising effects on the stabilizing the hairpin structures of tandem repeats of DNA.

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