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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 鄧述諄 | |
| dc.contributor.author | Meng-Hsun Hsieh | en |
| dc.contributor.author | 謝孟勳 | zh_TW |
| dc.date.accessioned | 2021-06-17T01:31:59Z | - |
| dc.date.available | 2017-09-12 | |
| dc.date.copyright | 2017-09-12 | |
| dc.date.issued | 2017 | |
| dc.date.submitted | 2017-08-03 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/67432 | - |
| dc.description.abstract | 端粒酶在癌症和胚胎幹細胞中高度表現，並參與調控基因的完整性，癌症形成和幹細胞潛能性。先前研究發現類Krüppel轉錄因子4（KLF4）活化端粒酶逆轉錄酶（TERT）的表現，並有助於維持胚胎幹細胞中的自我更新。然而，對於KLF4如何調節TERT表現尚未了解透徹。在本篇研究中，我們發現聚（ADP-核糖）聚合酶1（PARP1）為一個新穎的KLF4結合蛋白。 剔除PARP1除了在癌細胞外，在人和小鼠胚胎幹細胞中都能降低TERT的表現和端粒酶活性。抑制PARP1會降低KLF4對結合TERT 啟動子的能力。寡聚（ADP-核糖）聚合酶活性 (oligo(ADP-ribose) polymerase activity) 為PARP1和KLF4的活化TERT所必需的酵素活性。在小鼠胚胎幹細胞中抑制Parp1會降低多能標記物的表現並誘導分化。這些結果表明，PARP1能結合KLF4以活化端粒酶表現和幹細胞多能性，顯示PARP1-KLF4複合物在癌細胞及幹細胞中端粒酶的表現具有正向的調節作用。
染色體的穩定需要端粒來維持，端粒長度在DNA複製後通常被端粒酶延長。在缺乏端粒酶的腫瘤和酵母細胞中，通過替代重組機制維持端粒。先前的研究表明酵母Sgs1和Top3可以一起去除由重組產生的高度負超螺旋。然而，細胞在重組期間消除高正向超螺旋的機制仍不清楚。在本研究中，我們證明抑制拓撲異構酶II (Topoisomerase II; Top2) 參與了端粒重組。 RIF1或RIF2缺失所引起的端粒結構干擾減輕了端粒末端重組中Top2的需求。在人類端粒酶陰性ALT （Alternative lengthening of telomeres, 替代延長端粒）細胞中，TOP2α或TOP2β的抑制能減少ALT相關的PML體，增加端粒失能引起的病灶並導致端粒縮短。當用ICRF-193（TOP2抑制劑）處理ALT細胞時，也能觀察到類似的結果。重要的是，ICRF-193也能阻斷ALT細胞的相關表型，引起端粒縮短，也能抑制小鼠的ALT細胞增殖。總而言之，這些發現意味著TOP2參與在ALT途徑中，可能是透過解決解旋酶前面的高度正向超螺旋結構，而抑制拓撲異構酶II可望能成為預防ALT型癌症的新穎治療方法。 | zh_TW |
| dc.description.abstract | Telomerase is highly expressed in cancer and embryonic stem cells and implicated in controlling genome integrity, cancer formation, and stemness. Previous studies identified that Krüppel-like transcription factor 4 (KLF4) activates telomerase reverse transcriptase (TERT) expression and contributes to the maintenance of self-renewal in embryonic stem cells (ESCs). However, little is known about how KLF4 regulates TERT expression. Here, I discover poly(ADP-ribose) polymerase 1 (PARP1) as a novel KLF4-interacting partner. Knockdown of PARP1 reduces TERT expression and telomerase activity not only in cancer cells but also in human and mouse ESCs. Recruitment of KLF4 to TERT promoter is reduced in PARP1 suppressed cells. The poly(ADP-ribose) polymerase activity is dispensable while the oligo(ADP-ribose) polymerase activity is required for the PARP1- and KLF4-mediated TERT activation. Repression of Parp1 in mouse ESCs decreases expression of pluripotent markers and induces differentiation. Expression of Tert rescues Parp1 depletion-mediated changes to maintain their self-renewal. These results suggest that PARP1 recruits KLF4 to activate telomerase expression and stem cell pluripotency, indicating a positive regulatory role of the PARP1-KLF4 complex in telomerase expression in cancer and stem cell.
