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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 李財坤(Tsai-Kun Li) | |
| dc.contributor.author | Shih-Yun Huang | en |
| dc.contributor.author | 黃詩勻 | zh_TW |
| dc.date.accessioned | 2021-06-17T00:17:36Z | - |
| dc.date.available | 2012-09-24 | |
| dc.date.copyright | 2012-09-24 | |
| dc.date.issued | 2012 | |
| dc.date.submitted | 2012-06-29 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/65979 | - |
| dc.description.abstract | 拓樸異構酶(topoisomerase I/II/III, TOP I/II/III)可以藉催化DNA短暫的斷裂和重新黏合而解決DNA的拓樸結構問題。另外，拓樸酶亦被證明為治療癌症及抗生素的藥物標靶；此類藥物可以阻止酵素催化的DNA重新黏合，進而穩定拓樸異構酶可切性複合體(topoisomerase cleavable complex, TOPcc)，造成DNA斷裂及細胞死亡。TOPcc是一個DNA和拓樸酶以共價鍵連結的複合體(蛋白質上的酪胺酸和DNA上的磷酸共價連結)；值得注意的是，DNA斷點是被包覆在蛋白質裡的，因此必須經過細胞處理路徑(cellular processing pathway)讓斷點裸露出來以進行修補及其他訊息傳遞。TOP1會經由酪胺酸和DNA 3’端的磷酸形成共價鍵造成單股DNA斷裂；TOP2則是經由酪胺酸和DNA 5’端的磷酸形成共價鍵造成雙股DNA斷裂。此外，許多報導指出，人類酪胺酸DNA磷脂酶(human Tyrosyl-DNA Phosphodiesterase 1/2, hTDP1/2)可以藉由切斷拓樸酶和DNA間的共價鍵而使DNA斷點裸露出來，才能啟動DNA損傷反應及路徑(DNA damage response, DDR)。然而，我們對於人類細胞hTDP1/2處理TOP2cc的功能及特異性以及hTDP1/2和細胞處理路徑(TIP : 轉錄起始的處理，RIP : DNA複製起始的處理)間的關係依然不清楚。為了釐清這些問題，我們利用RNA干擾技術、強制蛋白表現以及藥物處理調控…等方法來探討hTDP1/2對於TOPcc所引發的DNA damage所造成的影響以及DNA的傷害反應。我們的結果證明，在人類細胞中hTDP1參與在TOP1cc的修復過程，而hTDP1和hTDP2皆參與在TOP2cc的修復過程。此外，在修復TOP2cc所造成的DNA損害的過程當中，hTDP1和hTDP2可能參與在TIP和RIP的路徑中，且作用在TOP2cc上的酵素降解之後，切掉最後的磷酸酪胺酸共價鍵。此外，缺少hTDP1或hTDP2的細胞對於針對TOP2的藥物皆有較高的感受性。綜合以上實驗結果，我們的研究證實hTDP1/2在解決TOP2cc所造成的DNA斷裂中所扮演的角色；此外，TOP和TDP藥物的合併使用或許也可以更有效治療癌症。 | zh_TW |
| dc.description.abstract | Topoisomerases (TOP1/2/3) can solve the topological problems of DNA through transient breakage and religation reactions and has become excellent targets of anticancer drugs. Drugs targeting topoisomerases induce the formation of topoisomerase cleavable complex (TOPcc) in a special form of protein-embedded, phosphotyrosyl-linked DNA breakage and hence blocking the accessibility of signaling and repair proteins. During the formation of TOPcc, TOP1 and TOP2 covalently links to DNA though a 3’-phosphotyrosyl bond and 5’-phosphotyrosyl bond, respectively. Tyrosyl-DNA phosphodiesterases (TDP1/2) have recently been reported to process the hidden DNA breakage in TOPcc into uncovered DNA lesions by mediating the cleavage of enzyme-DNA phosphotyrosyl linkage. However, the specificity to 3’- and 5’-phosphotyrosyl linkage and corresponding functions of hTDP1/2 in processing of TOP1/2cc remain ill defined. Toward this aim, we used RNA interference (RNAi) technology and overexpression system to investigate the roles of hTDP1/2 in the TOP1/2cc-mediated DNA breakage and DNA damage responses (DDR). In addition, the potential relationship among hTDP1/2, transcription- and replication-initiated processing (TIP and RIP) pathways are also studied. We found that hTDP1 contributes to the repair of TOP1cc while hTDP1 and hTDP2 both participate in the repair of TOP2cc in human cells. Moreover, our results also suggest that hTDP1/2 are involved in TOP2cc-mediated DDR that are activated by transcription- and replication-initiated processing pathway. Consistently, both hTDP1- and hTDP2-deficient cells are hypersensitive to TOP2-targeting drugs. Together, our studies not only demonstrated the distinctive roles of hTDP1/2 in the processing of TOP1/2cc but also suggest a novel combination therapeutic strategy of using TOP1/2- and TDP1/2-targeting agents. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T00:17:36Z (GMT). No. of bitstreams: 1 ntu-101-R99445125-1.pdf: 2539679 bytes, checksum: ed94d1a9cac47e169431ea1226f239b0 (MD5) Previous issue date: 2012 | en |
| dc.description.tableofcontents | 口試委員審訂書…………………………………………………………………………i
