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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 陳美如(Mei-Ru Chen) | |
dc.contributor.author | Mei-Tzu Su | en |
dc.contributor.author | 蘇美慈 | zh_TW |
dc.date.accessioned | 2021-05-14T17:44:39Z | - |
dc.date.available | 2020-09-25 | |
dc.date.available | 2021-05-14T17:44:39Z | - |
dc.date.copyright | 2015-09-25 | |
dc.date.issued | 2015 | |
dc.date.submitted | 2015-07-27 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/4650 | - |
dc.description.abstract | EB病毒是普遍感染全球人口的gamma型疱疹病毒。EB病毒與Burkitt’s淋巴瘤、Hodgkin’s症、鼻咽癌等許多人類惡性疾病形成有高度相關性。EB病毒感染後,環狀病毒基因體利用細胞內DNA複製機組進行複製並潛伏在宿主細胞中。 EB病毒由潛伏再活化後,轉活化因子Zta及Rta的表現會活化一連串溶裂期基因表現以利病毒複製。EB病毒與哺乳細胞之DNA複製複合體類似,包含導引酶(primase, BSLF1)、導引酶輔助蛋白(primase accessory protein, BBLF2/BBLF3)、解螺旋酶(helicase, BBLF4)、DNA聚合酶(DNA polymerase, BALF5)、單股DNA結合蛋白質(single-stranded DNA-binding protein, BALF2)、尿嘧啶醣苷酶(uracil-DNA glycosylase, BKRF3)和DNA聚合酶輔助因子(DNA polymerase processivity factor, BMRF1)已被證實會聚集在病毒DNA複製區。BMRF1除了幫助病毒DNA複製,同時也可作為轉活化因子調節溶裂期病毒基因體複製起始區的BHLF1啟動子,或作為共同活化因子調節單股DNA結合蛋白BALF2啟動子,顯示BMRF1在病毒溶裂期DNA複製及基因表現都扮演重要角色。本論文中對於BMRF1相關生物功能進行兩個研究主題: (I) BMRF1調控BKRF3進入細胞核,以及BKRF3在溶裂期病毒核酸複製複合體中所扮演的生物功能。研究結果發現BMRF1可與BKRF3交互作用進而促使BKRF3由細胞質進入細胞核中,而BKRF3與DNA複製相關蛋白的結合可以提高BKRF3之酵素活性。剔除BKRF3基因導致病毒DNA複製功能受損, 並且以互補試驗證明BKRF3的leucine loop對BKRF3協助病毒基因體複製是重要的。(II)利用基因剃除病毒系統探討BMRF1對病毒基因的轉錄調控。實驗結果發現BMRF1參與部分病毒晚期基因之轉錄調控,而BMRF1轉活化功能區會影響其調控病毒基因表現的功能。以免疫沉澱法搭配質譜科學分析法(Immunoprecipitation-mass spectrometry)分析與BMRF1相互作用之蛋白質,發現BMRF1不僅與DNA複製/修復及RNA剪接相關蛋白形成蛋白質複合體,也與染色質調控分子像是BRG1 (BRM/SWI2-related gene 1)有相互作用。進一步發現BMRF1與BRG1在細胞內及體外試驗皆有交互作用。以干擾RNA抑制BRG1表現會降低BMRF1對部分病毒啟動子的轉活化功能,顯示BRG1可能參與BMRF1調節的病毒基因之轉錄調控。本論文證明BMRF1調控BKRF3參與細胞核內複製複合體是病毒DNA複製的關鍵;除了參與病毒基因體複製,BMRF1也可能與染色質調控分子BRG1共同調控病毒基因表現以利EB病毒溶裂期複製。 | zh_TW |
dc.description.abstract | Epstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus that infects most of the population worldwide. EBV is highly associated with various human malignancies, including Burkitt’s lymphoma (BL), Hodgkin’s disease (HD) and nasopharyngeal carcinoma (NPC). After primary infection, the circularized EBV genome persists latently in the host cell, using cellular DNA replication machinery for replication. Once EBV reactivation from latency, the expression of transactivators Zta and Rta turn on cascade expression of viral lytic genes which are required for efficient viral replication. Similar to mammalian DNA replication machinery, a large protein complex including primase (BSLF1), primase accessory protein (BBLF2/3), helicase (BBLF4), DNA polymerase (BALF5), single-stranded DNA-binding protein (BALF2), uracil-DNA glycosylase (UDG, BKRF3), and DNA polymerase processivity factor (BMRF1) are demonstrated to associate with viral DNA replication compartment. Other than the role in DNA replication, BMRF1 also functions as a transactivator on BHLF1 promoter and as a coactivator on BALF2 promoter, indicating that BMRF1 plays important roles in viral DNA replication and viral gene expression. To explore the biological functions of BMRF1, two specific aims are addressed in this study. (I) The first part is to explore whether BMRF1 mediates nuclear translocation of BKRF3 and to study the biological function of BKRF3 in viral DNA replication complex during lytic cycle. It was found that BMRF1 interacts with BKRF3 and regulates the nuclear targeting of BKRF3. The interaction of BKRF3 with viral proteins in replication compartment enhances the enzymatic activity of BKRF3 