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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 張茂山(Mau-Sun Chang) | |
| dc.contributor.author | Chi-Fang Chang | en |
| dc.contributor.author | 張綺芳 | zh_TW |
| dc.date.accessioned | 2021-06-16T13:29:33Z | - |
| dc.date.available | 2014-08-09 | |
| dc.date.copyright | 2013-08-09 | |
| dc.date.issued | 2013 | |
| dc.date.submitted | 2013-07-22 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/62133 | - |
| dc.description.abstract | 當細胞受到游離輻射 (ionizing radiation, IR) 或基因毒性藥物處理時會發生DNA雙股斷裂情形，為了維持遺傳物質的正確性，細胞進行DNA損傷反應機制偵測不同的DNA受損型態，整合所有訊息使細胞對於DNA損傷做出反應，包括停止轉錄、調控細胞週期、進行DNA修復和促進細胞凋亡等。在先前的文獻中人類PHD and RING finger domain-containing protein 1 (PHRF1) 蛋白被報導會受到蛋白激酶ataxia telangectasia-mutated (ATM) 或ataxia telangectasia and Rad3-related (ATR) 磷酸化修飾的調控，但PHRF1真正生理功能仍舊未知。為了進一步探討PHRF1蛋白質在DNA損傷反應中所扮演的角色，分別利用紫外線 (ultraviolet light, UV) 及喜樹鹼 (camptothecin, CPT) 處理細胞，發現細胞的存活能力會因為PHRF1蛋白的表現量而有不同結果；缺少PHRF1表現的細胞比正常細胞在UV和CPT處理下引發更嚴重的細胞凋亡；相對的，PHRF1大量表現細胞在UV和CPT處理下較正常細胞的凋亡現象明顯下降，因此得知PHRF1的表現會增加細胞對於DNA傷害的耐受性。
這一個新發現激勵我們深入探討PHRF1是否參與早期DNA損傷反應， 根據目前的研究結果，排除 PHRF1參與在早期的DNA損傷反應和雙股DNA同源性重組修復的可能性，反而是藉由非同源性末端接合 (Non-homologous end joining, NHEJ) 的方式維持基因體的完整性。另外，PHRF1具有特殊可與甲基化組蛋白接合的plant homeodomain (PHD) finger domain，免疫沉澱實驗顯示PHRF1能夠辨認組蛋白H3K36me2、H3K36me3和H4K20me3甲基化修飾，因此我們提出一個假說PHRF1可能透過與組蛋白甲基化的作用去影響DNA雙股斷裂後的非同源性末端接合。 | zh_TW |
| dc.description.abstract | An effective response to damaged or abnormally replicated DNA in the mammalian cell cycle is propagated by the DNA damage checkpoint pathway. The signal transducing kinases, ataxia telangectasia-mutated (ATM), ataxia telangectasia and Rad3-related (ATR), are essential in DNA damage response. Human PHD and RING finger domain-containing protein 1 (PHRF1/KIAA1542) contains a plant homeodomain (PHD) finger, a putative methylated histone binding domain, and is identified as a phosphorylation substrate of ATM/ATR kinase. However, very little is known about its function in DNA damage response. Using different genotoxic treatments, we found that depletion of PHRF1 sensitized cells to apoptosis when cells were exposed to camptothecin (CPT) and UV light. However, PHRF1-overexpressing cells had a higher viability than control cells after genotoxic treatments.