ACKNOWLEDGEMENTS…………………….…………………………………ii 中文摘要…….………………………………………………………………………….iii ABSTRACT……………………………………………………………………………iv CONTENTS………………………………………………………………………........v INTRODUCTION……………………………………………………………………..1 1. DNA topoisomerases and topoisomerase cleavable complex (TOPcc)………..1 1.1 Type I DNA topoisomerases……………………………………..……………2 1.2 Type II DNA topoisomerases………………………………………..…………2 1.3 DNA topoisomerases-targeting drugs and their importance in cancer therapy and bacterial infections………………………………………………………3 2. The cellular processing pathways and the repairing mechanisms of TOP1/2cc-mediated DNA damages………………………………………….....5 2.1 Cellular processing pathways of TOP1/2cc-mediated DNA damages…………5 2.1.1 Transcription-initiated processing (TIP) pathway…………………………5 2.1.2 B cell-specific Moloney murine leukemia virus intergration site 1(Bmi1)..6 2.1.3 Replication-initiated processing (RIP) pathway…………………………7 2.2 The repairing mechanisms of TOP1/2cc-mediated DNA damages…………….8 2.2.1 Tyrosyl-DNA phosphodiesterase 1 (TDP1)……………………………….8 2.2.1.1 Structure and biological functions of TDP1…………………………8 2.2.1.2 Spinocere ataxia with axonal neuropathy……………………………..9 2.2.1.3 Tyrosyl-DNA phosphodiesterase 1 repair pathway…………………9 2.2.2 Tyrosyl-DNA phosphodiesterase 2 (TDP2)……………………………10 2.2.2.1 Structure of TDP2………………………………………………….11 2.2.2.2 Biological functions of TDP2 – transcription regulation…………..11 2.2.2.3 Biological functions of TDP2 – signal transduction………………12 2.2.2.4 Biological functions of TDP2 – tyrosyl-DNA phosphodiesterase activity……………………………………………………………12 2.2.3 Poly(ADP-ribose)polymerase-1 (PARP-1)………………………………13 SPECIFIC AIMS……………………………………………………………………15 MATERIALS AND METHODS…………………………………………………16 - Chemicals and Cell Culture………………………………………………………16 - RNA interference (RNAi) knockdown technology………………………………..16 - Plasmids and Cell Transfection…………………………………………………….17 - Antibodies and Western blot analysis…………………………………………….17 - In Vivo complexes of Enzyme (ICE) bioassay…………………………………….18 - Alkaline single cell gel electrophoresis (Comet) assay…………………………….19 - Colony formation assay…………………………………………………………….20 - Immunofluorescence assay (IFA)…………………………………………………..20 - Quantitative and statistic analysis…………………………………………………21 RESULTS……………………………………………………………………………22 - Establishment of human TDP1 (hTDP1)- and human TDP2 (hTDP2)-specific knockdown and overexpressing in HCT116 cell line………………………………22 - The protective role of hTDP1 and hTDP2 in protecting TOP2-mediated cell killing by colony formation assay in HCT116 cells…………………………………………22 - The levels of chromosome DNA breakage induced by the TOP2-targeting drugs were higher in both the shTDP1 and shTDP2 cells………………………………….23 - The γH2AX activation levels induced by TOP2-targeting drugs are increased in HCT116 cells deficient in hTDP1 or hTDP2………………………………………24 - Transient knockdown of hTDP1 or hTDP2 in HEK293 cells also exacerbate DNA damage mediated by TOP2…………………………………………………………25 - Ectopic expression of hTDP1 or hTDP2 alleviated DNA damages mediated by TOP2…………………………………………………………………………………25 - Re-introduction of hTDP1/2 into hTDP1/2-deficient HEK293 cells decrease the TOP2-mediated DNA damages………………………………………………………26 - The formation and degradation of TOP2cc was not affected by the level of hTDP1 and hTDP2 in HCT116 and HEK293 cells…………………………………………..26 - hTDP1 and hTDP2 may participate both in TIP and RIP pathway………………27 - The degradation rate of TOP2α is slower in HEK293 cells deficient in Bmi1 (TOP2α specific proteasome E3 ligase)………………………………………………………28 - hTDP1 and hTDP2 must worked downstream of TOP2α degraded by UB/26S proteasome…………………………………………………………………………..29 - PARP-1 plays a minimal role in the repair of TOP2cc-mediated DNA damage…31 DISCUSSION……………………………………………………………………….32 REFERENCES……………………………………………………………………36 FIGURES AND APPENDIX……………………………………………………….47 - Figure 1. Transient knockdown or overexpression of hTDP1 or hTDP2 in HCT116 cells…………………………………………………………………………………….48 - Figure 2. HCT116 cells deficient in hTDP1 or hTDP2 are more sensitive to the