during lytic cycle. In BKRF3 knockout recombinant virus, lytic DNA replication is blocked and can be rescued by trans-complementation of BKRF3, indicating that BKRF3 is required for EBV DNA replication and the leucine loop of BKRF3 is critical for its function. (II) The second part is to investigate the transcription regulatory function of BMRF1 using specific gene knockout bacmid system. In gene regulation analyses, we found that BMRF1 regulates a number of viral late gene expression through its transactivation domain. According to immunoprecipitation-mass spectrometry analysis, BMRF1 associates with not only DNA replication/repair and RNA splicing association factors but also chromatin modifiers such as BRG1 (BRM/SWI2-related gene 1). Moreover, BMRF1 interacts with BRG1 in the cells and in vitro. Knockdown of BRG1 reduces transactivation activity of BMRF1 on a subset of viral promoters, suggesting BRG1 may participate in the regulation of BMRF1 on viral gene expression. In conclusion, BMRF1 recruits viral UDG BKRF3 to the replication compartment, which is crucial for viral DNA replication. In addition to the role in DNA replication machinery, BMRF1 may also mediate gene expression through interacting with chromatin modifier BRG1 to benefit EBV lytic replication. | en |
dc.description.provenance | Made available in DSpace on 2021-05-14T17:44:39Z (GMT). No. of bitstreams: 1 ntu-104-D97445010-1.pdf: 5335418 bytes, checksum: 2b80ef0067b5a2f2c6a865c082c91399 (MD5) Previous issue date: 2015 | en |
dc.description.tableofcontents | 論文口試委員會審定書 I 誌謝 II 中文摘要 III Abstract V Contents VII Chapter 1: Epstein-Barr virus DNA replication and gene regulation 1 1.1. Discovery and characterization of Epstein-Barr Virus 1 1.2. Latent infection of EBV 2 1.3. Reactivation and lytic replication of EBV 3 1.3.1. Activation of lytic cycle 3 1.3.2. Immediate early proteins 4 1.3.2.1. Zta 4 1.3.2.2. Rta 5 1.3.3. Early gene products 6 1.3.3.1. Lytic DNA replication 6 1.3.3.2. DNA polymerase processivity factor, BMRF1 7 1.3.3.3. Uracil-DNA glycosylase, BKRF3 8 1.3.4. Late gene products 9 1.4. EBV gene expression and regulation 10 1.4.1. Regulation of early lytic gene 10 1.4.1.1. Regulation of host transcription factors on viral early gene expression 11 1.4.1.2. BGLF4-mediated regulatory effects on the transactivation activities of Zta and BMRF1 11 1.4.2. Regulation of late viral genes 12 1.5. Interaction of viral transcription factors and cellular factors in lytic phase 13 1.6. Aims of this study 14 Chapter 2: Uracil-DNA glycosylase BKRF3 contributes to Epstein-Barr virus DNA replication through physical interactions with proteins in viral DNA replication complex 15 2.1. Introduction 15 2.2. Results 20 2.2.1. BKRF3 was translocated into the nucleus during EBV lytic replication 20 2.2.2. Physical interactions of BKRF3 with other EBV DNA replication proteins and the nuclear targeting of BKRF3 22 2.2.3. Complex formation of BKRF3 with viral proteins correlated with higher UDG activity of BKRF3 during EBV reactivation 25 2.2.4. Generation of a BKRF3 knockout and the revertant EBV bacmid clones 26 2.2.5. BKRF3 was required for EBV genome replication 26 2.2.6. The interaction of BKRF3 with viral proteins in replication complexes promoted EBV DNA replication through enzymatic activity independent pathways 27 2.3. Conclusion 31 Chapter 3: Transcriptional regulation activities of EBV DNA polymerase processivity factor BMRF1 on viral gene expression 32 3.1. Introduction 