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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 張鑫(Shin C. Chang) | |
| dc.contributor.author | Yuan-Kai Hsu | en |
| dc.contributor.author | 許原愷 | zh_TW |
| dc.date.accessioned | 2021-06-17T04:29:24Z | - |
| dc.date.available | 2023-09-04 | |
| dc.date.copyright | 2018-09-04 | |
| dc.date.issued | 2018 | |
| dc.date.submitted | 2018-08-13 | |
| dc.identifier.citation | 1. Manns MP. et al. Hepatitis C virus infection. Nat. Rev. Dis. Primers. 2017; 3: 1-19.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/70492 | - |
| dc.description.abstract | C型肝炎是由C型肝炎病毒(hepatitis C virus, HCV)所引發的人類肝臟疾病。目前全球約有七千萬人次的慢性感染。HCV的急性感染能引發患者出現發燒、疲倦或嘔吐等症狀，最嚴重能導致患者出現猛爆性肝炎；HCV的慢性感染則可能進一步引發肝硬化或肝癌，每年約造成四十萬人次的死亡。過去研究已知HCV能使受感染細胞的DNA 雙股斷裂程度增加，並且抑制細胞負責修復雙股斷裂的non-homologous end joining (NHEJ)修復機制。除此之外，當細胞內單獨表達HCV 的非結構性蛋白質NS3時也能造成細胞DNA雙股斷裂程度增加與NHEJ的抑制。在實驗室先前的研究當中亦發現NS3在細胞當中的表現能使homologous recombination (HR)效率增加。為了進一步探討NS3對整體DNA 雙股斷裂修復的影響，本研究利用in vivo NHEJ assay以及microhomology-mediated end joining (MMEJ) assay 觀察NS3對DNA雙股斷裂修復機制的影響。結果發現，NS3在細胞當中的表現能使NHEJ的效率下降，但卻使MMEJ效率增加。接著本研究以Western blotting觀察與DNA 雙股斷裂修復調控有關的蛋白質在細胞中的表現量是否會受到NS3表現的影響，以及利用GST pull-down assay 與immunoprecipitation assay觀察NS3是否與這些蛋白質有交互作用。實驗結果未偵測到NS3對蛋白質在細胞當中的表現有任何顯著的影響，但是NS3能夠利用其protease以及helicase domain和宿主細胞中的WRN與Ku70蛋白質產生交互作用。藉由 DNA pull-down assay以及 co-immunoprecipitation assay 更進一步發現，NS3能夠干擾在ionizing radiation (IR)照射下Ku70對DNA雙股斷裂處的辨認，且干擾WRN與γH2AX間的交互作用，然而詳細的機轉仍有待進一步的研究。 | zh_TW |
| dc.description.abstract | Hepatitis C is a liver disease caused by hepatitis C virus (HCV), which can cause both acute and chronic hepatitis. Chronic hepatitis C might lead to liver fibrosis, cirrhosis, hepatocellular carcinoma and death. Previous studies showed that HCV infection could cause DNA double-strand break (DSB) accumulation and the inhibition of non-homologous end joining (NHEJ). Moreover, overexpression HCV nonstructural protein 3 (NS3) could also cause DSB accumulation and NHEJ inhibition. In this study, in vivo NHEJ assay and microhomology-mediated end joining (MMEJ) assay were performed to figure out the underlying mechanism of how NS3 attenuates host DNA repair pathway. Results showed that NS3 overexpression could downregulate NHEJ, while upregulate MMEJ efficiency. Previous lab study also showed that Homologous recombination (HR) efficiency was upregulated during NS3 overexpression. Western blot analysis and GST pull-down assay was performed to figure out whether NS3 could influence the expression level of DNA repair associated proteins or physically interact with them. Results showed that the expression level of DNA repair associated proteins did not significantly change under NS3 overexpression. However, NS3 associated with Ku70 and WRN by its protease and helicase domains. NS3 was also found to interrupt Ku70-mediated DSB end recognition and WRN-γH2AX interaction under ionizing radiation (IR) induced DNA damage. The detail mechanism on how NS3 interfere DNA repair through interacting with Ku70 and WRN remains to be elucidated. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T04:29:24Z (GMT). No. of bitstreams: 1 ntu-107-R05445133-1.pdf: 2375840 bytes, checksum: e67d2e44ef69e478e50c1b2a2ec0a4a6 (MD5) Previous issue date: 2018 | en |
| dc.description.tableofcontents | Contents
摘要………………………………………………………………………..…..……i Abstract……………………………………………………………….……………ii Contents……………………………………………………………………………iv Contents of Figures……………………………………………………...…………vi I. Introduction ………………….…………………………………………….………1 i. Hepatitis C Virus………………………………………………………………1 ii. DNA damage response……………………………………..…………………6 iii. DNA repair pathways and cancers……………………………………………7 iv. DNA double strand break repair……………………………………..……….8 II. Specific aim……………………………………………………………..………..16 III. Materials and Methods……………………………………………………….….17 i. Materials………………........................……………………………………17 ii. Methods……………………………………………………………………23 IV. Results…………………………………………………………………….……..28 i. The expression of NS3 and NS3/4A inhibits NHEJ but promote HR and MMEJ……………………………………………………….……………….28 ii. NS3 and NS3/4A do not alter the expression level of DNA DSB repair proteins…………………………………………………………………..…..28 iii. NS3 interacts with endogenous WRN and Ku70…………………..………..29 iv. NS3 interacts with WRN and Ku70 via protease domain and helicase domain…………………………………………………………………….…29 v. NS3-Ku70 and NS3-WRN interactions require DNA as a mediator……….30 vi. NS3 impairs Ku-mediated DSB end recognition…………………………..31 vii. NS3 inhibits WRN-γH2AX interaction……………………………………..31 V. Discussion…………………………………………………………….………….33 VI. Figures………………………………………………………………..…………..37 VII. References………………………………………………………………………..47 | |
| dc.language.iso | en | |
| dc.subject | Ku70 | zh_TW |
| dc.subject | C型肝炎病毒 | zh_TW |
| dc.subject | 非結構性蛋白 | zh_TW |
| dc.subject | DNA雙股斷裂修復 | zh_TW |
| dc.subject | WRN | zh_TW |
| dc.subject | nonstructural protein 3 | en |
| dc.subject | DNA double strand break | en |
| dc.subject | Ku70 | en |
| dc.subject | hepatitis C virus | en |
| dc.subject | WRN | en |
| dc.title | C型肝炎病毒非結構性蛋白質NS3與DNA雙股斷裂
修復因子之交互作用 | zh_TW |
| dc.title | Interactions between hepatitis C virus NS3 protein and DNA double-strand break repair factors | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 106-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 鄧述諄(Shu-Chun Teng),陳美如(Mei-Ru Chen) | |
| dc.subject.keyword | C型肝炎病毒,非結構性蛋白,DNA雙股斷裂修復,Ku70,WRN, | zh_TW |
| dc.subject.keyword | hepatitis C virus,nonstructural protein 3,DNA double strand break,Ku70,WRN, | en |
| dc.relation.page | 55 | |
| dc.identifier.doi | 10.6342/NTU201802810 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2018-08-13 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 微生物學研究所 | zh_TW |
| 顯示於系所單位： | 微生物學科所 | |
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