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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 冀宏源(Hung-Yuan Chi) | |
dc.contributor.author | Guan-Chin Su | en |
dc.contributor.author | 蘇綸勤 | zh_TW |
dc.date.accessioned | 2021-06-15T11:19:00Z | - |
dc.date.available | 2021-08-26 | |
dc.date.copyright | 2016-08-26 | |
dc.date.issued | 2016 | |
dc.date.submitted | 2016-08-18 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/49197 | - |
dc.description.abstract | 同源重組酵素RAD51 會進行同源重組去修復DNA 雙股斷裂。RAD51 會形成核蛋白絲來去啟動同源重組反應。最近哺乳類細胞實驗指出SWI5 和 SFR1 會形成複合體並參與在RAD51 所主導的同源重組修復。為了探討哺乳類的SWI5-SFR1 在RAD51 所主導的同源重組修復的生化角色,我們建立了蛋白表現及純化的步驟得到老鼠SWI5-SFR1 蛋白複合體。經由我們的生化研究指出,SWI5-SFR1 會刺激RAD51 所進行的同源DNA 配對以及穩定RAD51 核蛋白絲。這樣的研究顯示出SWI5-SFR1 刺激RAD51 活性主要是來自於穩定RAD51 核蛋白絲的生成。RAD51
是ssDNA 依賴的ATP 水解酵素。ATP 結合會促進RAD51 核蛋白絲的形成和股交換活性。然而,由於ATP 水解和低的ADP 釋放速率,會使有活性的ATP 結合的RAD51 核蛋白絲變成沒有活性的ADP結合的RAD51 核蛋白絲。我們進一步發現,SWI5-SFR1 會促進RAD51 核蛋白絲的ADP 釋放。這代表SWI5-SFR1 可以協助RAD51 核蛋白絲處在有活性的ATP 結合態。此外,我們也更進一步闡明SWI5-SFR1 和RAD51 交互作用的模式和區域。我們發現SWI5-SFR1 主要是跟多聚體RAD51 有交互作用。另外,我們也找到SWI5 的F83 和L85 對於和RAD51的交互作用是必要的。更重要的是,對於刺激RAD51 的活性是需要SWI5-SFR1和RAD51 的彼此交互作用。我們的研究結果闡釋了SWI5-SFR1 複合體刺激RAD51所主導的同源去氧核醣核酸的作用機轉。 | zh_TW |
dc.description.abstract | Homologous recombination (HR) mediated by RAD51 recombinase eliminates DNA double-strand breaks in the genome. RAD51 forms a nucleoprotein filament on single-stranded DNA (ssDNA), termed the presynaptic filament, to initiate homologous recombination. Cytological studies in mammal indicate that SWI5 and SFR1 form a complex and participate in RAD51-mediated recombination repair. To decipher the mechanistic role of mammal SWI5-SFR1 complex in RAD51-mediated HR, we established the expression and the purification procedure to obtain mouse SWI5-SFR1 protein complex. Our biochemical study showed that SWI5-SFR1 complex stimulates homologous DNA pairing by RAD51 and stabilizes the RAD51 presynaptic filament, demonstrating that the stimulation of RAD51 activity stems from the stabilization of RAD51 filament by SWI5-SFR1 complex. RAD51 is an ssDNA dependent ATPase. ATP binding promotes the formation of a functional RAD51 nucleoprotein filament and DNA stand exchange activity. However, owing to ATP hydrolysis and slow dissociation rate of ADP, active RAD51 filament is converted into an inactive RAD51-ADP-ssDNA filament. We further documented that SWI5-SFR1 acts by facilitating the release of ADP from the RAD51 presynaptic filament, indicating that SWI5-SFR1 helps maintain RAD51 presynaptic filament in its active ATP bound form. Furthermore, we determined the interaction mode and region between SWI5-SFR1 and RAD51. We found that SWI5-SFR1 preferentially interacts with oligomeric form of RAD51. Importantly, the residue F83 and L85 in C-terminal SWI5 of SWI5-SFR1 complex is essential for the interaction of RAD51. The interaction of SWI5-SFR1 to RAD51 is indispensable for stimulation of RAD51 activity. Our results thus provide the insight for the action mechanism of RAD51-mediated DNA exchange by SWI5-SFR1 complex. | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T11:19:00Z (GMT). No. of bitstreams: 1 ntu-105-D00b46013-1.pdf: 60939001 bytes, checksum: 31e77ca623ded4134ce341ccf30206fe (MD5) Previous issue date: 2016 | en |
dc.description.tableofcontents | 中文摘要………………………………………………………………………………...1
