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系統識別號 U0026-0812200915230865
論文名稱(中文) 探討DBY基因在體細胞中蛋白質合成之抑制機轉
論文名稱(英文) To study the repression mechanism of DBY protein synthesis in somatic cell
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系碩博士班
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 97
學期 2
出版年 98
研究生(中文) 鍾湘汝
研究生(英文) Siang-ru Jhong
學號 T3696108
學位類別 碩士
語文別 中文
論文頁數 84頁
口試委員 口試委員-張典顯
指導教授-曾大千
指導教授-郭保麟
口試委員-孫孝芳
口試委員-黃溫雅
中文關鍵字 DBY基因  後轉錄調控  男性不孕症 
英文關鍵字 male infertility  DBY gene  post-transcriptional regulation 
學科別分類
中文摘要 造成夫妻有不孕症困擾的原因當中,一半因素來自於男性,而其中約有10%造精功能障礙的不孕男性可以檢測到Y染色體的顯微刪除(microdeletion)。而染色體Yq11位置上的無精蟲症因子(azoospermia factor, AZF)在男性精子細胞發育過程中扮演重要角色,利用deletion mapping analysis技術,AZF又加以區分成AZFa、AZFb、AZFc區域。DBY (DDX3Y)位在AZFa區域,其缺失會造成嚴重造精功能缺陷。DBY屬於DEAD box蛋白家族的成員之一,其蛋白質結構包含有兩個高度保留的區域:含有DEAD (Asp-Glu-Ala-Asp) motif的DEAD box helicase domain以及helicase superfamily c-terminal domain。在之前研究指出,DBY基因不論在體細胞或睪丸組織都會表現mRNA,但卻只在睪丸組織可以轉譯成蛋白質。換句話說,DBY mRNA在體細胞中受到轉譯抑制。此外,DBY mRNA經選擇性polyadenation會產生三種不同長度的3’端非轉譯區域(3’untranslated regions, 3’UTRs),分別為short form-265 bps, middle form-421 bps及long form-2362 bps。利用反轉錄聚合酶鏈鎖反應(RT-PCR),我們初步發現其中最長的(long form) DBY mRNA 3’端非轉譯區域廣泛表現在睪丸組織以外的體細胞中,而在睪丸組織中則主要表現出short form及少量的middle form之transcripts。
在本論文中,主要的目的是探討體細胞所表現最長的(long form) DBY mRNA 3’端非轉譯區域中,是否具有調控功能的序列(cis-acting elements)以及相互作用的RNA結合蛋白質(trans-acting factors),使得體細胞中的DBY mRNA無法加以轉譯成蛋白質。
利用生物資訊分析發現,DBY mRNA 3’端非轉譯區域含有對於調控RNA穩定性及轉譯能力相當重要的第一型AU-rich element (ARE)。經由RNA-EMSA及UV cross-linking實驗技術,我們確認了3’端非轉譯區域中與RNA結合蛋白質的結合區域。進一步再利用supershift assay, biotin pull down assay和 RNA免疫沈降法(RNA-immunoprecipitation),我們找到Hu antigen R (HuR)和T-cell intracellular antigen-1 (TIA-1)這兩個RNA結合蛋白質會結合上DBY mRNA 3’端非轉譯區域的406-799th核甘酸位置。接著透過protein免疫沈降法(protein-immunoprecipitation)實驗證實,HuR與TIA-1是經由DBY mRNA而產生交互作用。從文獻報導指出,HuR與TIA-1可以結合上3’端非轉譯區域的ARE且具有進一步影響mRNA穩定度(mRNA stability)與調控轉譯效率(translational efficiency)的功能。因此,我們有興趣更深入探討在體細胞中,DBY mRNA無法加以轉譯成蛋白質是否和HuR、TIA-1結合上DBY mRNA 3’端非轉譯區域的406-799th核甘酸位置有關。利用Luciferase reporter assay及ribosome complex pulldown (S6-IP)的實驗,將HuR knockdown後會增加DBY mRNA 3’端非轉譯區域的406-799th核甘酸位置之轉譯;相反的,HuR overexpression則會抑制DBY mRNA 3’端非轉譯區域的406-799th核甘酸位置之轉譯。
綜合以上結果,我們推論在體細胞中,DBY mRNA無法加以轉譯成蛋白質是和HuR、TIA-1結合上最長的(long form) DBY mRNA 3’端非轉譯區域的406-799th核甘酸位置有關。
英文摘要 About 10-15% health couples are infertile, and half of these cases could be attributed to a male factor. A significant proportion of infertility males are affected by spermatogenic defect. In cases with severe spermatogenic defect, approximately 10% of cases have microdeletions of the Y chromosome. The Y chromosomal azoospermia factor (AZF) is essential for human spermatogenesis. By using deletion mapping analysis, it is mapped to Yq11 and divided into three subintervals, named as AZFa, AZFb and AZFc. DBY (DDX3Y) has been reported as an AZFa candidate, of which deletion results in severe spermatogenic defect. DBY belongs to DEAD box protein family, which are putative RNA helicases characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD). In previous study, DBY is widely transcribed but the protein is limited to the male germ cells. In other words, DBY transcripts undergo translational suppression in somatic cells. Sequences of three different 3’untranslated regions (3’UTRs) were obtained from databases: the short form is 265 bps in length, the middle form is 421 bps in length, and the long form is up to 2362 bps in length. According to our preliminary data, the long form is abundant in various human tissues except testis.