32 3.2. Results 35 3.2.1. Construction of p2089BMRF1 and selection of inducible cells 35 3.2.2. Knockout of BMRF1 reduced a subset of viral lytic gene expression 36 3.2.3. BMRF1 functions as a transactivator or a coactivator to turn on certain Rta responsive late gene promoters 38 3.2.4. BMRF1 turned on the promoter of BDLF3 through an SP1-dependent pathway 39 3.2.5. BMRF1 associates with cellular factors involved in DNA replication, chromatin remodeling and RNA splicing 39 3.2.6. BMRF1 interacts with chromatin modifier BRG1 in a DNA independent manner. 41 3.2.7. BRG1 contributes to BMRF1 transactivation of BHLF1, BLLF1 and BcLF1 promoters. 42 3.2.8. Chromatin modifier BRG1 probably sustained the latency of EBV. 42 3.3. Conclusion 43 Chapter 4: Discussion 45 4.1. BKRF3 participates in viral DNA replication compartments during EBV reactivation 45 4.1.1. EBV uracil-DNA glycosylase BKRF3 expresses and associates with BMRF1 and other replication proteins in the nucleus during lytic cycle 45 4.1.1.1. The up-regulated expression of BKRF3 accompanies with down-regulation of cellular UNG2. 45 4.1.1.2. The mechanism of BKRF3 nuclear targeting during EBV reactivation 46 4.1.1.3. Interaction with replication proteins augments the UDG activity of BKRF3 47 4.1.2. The presence of BKRF3 is essential for EBV lytic DNA replication. 47 4.1.3. The protein interaction ability of BKRF3, but not the enzymatic activity of that, is critical for lytic reactivation 49 4.2. Transcriptional regulation of BMRF1 on EBV gene expression 51 4.2.1 BMRF1 contributes to regulation of late gene transcription in a DNA replication independent manner 51 4.2.2 BMRF1 and Rta act in an additive manner to activate a subset of late promoters 52 4.2.3 BMRF1 associates with cellular factors to regulate EBV gene expression 53 4.2.3.1 BMRF1 transactivates BDLF3 promoter through a SP1 dependent pathway 53 4.2.3.2 Chromatin regulators may participate in the transcriptional regulation of BMRF1 53 4.2.3.2.1 BRG1 is required for BMRF1-mediated activation of BHLF1, BcLF1 and BLLF1 promoters 54 4.2.3.2.2 Mi-2/NuRD complex, the potential BMRF1-interacting complex, may function as a repressor in EBV gene regulation 55 4.2.3.3 BRG1 mediated regulation of herpesvirus replication 56 4.3. The biological functions of BKRF3 and BMRF1 in EBV reactivation 56 Chapter 5: Materials and Methods 58 5.1. Plasmids 58 5.2. Cell lines and transfection 60 5.3. Immunofluorescence assay 61 5.4. Western blot analysis 61 5.5. Subcellular fractionation 62 5.6. Co-immunoprecipitation assay 62 5.7. GST pull-down assay 63 5.8. Uracil-DNA glycosylase (UDG) assay 64 5.9. Construction of the BKRF3 knockout and revertant EBV bacmids 64 5.10. Construction of the BMRF1 knockout EBV bacmid 65 5.11. Selection of doxycycline inducible cells containing EBV bacmid DNA 66 5.12. Immunoprecipitation-UDG assays 66 5.13. Genomic DNA extraction and quantitative real-time PCR for EBV copy number 67 5.14. DNA binding assay with single-stranded DNA cellulose 68 5.15. EBV DNA Microarray analysis 68 5.16. RT-PCR and RT-qPCR 69 5.17. Luciferase assay 70 5.18. Immunoprecipitation -spectrometry assay 70 5.19. shRNA lentivirus production 71 Tables and Figures 72 Table 1. Viral proteins acting at EBV oriLyt and their functions 73 Table 2. The regulation fold of BMRF1-mediated EBV genes in Rta or Zta inducible cells 74 Table 3. The BMRF1-associated proteins analyzed by Mass-spectrometry 75 Table 4. EBV primers used for RT-PCR and RT-qPCR 76 Fig. 1. Functional domains of BMRF1. 