Abstract…………………………………………………………………………………2 Chapter 1. Literature Review and General Introduction (1) DNA damage response and double strand break repair…………………………...9 (2) Homologous recombination-mediated DNA repair……………………………...11 (3) RAD51 recombinase……………………………………………………………..12 (4) BRCA2…………………………………………………………………………...14 (5) SWI5-SFR1 complex…………………………………………………………….15 (6) Aim of study……………………………………………………………………..17 Chapter 2. The stabilization of RAD51 filament by SWI5-SFR1 complex A. Abstract………………………………………………………………………….19 B. Introduction……………………………………………………………………..20 C. Materials and Methods………………………………………………………....22 (1) DNA substrates…………………………………………………………………..22 (2) Plasmids………………………………………………………………………….23 (3) Protein expression and purification ……………………………………………..24 (4) Exonuclease I protection assay…………………………………………………..28 (5) DNA strand exchange reaction…………………………………………………..29 (6) Isothermal titration calorimetry………………………………………………….29 (7) Analytical ultracentrifugation……………………………………………………30 (8) Affinity pulldowns……………………………………………………………….31 (9) Topological assay to measure presynaptic filament turnover……………………31 (10) DNA mobility shift assay………………………………………………………32 D. Results……………………………………………………………………………33 (1) Mammalian SWI5, SFR1 and the SWI5-SFR1 complex…………………. …….33 (2) Biophysical characterization of the SWI5-SFR1 complex…………….. ……….33 (3) SWI5–SFR1 stimulates RAD51 recombinase activity…………………………..34 (4) Interaction of SWI5–SFR1 with RAD51………………………………………...35 (5) Stabilization of the RAD51 presynaptic filament by the SWI5-SFR1 complex……………………………………………………………………...........36 (6) A stabilized RAD51 presynaptic filament is unresponsive to SWI5-SFR1……..38 (7) The RSfp motif in SFR1 is inhibitory to SWI5–SFR1 function…………………39 4 E. Discussion……………………………………………………………………….41 (1) Physical and functional interactions of the mammalian SWI5-SFR1 complex with Rad51……………..…………………………………………………………41 (2) Comparison of the mouse SWI5–SFR1 complex with its Schizosaccharomyces pombe and Saccharomyces cerevisiae orthologs………………………..………..42 (3) The regulatory role of the RSfp motif in SFR1………………………………….43 (4) Other Rad51 accessory factors with a presynaptic filament maintenance role….44 Chapter 3. Enhancement of ADP release from RAD51 filament by SWI5-SFR1 complex A. Abstract………………………………………………………………………….46 B. Introduction……………………………………………………………………..47 C. Materials and Methods…………………………………………………………49 (1) DNA substrates…………………………………………………………………..49 (2) Plasmids………………………………………………………………………….50 (3) Protein expression and purification……………………………………………...51 (4) Affinity pulldowns……………………………………………………………….53 (5) DNA strand exchange reaction ……………………………………………….…53 (6) Exonuclease I protection assay…………………………………………………..54 (7) Nitrocellulose filter binding assay to monitor ADP release from RAD51 filament………………………………..…………………………………………..54 (8) Single-molecule optical tweezers……………..…………………………………57 (9) ATPase activity…………………………………………………………………..58 D. Results……………………………………………………………………………60 (1) Single-molecule optical tweezers measurement provides evidence for stabilization of RAD51-DNA nucleoprotein filaments by SWI5-SFR1……..…...60 (2) SWI5-SFR1 enhances ATP hydrolysis by the RAD51 presynaptic filament……62 (3) Enhancement of RAD51 ATPase activity requires a specific interaction of SWI5-SFR1 with RAD51…………………………………………......64 (4) SWI5-SFR1 facilitates ADP/ATP exchange in the RAD51 presynaptic filament………………………..…………………………………………………..64 (5) SWI5-SFR1 enhances ADP release from the RAD51 filament…………………66 (6) SWI5-SFR1 has no significant effect on ATP-binding affinity of RAD51 filament…………..………………………………………………………………..68 E. Discussion…………………………………………………………......................68 5 (1) The function of SWI5-SFR1 in RAD51-mediated HR………………………….68 (2) Implications for the yeast Swi5-Sfr1 orthologs………………………………….69 Chapter 4. The interaction of RAD51-SWI5-SFR1 in homologous recombination A. Abstract………………………………………………………………………….72 B. Introduction……………………………………………………………………...73 C. Materials and Methods…………………………………………………………75 (1) DNA substrates…………………………………………………………………..76 (2) Plasmids………………………………………………………………………….76 (3) Protein expression and purification…………………………………….