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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 李財坤(Tsai-Kun Li) | |
| dc.contributor.author | Chen-Yu Wen | en |
| dc.contributor.author | 溫振宇 | zh_TW |
| dc.date.accessioned | 2021-06-15T02:21:52Z | - |
| dc.date.available | 2014-09-15 | |
| dc.date.copyright | 2009-09-15 | |
| dc.date.issued | 2009 | |
| dc.date.submitted | 2009-08-19 | |
| dc.identifier.citation | Anderson DG & Kowalczykowski SC (1997a) The recombination hot spot chi is a regulatory element that switches the polarity of DNA degradation by the RecBCD enzyme. Genes Dev 11, 571-581.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/43449 | - |
| dc.description.abstract | 伴隨著轉錄延長作用進行時，新生成的RNA如果繼續和模板DNA互補配對，而讓非模板DNA以單股的形式存在，那麼這個與RNA相關的DNA結構就稱為R-loop。然而在細胞內，R-loop的調控機制及其扮演的生理功能仍然是不清楚的。為了尋找並研究胞內調控R-loop的因子，我們以大腸桿菌作為模式系統，在細菌體內大量表達活化誘導胞嘧啶核苷脫氨酶(activation-induced cytidine deaminase; AID)，以刺激產生突變。不同菌株所展現不同的AID刺激突變倍數(AID-stimulated mutagenesis fold; ASM fold) 用來表示這些細胞內存在著不同程度的R-loop。我們在實驗中發現 (i) RecF活化的菌株(RecF-activated strain, JC7623)擁有極高的ASM fold；同時這個ASM fold可以被額外表達的TopA或RNase H所降低，暗示著R-loop結構確實在此菌的ASM過程中存在。(ii) RecF活化的菌株展現許多獨特的表現性狀，包括質體造成的細胞死亡(plasmid-mediated lethality)、逃跑式DNA複製(run-away DNA replication)以及細胞長絲化(cellular filamentation) ; (iii) 最重要的是，所有的特徵都可以利用送入表達TopA或RNase H來消弭或減少他們展現的程度; (iv) 其中，當我們額外送入兩種活性相反的酵素表達時(TopA及gyrase)，細胞長絲化的現象也完全相反(分別是減少絲化及增加長絲)。綜合以上，我們在本研究中發現RecF蛋白(或RecF途徑)可能有幫助R-loop形成或維持其結構的功能，而過多的R-loop可能就是造成RecF活化菌株展現這些獨特性狀的原因。藉著在分子層級對RecF蛋白、RNase H以及不同DNA拓樸異構酶的操作，我們的研究結果暗示了R-loop的生物功能在DNA複製模式的轉換、DNA損傷訊號、以及DNA重組和細胞存活上的重要性。 | zh_TW |
| dc.description.abstract | The R-loop structure, an RNA-DNA hybrid with a single-stranded DNA region, has been observed during transcription elongation. However, the regulation and biological functions of R-loop still remain largely unknown. In this study, we took advantage of the bacterial genetic model system to solve these problems. We have found that several cellular factors, such as RecF, RNase H and DNA topoisomerases, are involved in the regulation of R-loop formation and thereby modulating its associated cellular functions.
Forced expression of human activation-induced deaminase (hAID) in bacteria was utilized to stimulate mutagenesis and the stimulated folds were then used to represent the different levels of R-loop in various strains and conditions. Specifically, the involvement of RecF pathway is supported by the following observations: (i) The fold of AID-stimulated mutagenesis (ASM) in RecF-activated strain JC7623 (recBC sbcBC) was much higher than those measured in other related mutants; furthermore, additional expression of RNase H or TopA suppressed the ASM fold. (ii) Plasmid-mediated lethality, run-away plasmid replication and cellular filamentation phenotype were also exclusively observed in JC7623 cells. (iii) Most importantly, all these phenotypes could be suppressed by ectopic expression of functional RNase H and TopA. (iv) Over-expression of TopA and gyrase reduced and enhanced the filamentation phenotype in RecF-activated bacteria, respectively. In sum, our results suggested that formation of excess R-loops contributes to all the phenotypes observed in RecF-activated JC7623 cells. Furthermore, we have also revealed many novel functions of R-loop in recombination, DNA replication, cellular filamentation and lethality. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T02:21:52Z (GMT). No. of bitstreams: 1 ntu-98-R96445110-1.pdf: 1473086 bytes, checksum: f0cb73ce97b56272500c0de97381bf43 (MD5) Previous issue date: 2009 | en |
| dc.description.tableofcontents | 口試委員審定書…………………………………………………………………………i
中文摘要………………………………………………………………………………...ii ABSTRACT………………………………………………………………………….....iii INTRODUCTION…………………………………………………………………….....1 1. R-loop………………………………………………………………………….... 1 1-1. Formation of R-loop………………………………………………….......1 1-2. Regulation of R-loop……………………………………………………..2 1-3. Biological Functions of R-loop………………………………………...... 7 2. DNA Topoisomerases………………………………………………………….. 10 2-1. Type I DNA Topoisomerases…………………………………………....10 2-2. Type II DNA Topoisomerases………………………………………….. 12 3. Activation-induced Cytidine Deaminase (AID) and Germline Transcription for Antibody Diversification…………………………...……………………… 14 3-1. Activation-induced Cytidine Deaminase (AID)…………………...........14 3-2. Germline Transcription in S Regions…………………………………...15 4. Recombination Pathway in E. coli…………………………………………….. 17 4-1. RecBCD Pathway……………………………………………………….17 4-2. RecF Pathway…………………………………………………………...18 SPECIFIC AIMS………………………………………………………………………. 