77 Fig. 2. Sequence alignment of human UNG2 and EBV BKRF3. 78 Fig. 3. Translocalization of BKRF3 during the lytic cycle. 79 Fig. 4. BKRF3 interacts with viral DNA replication-associated proteins. 81 Fig. 5. BKRF3 is translocated into the nucleus in the presence of BMRF1. 82 Fig. 6. BKRF3 interacts with viral replication-associated proteins, including BALF5 and BMRF1. 83 Fig. 7. Mapping the interaction domains of BKRF3 using a GST pulldown assay. 84 Fig. 8. Complex formation with viral DNA replication machinery in Rta reactivated NA cells stimulates BKRF3 UDG activity. 85 Fig. 9. Construction and characterization of BKRF3 knockout and the revertant EBV bacmids. 86 Fig. 10. EBV genome replication was deficient in cells containing BKRF3 knockout bacmids. 88 Fig. 11. Trans-complementation by wild-type or enzymatically dead BKRF3(Q90L,D91N), but not leucine loop mutant BKRF3(H213L), bacmids rescued lytic viral DNA replication in BKRF3STOP cells. 89 Fig. 12. The predicted 3D structure of BKRF3 wild-type and mutants. 91 Fig. 13. Point mutation at His213 of BKRF3 attenuated its recruitment to the viral DNA replication compartment. 92 Fig. 14. Point mutation at His213 of BKRF3 attenuated its ability to interact with the viral DNA polymerase BALF5 and immediate-early gene, Rta. 93 Fig. 15. Construction of BMRF1 knockout EBV bacmid and establishment of inducible bacmid 293TetER cell lines. 94 Fig. 16. Effects of BMRF1 on viral gene expression in Rta or Zta inducible 293 cells. 95 Fig. 17. Ectopic expression of BMRF1 rescues viral DNA replication and transcription of viral genes BcLF1, BLLF1 and BLLF2 in 293TetEZ/p2089BMRF1 cell. 97 Fig. 18. Expression of BMRF1 alone turns on the promoter activities of EBV late genes in 293T cells. 98 Fig. 19. BMRF1 enhances Rta-mediated transcriptional activities through its transactivation domain. 99 Fig. 20. BMRF1 regulates the promoter activity of BDLF3 through a SP1-dependent pathway. 100 Fig. 21. Determination of BMRF1 interacting proteins. 102 Fig. 22. Nuclear co-localization of BMRF1 and chromatin modifier BRG1. 103 Fig. 23. BMRF1 associates with BRG1 in coimmunoprecipitation and in GST-pull down assays. 104 Fig. 24. Knockdown of BRG1 reduces the transactivation activity of BMRF1 on the promoters of BHLF1, BLLF1 and BcLF1. 105 Fig. 25. BRG1 knockdown induced spontaneous EBV reactivation in 293TetEZ/p2089 wild-type cells. 106 Reference 107 | |
dc.language.iso | en | |
dc.title | BMRF1調節EB病毒溶裂期基因表現及影響BKRF3 DNA-尿嘧碇糖苷酶功能之探討 | zh_TW |
dc.title | BMRF1-Mediated Regulation of Viral Gene Expression and the Biological Function of BKRF3 Uracil-DNA Glycosylase in Epstein-Barr Virus Lytic Replication | en |
dc.type | Thesis | |
dc.date.schoolyear | 103-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 蔡錦華(Ching-Hwa Tsai),林素芳(Su-Fang Lin),張麗冠(Li-Kwan Chang),陳紀如(Chi-Ju Chen),李重霈(Chung-Pei Lee) | |
dc.subject.keyword | EB病毒,DNA聚合?輔助因子BMRF1,尿嘧啶醣??BKRF3,病毒核酸複製,病毒基因表現, | zh_TW |
dc.subject.keyword | Epstein-Barr virus,DNA polymerase processivity factor BMRF1,uracil-DNA glycosylase BKRF3,viral DNA replication,viral gene expression, | en |
dc.relation.page | 127 | |
dc.rights.note | 同意授權(全球公開) | |
dc.date.accepted | 2015-07-28 | |
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 |
文件中的檔案:
檔案 | 大小 | 格式 | |
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ntu-104-1.pdf | 5.21 MB | Adobe PDF | 檢視/開啟 |
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