TOP2-mediated cytotoxicity……………………………………………………………49 - Figure 3. DNA damage induced by TOP-targeting drugs are increased in HCT116 cells deficient in hTDP1 or hTDP2…………………………………………………….50 - Figure 4. The γH2AX activation levels induced by TOP2-targeting drugs were increased in HCT116 cells deficient in hTDP1 or hTDP2……………………………51 - Figure 5. Transient knockdown or overexpression of hTDP1 or hTDP2 in HEK293 cells…………………………………………………………………………………52 - Figure 6. The extents of chromosomal DNA break induced by TOP2-targeting drugs are increased in HEK293 cells deficient in hTDP1 or hTDP2…………………………53 - Figure 7. The γH2AX activation induced by TOP2-targeting drugs are increased in HEK293 cells deficient in hTDP1 or hTDP2…………………………………………54 - Figure 8. hTDP1 plays a role in processing of TOP1cc and TOP2cc in HCT116 cells……………………………………………………………………………………..55 - Figure 9. hTDP1 plays a role in processing of TOP1cc and TOP2cc in HEK293 cells……………………………………………………………………………………56 - Figure 10. The levels of γH2AX activation induced by Topoisomerase-targeting drugs are increased in HCT116 or HEK293 cells overexpressing hTDP1 or hTDP2………57 - Figure 11. Re-introduction of hTDP1/2 in hTDP1/2-deficient HEK293 cells reduce the levels of DNA breakage upon TOP2-targeting drug treatment………………………59 - Figure 12. The VP-16-induced TOP2cc formation and degradation were not affected in HCT116 cells with reduced expression of hTDP1 or hTDP2……………………….60 - Figure 13. The VP-16-induced TOP2cc formation and degradation were not affected in HEK293 cells with reduced expression of hTDP1 or hTDP2…………………….…61 - Figure 14. TOP2cc formation and degradation induced by VP-16 were not affected in HCT116 cells overexpressing hTDP1 or hTDP2…………………………………….62 - Figure 15. TOP2cc formation and degradation induced by VP-16 were not affected in HEK293 cells overexpressing hTDP1 or hTDP2………………………………………63 - Figure 16. Phosphorylations of Chk2 and p53 were increased upon VP-16 treatment in hTDP1 or hTDP2 knowck down HCT116 cells……………………………………….65 - Figure 17. The Phosphorylation level of Chk2 and p53 upon VP-16 treatment in hTDP1 or hTDP2 knowck down HCT116 are faster………………………………….66 - Figure 18. The degradation rate of TOP2α is slower in HEK293 cells deficient in Bmi1 (E3 ligase)………………………………………………………………………68 - Figure 19. hTDP1 and Bmi1 appear to function in the same pathway fot TOP2cc but not for TOP1cc………………………………………………………………………..69 - Figure 20. hTDP2 and Bmi1 appear to function in the same pathway fot TOP2cc but not for TOP1cc…………………………………………………………………………71 - Figure 21. hTDP1, hTDP2 and Bmi1 work in the same processing pathway of TOP2cc…………………………………………………………………………………72 - Figure 22. PARP is involeved in the repair of TOP1cc but not TOP2cc-mediated DNA damage…………………………………………………………………………73 - Figure 23. A scheme illustrating the processing of TOP2cc………………………….74 - Appendix 1. Alkaline single cell gel electrophoresis (Comet) assay…………………75 - Appendix 2. In Vivo Complexes of Enzyme (ICE) Bioassay………………………..76 | |
| dc.language.iso | en | |
| dc.title | 探討人類酪胺酸DNA磷脂酶在拓樸異構酶可切性複合體之處理路徑上所扮演的角色 | zh_TW |
| dc.title | Roles of Human Tyrosyl-DNA Phosphodiesterases in Processing Topoisomerase Cleavable Complexes | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 100-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 鄧述諄(Shu-Chun Teng),楊宏志(Hung-Chih Yang) | |
| dc.subject.keyword | 拓樸異構酶,拓樸異構酶,可切性複合體,人類酪胺酸DNA磷脂酶,細胞處理路徑,DNA損傷反應,轉錄起始的處理,DNA複製起始的處理, | zh_TW |
| dc.subject.keyword | topoisomerase,topoisomerase cleavable complex,DNA Phosphodiesterase,cellular processing pathway,DNA damage response,transcription- and replication-initiated processing pathways, | en |
| dc.relation.page | 76 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2012-06-29 | |
| 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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