……......77 (4) Gel filtration analysis…………………………………………………………….80 (5) Affinity pulldown………………………………………………………………..80 (6) Limited proteolysis………………………………………………………………81 (7) DNA strand exchange……………………………………………………………81 (8) Exonuclease I protection…………………………………………………………81 (9) Analytical ultracentrifugation……………………………………………………82 (10) Circular dichroism analysis…………………………………………………….82 (11) ATPase activity…………………………………………………………………83 (12) Electron microscopy……………………………………………………………83 D. Results……………………………………………………………………………84 (1) SWI5–SFR1 interacts with the oligomeric form of RAD51……….……………84 (2) The amino-terminal half of SFR1 is dispensable for complex formation with SWI5 and interaction with RAD51………………………………………….....86 (3) The carboxyl-terminal region of SWI5 is critically important for RAD51 interaction……………………………………………………………………......87 (4) Physical interaction is prerequisite for RAD51 activity regulated by SWI5– SFR1…………………………………….……………………………………..89 E. Discussion………………………………………………………………………..91 (1) The physical interaction is prerequisite for the enhancement of SWI5–SFR1 by RAD51……………..…………………………………………………………..91 (2) Differential interaction modes of RAD51 and SWI5–SFR1 from yeast to mammal………………………………………………………………………….92 (3) The implication of SWI5–SFR1 interacts with oligomeric form of RAD51…….93 Chapter 5. Conclusions and Perspectives A. Summary of Key Findings……………………………………………….……..94 6 B. Future Directions……………………………………………………………..…96 (1) Functional relationship of SWI5-SFR1, RAD51 and DMC1 in meiotic recombination…………..………………………………………………………96 (2) Structural analysis for the function of SWI5-SFR1 complex in RAD51- mediated HR……….…………………………………….……………………..98 (3) Single-molecule approach to determine the assembly and disassembly of RAD51 filaments by SWI5-SFR1 complex……………………………….100 (4) Searching for SWI5-SFR1 interacting partners……………………………102 Figures………………………………………………………………………………..104 Figure A. Molecular mechanism of homologous recombination. ……………………104 Figure B. Recombinase RAD51 filament and displacement loop (D-loop) formation.105 Figure C. The role of ATP hydrolysis and ATP binding of RAD51 filament ……….106 Figure D. The function of BRCA2 in the formation of RAD51 filament…………….107 Figure 1. Biophysical properties of the SWI5–SFR1 complex……………………….108 Figure 2. Sedimentation velocity analysis of SWI5-SFR1……………………………109 Figure 3. Promotion of RAD51-mediated DNA strand exchange by SWI5–SFR1…..110 Figure 4. SWI5–SFR1 complex but not SWI5 or SFR1 physically interacts with Rad51…………………………..………………………………………….112 Figure 5. Enhancement of RAD51-mediated DNA strand exchange by SWI5–SFR1.113 Figure 6. Stabilization of the RAD51 presynaptic filament by SWI5–SFR1…………114 Figure 7. RecA presynaptic filament is not stabilized by SWI5-SFR1……………….116 Figure 8. DNA topological experiment to examine the presynaptic filament stabilization activity of SWI5-SFR1………………………………………………..…..117 Figure 9. Presynaptic filament stabilization by AMP-PNP or Ca2+ alleviates dependence on SWI5-SFR1………………………………………………………..