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系統識別號 U0026-1508201621055100
論文名稱(中文) 乙醯轉移酶和甲基轉移酶SETD2以及SETMAR調控同源性重組修復之功能探討
論文名稱(英文) The function of histone acetyltransferase MORF and methyltransferases, SETD2 and SETMAR, in regulation of Homologous Recombination repair
校院名稱 成功大學
系所名稱(中) 生命科學系
系所名稱(英) Department of Life Sciences
學年度 104
學期 2
出版年 105
研究生(中文) 張佑慈
研究生(英文) Yu-Tzu Chang
學號 L56034104
學位類別 碩士
語文別 中文
論文頁數 64頁
口試委員 指導教授-廖泓鈞
口試委員-蘇文彬
口試委員-張松彬
口試委員-顏賢章
中文關鍵字 順鉑抗藥性  DNA修復路徑  MORF  組蛋白乙醯轉移酶  SETD2  SETMAR  組蛋白甲基轉移酶  姊妹染色分體互換  染色質免疫沉澱  轉錄因子  染色質重新塑造 
英文關鍵字 Cisplatin  drug resistance  DNA repair pathway  MORF  histone acetyl transferase  SETD2  SETMAR  histone methyltransferase  sister chromatid exchange  chromatin immunoprecipitation  transcription factor  chromatin remodeling 
學科別分類
中文摘要   順鉑是重要的化學治療藥劑之一,廣泛的使用在治療卵巢癌,子宮頸癌,頭頸癌,和非小細胞肺癌。然而,長期的順鉑藥物治療,往往會使癌細胞對順鉑藥物產生抗藥性。我們先前的研究指出, DNA修復途徑的活化與抗藥性生成有關。組蛋白修飾酶包含組蛋白乙醯轉移酶與組蛋白甲基轉移酶,不僅在調控基因轉錄上扮演很重要的角色,在DNA的修復上也扮演很重要的角色。我們假設鼻咽癌細胞在長期以順鉑化療治療後,會使其染色質重新塑造,使其產生抗藥性的性狀。而其染色質重新塑造是經由組蛋白乙醯轉移酶與組蛋白甲基轉移酶來達成。
  MORF是MYST家族成員之一,具有乙醯轉移酶特性且有調控轉錄的功能,會與BRPF1/2/3、ING5、hEAF6形成複合體。我們先前的研究已經證實,降低乙醯轉移酶MORF基因表現會使鼻咽癌細胞HONE6對順鉑藥物的抗藥性上升。在乙醯轉移酶MORF基因上,分別利用shRNA與siRNA抑制MORF在具有順鉑抗藥性的鼻咽癌細胞株(Hone6)表現後,發現在FA修復路徑與PRR和HR修復路徑上相關蛋白表現,其蛋白表現量也有所降低。在染色質免疫沉澱(Chromatin immunoprecipitation, ChIP)實驗中也發現,MORF會結合到FA以及HR之關鍵蛋白BRCA1以及FANCD2的啟動子上。SETD2與SETMAR是組蛋白甲基化轉移酶,可以甲基化H3K4與H3K36這兩個MORF複合體所會辨識並結合的位點。在我們先前研究中發現這兩個基因在具有抗藥性的細胞株有高量表現的情形。本篇研究發現,分別將具有順鉑抗藥性的鼻咽癌細胞株(Hone6)之SETD2與SETMAR基因抑制後,細胞對於順鉑藥物之敏感性有所提升,范可尼貧血修復、後複製修復和同源重組修復路徑上相關蛋白的mRNA與蛋白表現量皆有所降低,且其及姊妹染色分體互換率(Sister chromatid exchange, SCE)有降低的現象。綜合以上實驗結果推測,MORF,SETD2與SETMAR可能扮演了轉錄因子的角色,SETD2與SETMAR可能藉由甲基化H3K4與H3K36影響MORF複合體結合到DNA修復路徑相關基因的啟動子上,調控其基因表現量,活化DNA修復途徑,使癌細胞提高對順鉑藥物的抗藥性。以上實驗結果,或許能為具有順鉑抗藥性的癌症之治療上提供一個方向。
英文摘要 Cisplatin is a chemotherapeutic agent, commonly used to treat solid tumors. However, the major obstacle for the efficacy of the treatment is cisplatin resistance. Our recent study demonstrates that the activation of DNA repair pathway can contribute to the cisplatin resistant phenotype of nasopharyngeal carcinoma cells (NPC). Since histone modification and chromatin remodeling play an important role in regulation of gene expression, we hypothesize that chromatin could be remodeled to confer cancer cells the drug resistant phenotype. MORF is a histone acetyltransferase that specifically acetylates histone H3. The MORF complex contains several domains that can interact with methylated H3K4 and H3K36 specifically. SETD2 and SETMAR are histone methyltransferases that specifically methylate H3K4 and H3K36. Here we demonstrate depletion of MORF can reduce the expression of several genes in the FA, HR, and PRR pathways in HONE6 cells, and sensitize HONE6 cells to cisplatin. In addition, depletion of SETD2 and SETMAR can also sensitize HONE6 cells to cisplatin, reduces the expression level of several genes in the FA, HR, and PRR pathways. The frequency of sister chromatid exchange is also significantly reduced in the SETMAR-depleted HONE6 cells, suggesting the HR is reduced in these cells. Finally, MORF can bind to the promoters of BRCA1 and FANCD2 by the chromatin immunoprecipitation experiments. Our results indicate that SETD2 and SETMAR could methylate H3K4 and H3K36 at the promoters of genes in the FA and HR pathways, allowing the binding of the MORF complex to the promoters of these genes through the interaction with methylated H3K4 and H3K36. Therefore, MORF activates FA, HR, and PRR pathways to confer NPC cells the cisplatin resistant phenotype.