Telomere maintenance is required for chromosome stability, and telomeres are typically elongated by telomerase following DNA replication. In both tumor and yeast cells that lack telomerase, telomeres are maintained via an alternative recombination mechanism. Previous studies have indicated that yeast Sgs1 and Top3 may work together to remove highly negative supercoils that are generated from recombination. However, the mechanism by which cells eradicate highly positive supercoils during recombination remains unclear. In the present study, I demonstrate that Top2 is involved in telomere-telomere recombination. Disturbance of telomeres structure by RIF1 or RIF2 deletion alleviates the requirement for Top2 in telomere-telomere recombination. In human telomerase-negative ALT (alternative lengthening of telomere) cells, TOP2α or TOP2β knockdown decreases ALT-associated PML (Promyelocytic Leukemia) nuclear bodies, increases telomere dysfunction-induced foci and triggers telomere shortening. Similar results were observed when ALT cells were treated with ICRF-193, a TOP2 inhibitor. Importantly, ICRF-193 treatment blocks ALT-associated phenotypes in vitro, causes telomere shortening, and inhibits ALT cell proliferation in mice. Taken together, these findings imply that TOP2 is involved in the ALT pathway, perhaps by resolving the highly positive supercoil structure at the front of the helicase. Inhibition of topoisomerase II may be a promising therapeutic approach that can be used to prevent cell proliferation in ALT-type cancer cells. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T01:31:59Z (GMT). No. of bitstreams: 1 ntu-106-D99445005-1.pdf: 3424331 bytes, checksum: 319604e2e569232a8aca7d0300722f27 (MD5) Previous issue date: 2017 | en |
| dc.description.tableofcontents | 口試委員會審定書 v
中文摘要 vi Chapter 1: PARP1 Controls KLF4-Mediated Telomerase Expression in Stem Cells and Cancer Cells vi Chapter 2: Topoisomerase II inhibition suppresses the proliferation of telomerase-negative cancers vii Chapter 1: PARP1 Controls KLF4-Mediated Telomerase Expression in Stem Cells and Cancer Cells 1 ABSTRACT 1 INTRODUCTION 3 MATERIALS & METHODS 6 Cell Culture and Transfection 6 Immunoprecipitation and Mass Spectrometry Analysis 8 In vitro Binding Assay and Detection of poly(ADP-ribose) Chains 9 RNA Purification and Quantitative Reverse Transcription PCR (qRT-PCR) 10 siRNA and Telomeric Repeat Amplification Protocol (TRAP) 10 Luciferase Reporter Assay 12 Chromatin Immunoprecipitation (ChIP) Assay 12 Alkaline Phosphatase Staining 13 Statistical Analysis 13 RESULTS 14 Identification of PARP1 as a KLF4 Interacting Protein. 14 PARP1 Regulates KLF4-mediated hTERT Transcription. 15 PARP1 Controls KLF4 Binding to the hTERT Promoter to Facilitate KLF4-dependent Transcriptional Activation. 16 PARP1 is Required for Maintaining TERT Expression in ESCs. 18 The Parp1-Klf4 Interaction Promotes Pluripotency of Mouse ESCs. 20 DISCUSSION 22 Chapter 2: Topoisomerase II inhibition suppresses the proliferation of telomerase-negative cancers 26 ABSTRACT 26 INTRODUCTION 28 MATERIALS AND METHODS 32 Yeast Strain and Plasmid Constructions. 32 Yeast Culture Condition, DNA Preparation, Enzyme Digestion, Gel Electrophoresis, and Southern Analysis. 32 Mammalian Cell Culture, Transfection, RNA Interference, Synthesis of the TOP2 Inhibitor and Western Blot Analysis. 33 Telomere Restriction Fragment (TRF) Analysis. 34 Immunofluorescence Staining and Telomere Fluorescence in Situ Hybridization Staining. 35 In Vivo Pharmacology with Xenografted Mouse Tumors. 36 RESULTS 38 Top2 Contributes to Telomere Recombination in Telomerase-minus (tlc1Δ) Yeast 38 Mutations in RIF1 and RIF2 Restore Telomere-Telomere Recombination in tlc1 top2-ts Cells. 42 Expression of Yeast Top2 and Human TOP2α and TOP2β Restores Type II Survivors in tlc1 top2-ts Cells 44 Knockdown of TOP2α or TOP2β Inhibits Telomere Maintenance in ALT Cells 45 Topoisomerase II Inhibition Decreases ALT Cell Viability, Causes ALT Telomere Shortening, and Inhibits ALT Cancer Progression in Mice 47 DISCUSSION 50 FIGURES AND FIGURE LEGENDS 55 TABLES 97 Table 1. Constructs used in this study. 97 Table 2. Oligonucleotides used in qRT-PCR. 99 Table 3. Oligonucleotides used for ChIP assays. 101 Table 4. Strains used in this study. 102 REFERENCES 103 | |
| dc.language.iso | zh-TW | |
| dc.title | 尋找端粒維持途徑與藥物標靶的調控者 | zh_TW |
| dc.title | To Find Regulators of Telomere Maintenance Pathway and a Druggable Target | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 105-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 林敬哲,陳佑宗,呂仁,張玉芳 | |
| dc.subject.keyword | 幹細胞,端粒?, | zh_TW |
| dc.subject.keyword | Stem cells,telomerase, | en |
| dc.relation.page | 120 | |
| dc.identifier.doi | 10.6342/NTU201700981 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2017-08-03 | |
| 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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