These results prompted us to investigate whether PHRF1 is involved in early DNA damage response. However, based on our current studies, PHRF1 does not affect the formation of DNA damage foci consisted of γ-H2AX, RNF8, RNF168, and BRCA1 and the homologous recombination repair. Instead, we found PHRF1 significantly affect the efficiency of non-homologous end-joining. Furthermore, the PHD domain of PHRF1 is responsible for the association of PHRF1 with methylated histones, such as H3K36me2, H3K36me3, and H4K20me3. On the basis of my findings, PHRF1 may link methylated histones to promote non-homologous end-joining through the interaction with H3K36me2, H3K36me3, and H4K20me3, which in turn, may contribute to maintain the genome integrity. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T13:29:33Z (GMT). No. of bitstreams: 1 ntu-102-R00b46020-1.pdf: 2901283 bytes, checksum: 12078f9374886ec2c7da64fb0eb86bc3 (MD5) Previous issue date: 2013 | en |
| dc.description.tableofcontents | 中文摘要…………………………………………………………………………......Ⅰ
英文摘要……………………………………………...……………………………Ⅱ 縮寫表………………………………………………………………………………..Ⅲ 目錄…………………………………………………………………………………Ⅴ 第一章 前言…………………………………………………………………………..1 1.1 DNA損傷反應機制…………………………………………………………1 1.1.1 DNA雙股斷裂修復及其染色體重組….……………………………3 1.2組蛋白修飾………………………………………………………………….6 1.2.1組蛋白甲基化修飾…………………………………………………..6 1.2.2 PHD finger domain辨認組蛋白甲基化修飾………………………..7 1.3組蛋白H3K36甲基化修飾與轉錄活化…………………………………….8 1.4組蛋白H3K36甲基化修飾促進非同源性末端接合……………………...9 1.5 PHRF1蛋白介紹……………………………………………………………9 1.6研究動機……………………………………………………………...........10 第二章 材料與方法…………………………………………………………………12 2.1 細胞株培養與轉染………………………………………………………..12 2.2 細胞毒性處理……………………………………………………………..13 2.3 蛋白質分析法及抗體……………………………………………………..13 2.4 凋亡細胞偵測……………………………………………………………..16 2.5 免疫螢光染色………………………………………………………....…..17 2.6 免疫沉澱………………………………………………………...………...18 2.7 穩定大量表現細胞株(stable line)建立…………………………………...19 2.8 抑制蛋白表現細胞株建立...……………………………………………...19 2.9 銀離子染色…………………………….…………………………….……20 2.10 In gel digestion……………………………………………………………20 2.11 Homologous recombination assay：DR-GFP reporter……………….....21 2.12 Non-homologous end joining assay：H1299 dA3-1細胞株………….…...22 第三章 實驗結果……………………………………………………………….…...23 3.1 PHRF1蛋白質在細胞內的分布及其表現大小…………………….…….23 3.2建立PHRF1蛋白質干擾表現和大量表現的細胞株……………….…….23 3.3 PHRF1具有辨認di和tri-methyl histone H3-K36的特性………….……..24 3.4 DNA受到傷害時，PHRF1的表現程度對於細胞凋亡的影響........….…..25 3.5 PHRF1與早期DNA 損傷反應機制的關係….....................................…..27 3.6 PHRF1不影響DNA雙股斷裂時同源重組修補....………....……….……28 3.7透過LC-MS/MS尋找PHRF1可能的關聯蛋白……...…………………...29 3.8 DNA雙股斷裂時，PHRF1可能藉由非同源性末端接合促進修補…….. 30 第四章 總結與討論…………………………………………………………………31 第五章 實驗結果圖表………………………………………………………………35 圖一. PHRF1為蛋白大小約170 kDa的核蛋白………………………………35 圖二. 建立PHRF1蛋白干擾表現和大量表現的細胞株……………………..36 圖三. PHRF1可與甲基化組蛋白H3K36me2、H3K36me3和H4K20me3形成免疫沉澱複合物………………………………………………………………..37 圖四. PHRF1不與甲基化組蛋白H3K4、H3K9、H3K27作用………………...39 圖五. DNA受到傷害時，PHRF1的存在程度對細胞凋亡的影響……………40 圖六. PHRF1蛋白不影響早期DNA損傷反應………………………………..42 圖七. PHRF1不影響同源重組修補…………………………………………...44 圖八. PHRF1會影響非同源性末端接合修補………………………………...45 圖九. PHRF1與甲基化組蛋白H3K36me2、H3K36me3和H4K20me3偕同影響非同源性末端結合修補示意圖……………………………………………..46 表一. 蛋白質體學鑑定結果…………………………………………………...47 附錄…………………………………………………………………………………..49 參考文獻……………………………………………………………………………..54 | |
| dc.language.iso | zh-TW | |
| dc.subject | DNA損傷反應 | zh_TW |
| dc.subject | PHRF1 | zh_TW |
| dc.subject | DNA修復 | zh_TW |
| dc.subject | PHD finger domain | zh_TW |
| dc.subject | 甲基化組蛋白 | zh_TW |
| dc.subject | PHRF1 | en |
| dc.subject | DNA damage response | en |
| dc.subject | PHD finger domain | en |
| dc.subject | Histone H3K36 | en |
| dc.subject | DNA repair | en |
| dc.title | 探討PHRF1連接甲基化組蛋白以及影響DNA損傷反應中細胞存活能力之機制 | zh_TW |
| dc.title | PHRF1 links methylated histones and affects cell survival in response to DNA damage | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 101-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 余榮熾(Lung-Chih Yu),張震東(Geen-Dong Chang),陳宏文(Hung-Wen Chen),冀宏源(Hung-Yuan Chi) | |
| dc.subject.keyword | DNA損傷反應,PHRF1,DNA修復,PHD finger domain,甲基化組蛋白, | zh_TW |
| dc.subject.keyword | DNA damage response,PHRF1,DNA repair,PHD finger domain,Histone H3K36, | en |
| dc.relation.page | 62 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2013-07-22 | |
| 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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