…..118 Figure 10. Functional significance of the RSfp motif in SFR1……………………….119 Figure 11. RAD51 presynaptic filament stabilization by the SWI5-dN104SFR1…....121 Figure 12. SWI5-SFR1 is devoid of DNA binding activity…………………………..122 Figure 13. SWI5-SFR1 stabilizes RAD51 filament…………………………………..123 Figure 14. Stabilization of the RAD51 filament by AMP-PNP………………………124 Figure 15. SWI5-SFR1 enhances RAD51 ATPase activity…………………………..125 Figure 16. The effect of SWI5-SFR1 on ATP hydrolysis by the presynaptic filament is specific for RAD51. …………………………………………………….126 Figure 17. Functional interactions between RAD51 and SWI5-SFR1 complex……..127 7 Figure 18. SWI5-SFR1 but not RAD51AP1 mediates ADP–ATP exchange of RAD51 filament..………...……………………………………………………….129 Figure 19. SWI5, SFR1, or SWI5-SFR1 complex are devoid of nucleotide binding activity………………..………………………………………………….130 Figure 20. SWI5-SFR1 expedites ADP release from the RAD51 filament…………..132 Figure 21. SWI5-SFR1 facilitates ADP release from the RAD51 filament…………..133 Figure 22. SWI5-SFR1 does not alter ATP-binding affinity of RAD51 presynaptic filament...…….…………………….…………………………………….134 Figure 23. Inhibition of RAD51-mediated ATP hydrolysis by Ca2+………………….135 Figure 24. Effects of SWI5-SFR1 on the functional attributes of the RAD51-dsDNA filament…..……….………………...……………………………………136 Figure 25. Model depicting the mechanistic action of SWI5-SFR1 on RAD51 filament…………..………………………………………………………137 Figure 26. Oligomeric status of RAD51 wild-type (WT) or RAD51 S208E/A209D (RAD51 SA/ED) with or without the presence of BRC4 was analyzed by gel filtration analyses.………………………………………………………....138 Figure 27. SWI5–SFR1 interacts with the oligomeric formof RAD51……………….139 Figure 28. GST-BRC4 physically interacts with RAD51 but not SWI5-SFR1………141 Figure 29. Oligomeric status of mouse RAD51 (mRAD51) wild-type (WT), F86E, or A190L/A192L was analyzed by gel filtration………………..…………….142 Figure 30. Functional characterization of SWI5–SFR1dN202 complex………………..143 Figure 31. Sedimentation velocity analysis of the SWI5-SFR1dN202 complex………..145 Figure 32. SWI5dC20–SFR1, SWI5dC9–SFR1 and SWI5FL/AA–SFR1 are defective in RAD51 interaction……………………………..………………………..146 Figure 33. Biophysical properties of SWI5 F83A/L85A-SFR1 mutant complex…….148 Figure 34. SWI5 F83A/L85A-SFR1 is functionally impaired………………………..149 Figure 35. Representative images of negatively stained RAD51 presynaptic filaments as observed by electron microscopy.……………………………………...…151 Figure 36. SWI5-SFR1 has no effect on the functional attributes mouse DMC1 recombinase……………………..……………………………………….152 Figure 37. Gray scale of the residual bitmap for AUC and constant obtained by ITC for SWI5-SFR1…………………………..………………………………….153 Figure 38. The structure of SFR1dN202-SWI5 complex by SAXS and molecule modeling…………………………………………………………………154 8 Figure 39. The mechanistic function of SWI5-SFR1 complex on RAD51-mediated homologous recombination…………...…………………………………155 Abbreviation…………………………………………………………………………156 References……………………………………………………………........................157 | |
dc.language.iso | en | |
dc.title | 探討SWI5-SFR1 複合體在RAD51 參與的去氧核醣核酸修復的生化機制 | zh_TW |
dc.title | The mechanistic study of SWI5-SFR1 complex on RAD51-mediated DNA repair | en |
dc.type | Thesis | |
dc.date.schoolyear | 104-2 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 蔡明道(Ming-Daw Tsai),李弘文(Hung-Wen Li),鄧述諄(Shu-Chun Teng),呂平江(Ping-Chiang Lyu) | |
dc.subject.keyword | 同源重組,DNA 雙股斷裂,RAD51 核蛋白絲,SWI5-SFR1,ATP 水解,ADP 釋放, | zh_TW |
dc.subject.keyword | Homologous recombination,DNA double-strand breaks,RAD51 presynaptic filament,SWI5-SFR1,ATP hydrolysis,ADP release, | en |
dc.relation.page | 166 | |
dc.identifier.doi | 10.6342/NTU201603201 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2016-08-19 | |
dc.contributor.author-college | 生命科學院 | zh_TW |
dc.contributor.author-dept | 生化科學研究所 | zh_TW |
顯示於系所單位: | 生化科學研究所 |
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