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研究生(外文):Chu-Chun Huang
論文名稱(外文):Interactions between the internal ribosome entry site of hepatitis C virus and eukaryotic initiation factor 3 subunits
指導教授(外文):Ming-Fu Chang
外文關鍵詞:hepatitis C virustranslationinternal ribosome entry site
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C型肝炎病毒 (hepatitis C virus, HCV) 為非A非B型肝炎的主要致病原,與慢性肝炎、肝硬化及肝細胞癌的形成有密切關係。HCV為一具有正向單股且全長約9.6 kb之基因體的 RNA 病毒。病毒基因體組成包含5’ 端非轉譯區 (noncoding region, NCR)、可以轉譯後出約 3000 個胺基酸多蛋白質 (polyprotein) 之開放編閱架構 (open reading frame),以及3’ 端非轉譯區。5’ 端非轉譯區在不同病毒分離株之間具有高度保守性。轉譯起始是由internal ribosome entry site (IRES) 所調控,其範圍涵蓋幾乎整個 5’ 端非轉譯區與轉譯起始點 AUG後約 30 nt 之序列。IRES 可形成穩定的二級與三級結構,在功能上代替許多轉譯起始因子能直接吸引 40S 核醣體次單元及轉譯起始因子Ⅲ (eukaryotic initiation factor 3 ; eIF3)。eIF3 為一個 650 kDa 複合體,包含至少有十個不同蛋白質。利用純化之eIF3證明其中的p116和p170兩個次單元體會專一性結合至HCV IRES 的domain Ⅲ。根據二級結構預測,p116在靠近N端 (a.a. 185-268) 具有一個可能的 RNA recognition motif (RRM)。本實驗室過去也曾以gel retardation assay 及定點突變配合西北方墨點法,證實p116-RRM與domain Ⅲ 之間的交互作用。然而,在最近之報告中,利用 SERF (selection of random RNA fragments)方法發現p116 (a.a. 227-320) 會專一性的與HCV IRES的domain Ⅱ結合。因此本研究主要探討 eIF3 次單元 p116與 HCV IRES 之 domain Ⅱ 和 domain Ⅲ 結合能力之差異及 HCV IRES 上之 cis-elements 在轉譯功能所扮演之角色。利用filter binding assay顯示domainⅡ 頂端 (nt 65-102) 和 domain Ⅲabcd (nt 131-278) 對於 p116-RRM有相類似的結合能力。我們亦嘗試建立 SERF 方法,找尋 p116-RRM 在 IRES 上的最小結合區域。另外,在活體外轉譯實驗中加入 domain Ⅱ 頂端部分或domain Ⅲabcd RNA,會抑制 HCV IRES 所引導之核心蛋白質的合成。本研究對細胞因子 eIF3 次單元與 HCV IRES的交互作用的探討,有助於對 HCV 內部起始轉譯機制的進一步瞭解。
Hepatitis C virus (HCV), the major infectious agent of non-A, non-B hepatitis, often causes chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. HCV is a positive-sense, single-stranded RNA virus of genomic size 9.6 kb in length. The viral genome consists of a 5’ noncoding region (NCR), a large open reading frame encoding a polyprotein of approximately 3000 amino acids, and a 3’ NCR. The 5’NCR is highly conserved among HCV isolates. Translation initiation of HCV is controlled by the internal ribosome entry site (IRES) encompassing almost the entire 5’NCR and the sequences about 30 nt downstream the AUG codon. The IRES folds into a stable secondary and tertiary structure and functionally replaces several initiation factors by directly recruiting the 40S ribosomal subunit and eukaryotic initiation factor 3 (eIF3). The eIF3 complex is composed of at least ten different proteins with 650 kDa. Two subunits of eIF3 complex, p116 and p170, have been demonstrated to specifically bind to the domain Ⅲ of HCV IRES. According to secondary structure prediction, p116 contains a putative RNA recognition motif (RRM) near the N terminal region (a.a. 185-268). By performing gel retardation assay and site-directed mutagenesis previously, our laboratory has demonstrated the interaction between p116-RRM and the domain Ⅲ of HCV IRES. Nevertheless, the p116 subdomain from amion acid 227 to 320 was recently identified to interact with the domain Ⅱ apical part of HCV IRES by using the technique of SERF (selection of random RNA fragments). In this study, binding ability of eIF3 p116 subunit to HCV IRES domain Ⅱ and domain Ⅲ were further examined to learn the roles of the cis-elements involved in the internal initiation of translation. A similar binding ability of p116-RRM to the HCV IRES domain Ⅱ (nt 65-102) and the domain Ⅲabcd (nt 131-278) was found by filter binding assay. An attempt to set up the SERF technique was also made to determine the minimal binding region of p116-RRM on the HCV IRES. In addition, by adding the RNA representing the apical domain of domain Ⅱor domain Ⅲabcd as competitor in an in vitro translation assay, the synthesis of core protein mediated by the HCV IRES was inhibited. The studies of interaction between the eIF3 subunit and HCV IRES will help us to understand the control mechanisms of the internal initiation of HCV.
誌謝 ………………………………………………………… Ⅰ
中文摘要 …………………………………………………… Ⅱ
英文摘要 …………………………………………………… Ⅳ
縮寫表 ……………………………………………………… Ⅵ
緒論 ………………………………………………………… 1
實驗材料來源 ……………………………………………… 11
實驗方法 …………………………………………………… 14
實驗結果 …………………………………………………… 30
討論 ………………………………………………………… 35
圖表 ………………………………………………………… 39
參考文獻 …………………………………………………… 52
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