21 MATERIALS AND METHODS……………………………………………………….22 Escherichia coli Strains……………………………………………………...……22 Plasmids………………………………………………………………………...…22 Media and Growth Conditions…………………………………………………… 23 Preparation of Competent Cells…………………………………………………...23 Transformation…………………………………………………………………… 24 AID-stimulated mutagenesis assay………………………………………………..24 Plating efficiency………………………………………………………………….25 Fluorescence microscopy………………………………………………………… 26 RESULTS……………………………………………………………………………… 27 RecF pathway, but not RecBCD pathway, promoted AID-stimulated Mutagenesis (ASM)…………………………………………………………….28 The ASM fold in RecF-activated (recBCsbcBC) strain is reduced by additional expression of RNase H………………………………………….. 29 The ASM fold in RecF-activated (recBCsbcBC) strain is also reduced by additional expression of TopA………………………………………………30 The phenotypes of RecF-activated (recBCsbcBC) strain……………………….... 31 1. Plasmid-mediated lethality………………………………………………….. 31 2. Run-away plasmid replication (linear plasmid multimer synthesis)………...32 3. Cellular filamentation………………………………………………………..33 Modulation of the phenotypes exhibited by RecF-activated strain (recBCsbcBC mutant) and their association with R-loop………………………34 1. Ectopic expression of RNase H or TopA reduced the plasmid-mediated lethality………………………………………………….. 35 2. Ectopic expression of RNase H suppressed the run-away plasmid replication (linear plasmid multimer synthesis) ……………………….....… 35 3. Ectopic expression of RNase H or TopA suppressed the cellular filamentation, while additional expression of GyrA promoted the extent of cell filaments…………………………………...………………36 DISCUSSION…………………………………………………………………………..38 The involvement of RecA in the formation of R-loop and R-loop-associated phenotypes………………………………………….…… 38 R-loop, DNA damage and genome integrity……………………………...……… 39 R-loop and switch of replication mode……………………………………………42 REFERENCE……………………………….…………………………………………. 45 TABLES………………………………………………………………………….……. 55 Table I: Escherichia coli strains used in this study. ……………………………... 55 Table II: Plsmid and constructions used in this study……………………………. 56 Table III: AID-stimulated mutagenesis in recombination-related mutant strains………………………………………………………………….. 57 FIGURES……………………………………………………………………………… 58 Figure 1. Expression of activation-induced deaminase (AID) in E. coli yields a mutator phenotype, and the fold of AID-stimulated-mutagenesis (ASM) is higher in RecF-activated strain JC7623. ……………………………………….58 Figure 2. Ectopic expression of RNase H or TopA reduces the fold of AID-stimulated-mutagenesis (ASM) in RecF-activated strain…...... 62 Figure 3. Severe plasmid-mediated lethality in the RecF-activated strain……….. 64 Figure 4. Run-away plasmid replication in RecF-activated strain……………….. 66 Figure 5. RecF-activated strain JC7623 exhibited cellular filamentation phenotype.…………….................................................... 68 Figure 6. Ectopic expression of RNase H or TopA could suppress the plasmid-mediated lethality in the RecF-activated strain………………………. 70 Figure 7. Ectopic expression of RNaseH could rescue the run-away plasmid in RecF-activated striain.………………………………. 72 Figure 8. RNase H and DNA topoisomerases could modulate the level of R-loop-associated cellular filamentaion in RecF-activated JC7623 strain.…….73 Figure 9. Working hypothesis and proposed model for regulation and biological functions of R-loop………………………………….75 | |
| dc.language.iso | en | |
| dc.subject | 脫氨酶 | zh_TW |
| dc.subject | RecF途徑 | zh_TW |
| dc.subject | DNA拓樸異構酶 | zh_TW |
| dc.subject | 活化誘導胞嘧啶核苷 | zh_TW |
| dc.subject | R-圈 | zh_TW |
| dc.subject | Activation-induced deaminase (AID) | en |
| dc.subject | DNA topoisomerase | en |
| dc.subject | RecF pathway | en |
| dc.subject | R-loop | en |
| dc.title | R-loop的調控及其生物功能之探討:
RecF途徑與DNA拓樸異構酶所扮演的角色 | zh_TW |
| dc.title | Regulation and Biological Functions of R-loop:
Roles of RecF Pathway and DNA Topoisomerases | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 97-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 鄧述諄(Shu-Chun Teng),詹迺立(Nei-Li Chan) | |
| dc.subject.keyword | R-圈,RecF途徑,DNA拓樸異構酶,活化誘導胞嘧啶核苷,脫氨酶, | zh_TW |
| dc.subject.keyword | R-loop,RecF pathway,DNA topoisomerase,Activation-induced deaminase (AID), | en |
| dc.relation.page | 75 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2009-08-19 | |
| 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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