論文目次 中文摘要 1
ABSTRACT 3
致謝 8
目錄 9
圖目錄 11
表目錄 11
第壹章 緒言 12
第一節 前言 12
1-1 基因體的不穩定(GENOMIC INSTABILITY) 12
1-2 細胞中的DNA損害反應(DNA DAMAGE RESPONSE, DDR) 13
1-3 順鉑(CISPLATIN)作用機制與抗藥性生成 14
1-4 范可尼貧血(FANCONI ANEMIA PATHWAY)修復機制 15
1-5 後複製修復機制(POST-REPLICATION REPAIR, PRR) 16
1-6 同源重組(HOMOLOGOUS RECOMBINATION, HR) 17
1-7 組蛋白乙醯轉移酶MORF與甲基轉移酶SETD2、SETMAR 18
第二節 實驗目的 21
第貳章 實驗方法與材料 22
第一節 材料 22
2-1-1 人類細胞株 22
2-1-2 引子合成(OLIGO PRIMER)設計 23
2-1-3 SHRNA序列設計 25
2-1-4 SIRNA序列設計 25
2-1-5 抗體 25
第二節 實驗方法 26
2-2-1 細胞計數 26
2-2-2 慢病毒製備 (LENTIVIRAL PRODUCTION) 26
2-2-3 SIRNA轉染(SIRNA TRANSFECTION) 28
2-2-4 RNA萃取 (TRIZOL) 29
2-2-5 蛋白質萃取 29
2-2-6 即時聚合酶鏈式反應 (REAL-TIME POLYMERASE CHAIN REACTION) 30
2-2-7 西方墨點法(WESTERN BLOT) 30
2-2-8 3-(4, 5-DIMETHYLTHIAZOLYL-2)-2, 5 -DIPHEYLTETRAZOLIUM BROMIDE (MTT) ASSAY 31
2-2-9 細胞群落形成(COLONY FORMATION) 32
2-2-10 姊妹染色分體互換(SISTER CHROMATID EXCHANGE, SCE) 32
2-2-11 染色質免疫沉澱(CHROMATIN IMMUNOPRECIPITATION, CHIP) 34
第參章 結果 36
3-1 在HONE6細胞株降低MORF蛋白表現會使HR、FA、PRR修復路徑相關的蛋白表現量降低 36
3-2 在HONE6細胞株以SIRNA降低MORF表現會降低其抗藥性並使HR、FA、PRR修復路徑相關的MRNA與蛋白表現量降低 37
3-3 MORF會與目標基因啟動子結合來調控目標基因的表現 38
3-4 分別降低SETD2基因與SETMAR基因表現皆會使鼻咽癌細胞對順鉑藥物更加敏感 40
3-5 SETD2基因與SETMAR基因能調控HR、FA、PRR修復路徑相關的基因表現 41
3-6 在HONE6細胞株降低SETMAR基因表現會降低其姊妹染色分體互換率(SISTER CHROMATID EXCHANGE, SCE) 42
第肆章 討論 43
4-1 探討乙醯轉移酶MORF做為調節因子調控DNA修復與抗藥性 43
4-2探討甲基轉移酶SETD2和SETMAR調節DNA修復與抗藥性 45
參考文獻 47


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