川陳皮素(Nobiletin)為柑橘類果皮中含多甲基的酚類物質，目前已知其具有廣泛的生理活性，包括抗發炎及抗癌等。先前有研究指出由於川陳皮素的外圍含多個甲基，因此與一般常見富含氫氧基的酚類物質在生物體中的吸收與代謝途徑有所不同。此外，研究也證實川陳皮素經過生物體內代謝，會將其環上特定位置的甲基由氫氧基置換，產生去除單甲基或雙甲基的代謝物，而此置換的物質可能存在於生物體中作為某些功能使用。根據先前的研究顯示富含甲基的飲食，例如葉酸，可調節生物體中DNA或組蛋白的甲基化程度，而此種甲基化的調節可影響DNA受損後的修復途徑。因此，我們主要探討川陳皮素在UVB照射後的酵母菌中，對酵母菌DNA受損反應的影響。結果發現川陳皮素的添加會增加DNA受損指標γH2A的表現量，也會增加細胞週期檢查點蛋白Rad53的活化。而在細胞週期方面，川陳皮素的添加會使得細胞週期停滯在S期。組蛋白甲基化方面，川陳皮素的添加反而降低了H3K79三甲基化、對H3K4三甲基化無顯著影響並增加了H3K9乙醯化的程度。而在細胞內自由基表現量方面則沒有顯著差異。根據我們的研究，川陳皮素的添加會藉由增加γH2A的表現量進而活化檢查點蛋白Rad53，並使酵母菌停留在細胞週期的S期，使受損細胞DNA修復，最後達到增加酵母菌存活率的影響。

Nobiletin is a dietary phytochemical belonging to polymethoxy flavonoids from the peels of citrus fruits. It has a distinct metabolic feature compared to polyhydroxyflavonoids due to its high bioavailability. Nobiletin is shown to have health beneficial properties, including anti-inflammatory and anti-carcinogenic activities. We investigate how nobiletin affects DNA damage response after UVB treatment in unicellular model organism, baker’s yeast. The results show that nobiletin increases cell survival after UVB damage. UVB treatment induces histone H2A phosphorylation, a marker for DNA damage. The addition of nobiletin can increase both the phosphorylation levels of H2A and phosphotylation levels of Rad53, which is a DNA damage checkpoint protein, after UVB treatment. In the aspects of histone modification, nobiletin has no significant effect on H3K4 trimethylation and it reduces H3K79 trimethylation. Besides, nobiletin increases H3K9 acetylation, which represented that nobiletin promote cell arrest in cell cycle S phase. Furthermore, the addition of nobiletin also has no significant effect on reactive oxygen species (ROS) production after UVB treatment. Our results suggest nobiletin treatment increases the sensitivity of yeast cell to UV damage, promote cell cycle arrest and may facilitate cells to recruit repair proteins to DNA damage sites, thus, influence cell survival.

謝誌 .............................................................................................................................. i
摘要 ............................................................................................................................ iii
Abstract ...................................................................................................................... iv
目錄 ............................................................................................................................. v
圖目錄 ...................................................................................................................... viii
表目錄 ......................................................................................................................... x
第一章、 前言........................................................................................................ 1
第二章、 文獻整理................................................................................................ 2
第一節 多甲基的酚類物質--川陳皮素Nobiletin ......................................... 2
第二節 酵母菌 Saccharomyces cerevisiae、budding yeast為一探討真核生物的實驗模式........................................................................................................ 6
一、 酵母菌與哺乳動物在細胞週期調控蛋白上的相似性................ 7
二、 酵母菌用以探討部分癌症發生可能的調控機制........................ 8
三、 酵母菌用於神經疾病發生之研究................................................ 9
第三節 紫外線照射所引起生物體受損反應.............................................. 11
第四節 DNA修復方式 ................................................................................. 13
一、 非同源黏合系統 (Non-homologous end joining, NHEJ) .......... 13
二、 同源重組修復系統(Homologous recombination, HR)............... 14
三、 鹼基切除修復 (Base-excision repair, BER) .............................. 16
四、 核苷酸切除修復系統 (Nucleotide-excision repair, NER) ........ 16
五、 錯誤配對修復 (Mismatch repair, MMR) ................................... 16
六、 複製後修復 (Postreplication repair, PRR) ................................. 16
七、 股內連結修復 (Interstrand crosslink repair) .............................. 17
第五節 組蛋白修飾作用與調控DNA修復有關 ........................................ 18
一、 磷酸化 (phosphorylation)： ....................................................... 21
二、 乙醯化 (acetylation)： ............................................................... 22
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三、 類泛素化 (Ubiquitination).......................................................... 23
四、 甲基化 (Methylation) ................................................................. 24
第六節 酵母菌細胞週期yeast cell cycle的進程及調控蛋白細胞週期素 29
第七節 細胞週期檢查點蛋白的功能及調控DNA修復的機制細胞週期檢查點蛋白Rad53 .................................................................................................. 34
第三章、 材料方法.............................................................................................. 38
第一節 實驗方法與材料.............................................................................. 38
一、 酵母種類...................................................................................... 38
二、 培養方式...................................................................................... 38
三、 細胞生長曲線.............................................................................. 39
四、 西方點墨法.................................................................................. 39
五、 細胞週期...................................................................................... 46
六、 自由基測試.................................................................................. 47
第二節 實驗儀器.......................................................................................... 48
第三節 實驗架構.......................................................................................... 49
第四章、 結果與討論.......................................................................................... 50
第一節 川陳皮素可增加酵母菌經紫外線照射後的細胞存活率.............. 50
第二節 川陳皮素不影響酵母菌的正常生長.............................................. 52
第三節 紫外線處理後γH2A表現量的影響 .............................................. 53
一、 紫外線UVC照射增加γH2A的表現量 .................................. 53
二、 不同紫外線的照射對γH2A產生量的影響。 ......................... 55
三、 川陳皮素影響γH2A的表現量 ................................................. 57
四、 川陳皮素增加DNA損害訊號gammaH2A的表現量 ............... 59
第四節 川陳皮素對紫外線照射後的反應氧屬產生量無顯著影響.......... 63
第五節 川陳皮素對H3K4三甲基化程度沒有顯著影響 ........................... 65
第六節 川陳皮素降低H3K79三甲基化的表現程度 ................................. 68
第七節 川陳皮素增加細胞週期檢查點蛋白Rad53的磷酸化程度 ......... 71
第八節 川陳皮素促使正常細胞在紫外線照射後停滯在細胞週期S期 .. 74
第九節 川陳皮素增加正常細胞在紫外線照射後H3K9乙醯化程度 ....... 77
第五章、 參考文獻.............................................................................................. 83
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附件一、補充資料…………………………………………………………………………………………94
附件二、paper (draft)……….………..………………………………………………………………..96

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