In this study, we aimed to identify cis-acting elements and trans-acting factors in the long form 3’UTR of DBY which participated in the translational control in somatic cells.
By using bioinformatic prediction, DBY is an ARE-containing mRNA with class I AU-rich element (ARE) in the 3’UTR. From the RNA-EMSA, UV cross-linking experiments, several RNA-binding protein complexes interacted with DBY mRNA 3’UTR. Furthermore, we identified that Hu antigen R (HuR) and T-cell intracellular antigen-1 (TIA-1) could bind to the long form DBY mRNA 3’UTR in the region of 406-799th nucleotide as demonstrated by the supershift assay, biotin pull down assay and RNA-immunoprecipitation (RNA-IP) analyses. According to protein-immunoprecipitation (Protein-IP) data, the interaction of HuR with TIA-1 was through DBY mRNA. From literature, HuR and TIA-1 can bind to the ARE in the 3’UTR and regulate the mRNA stability and translation efficiency. Therefore, we tried to realize whether DBY transcripts undergo translational suppression in somatic cells because of HuR and TIA-1 binding to long-form 3’UTR of DBY. By using luciferase reporter assay and ribosome complex pulldown (S6-IP) experiments, HuR silencing significantly elevated DBY mRNA translation, whereas HuR overexpression repressed DBY mRNA translation mediated through the DBY 3’UTR in the region of 406-799th nucleotide.
In conclusion, our results supported that DBY transcripts undergo translational suppression in somatic cells as a result of HuR and TIA-1 binding to the long-form DBY 3’UTR in the region of 406-799th nucleotide.
論文目次 考試合格證名 I
中文摘要 II
英文摘要 IV
誌謝 VI
目錄 VII
表目錄 X
圖目錄 XI
附錄 XII

第一章 緒論 1
第一節 男性不孕症的定義與盛行率 1
第二節 男性不孕症之成因 2
第三節 Y染色體與男性不孕症的關係 4
第四節 位於AZFa區域的候選基因(candidate gene),DBY (DEAD box on Y)基因 6
第五節 真核細胞內基因表現的調控過程 7
第六節 後轉錄調控(post-transcriptional regulation) 7
第七節 AU-rich elements (AREs)影響mRNA的穩定性 9
第八節 Trans-acting factors參與後轉錄調控(post-transcriptional regulation) 10
第九節 HuR調控mRNA的穩定度與轉譯效率 11
第十節 TIA-1抑制轉譯效率 12
第十一節 研究動機與目標 13
第二章 實驗材料及方法 15
第一節 生物資訊分析:AU-rich element (ARE) search 15
第二節 細胞培養 15
第三節 In vitro transcription合成的(32P)rCTP標定DBY mRNA 3’端非轉譯區域(3’UTR) RNA probes 16
第四節 RNA electrophoretic mobility shift assay (RNA-EMSA) 17
第五節 UV cross-linking 19
第六節 Competition assay 21
第七節 Supershift assay 22
第八節 Biotin pull down assay 24
第九節 RNA-immunoprecipitation assay (RNA-IP) 29
第十節 Protein-immunoprecipitation assay (Protein-IP) 32
第十一節 分析HuR影響DBY mRNA 3’端非轉譯區域(3'UTR) L1片段(406-799th nucleotide)的轉譯效率 34
第三章 實驗結果 39
第一節 探討有無trans-acting factors結合至DBY mRNA 3’端非轉譯區域(3'UTR) 39
第二節 確認結合在DBY mRNA 3’端非轉譯區域(3'UTR) L1片段之trans-acting factors的蛋白特性 39
第三節 HuR及TIA-1會結合到DBY mRNA 3’端非轉譯區域(3'UTR)的L1片段 40
第四節 HuR與TIA-1是經由DBY mRNA而產生交互作用 41
第五節 HuR overexpression會抑制DBY mRNA 3’端非轉譯區域 (3'UTR) L1片段的轉譯;HuR knockdown
則會促進DBY mRNA 3’端非轉譯區域(3'UTR) L1片段的轉譯 42
第六節 HuR knockdown會促進endogenous DBY mRNA 3’端非轉譯區域(3'UTR) L1片段的轉譯 44
第四章 討論 46
第一節 HuR與TIA-1共同調控基因表現 46
第二節 Stress granules (SGs) 47
第三節 microRNAs (miRNAs)參與在後轉錄調控(post-transcriptional regulation) 48
第五章 參考文獻 50
表 65
圖 66
附錄 77
自述 84
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