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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林敬哲 | |
| dc.contributor.author | Wei-Ting Chen | en |
| dc.contributor.author | 陳蔚庭 | zh_TW |
| dc.date.accessioned | 2021-06-08T01:38:07Z | - |
| dc.date.copyright | 2017-03-01 | |
| dc.date.issued | 2016 | |
| dc.date.submitted | 2016-10-19 | |
| dc.identifier.citation | 1. Aguilera, A. & Garcia-Muse, T. (2012). R loops: from transcription byproducts to threats to genome stability. Mol Cell 46, 115-124.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/18870 | - |
| dc.description.abstract | 端粒是位於真核生物染色體末端的特殊結構，在細胞中扮演著重要腳色，功能為防止染色體間互相融合、保護染色體的完整複製以及穩定染色體末端結構。缺少端粒會造成細胞的老化及死亡。由於DNA末端複製的缺陷，端粒會隨著細胞複製次數的增加而逐漸縮短，以人類體細胞為例，大約分裂複製60至80次後，端粒因過短無法再保護DNA，而產生複製性衰老 (senescence) 的現象。然而，癌細胞卻可以逃過老化的命運，約85%的癌細胞可以透過活化端粒酶來重新複製端粒，使得癌細胞得以大量增生成為腫瘤; 約15%的癌細胞則會利用端粒重組(telomere recombination) 的機制來維持端粒長度，此類細胞稱作alternative lengthening of telomeres (ALT) cells。在酵母菌中，Rad52是調控端粒重組的重要蛋白，缺乏端粒酶活性的細胞會利用Rad52 蛋白調控的端粒重組機制來逃過複製性衰老，而這些逃過老化存活下來的細胞被稱作survivors。近來發現，端粒基因可被聚合酶(RNA polymerase II)轉錄成長片段的non-coding RNA，簡稱TERRA (long non-coding telomeric repeat-containing RNA)。TERRA與端粒的序列都有著G-rich的特性，所以容易與互相配對形成DNA:RNA和單股DNA的R-loop結構。這樣的結構存在會使得轉錄中的聚合酶受到阻礙而停滯，停滯聚合酶被視為細胞的損害，必須經由轉錄合併修復(transcription-coupled repair, TCR)或泛素化蛋白降 (ubiquitin-mediated proteolysis)等相關的方式來移除stalled polymerase。我們先前研究發現，TERRA、R-loop以及停滯的polymerase可能會經由引發類似於TCR的機制而促使端粒重組的發生。由於細胞利用端粒重組逃過老化產生survivor的背後機制尚未明瞭，故本篇研究利用染色質免疫沉澱 (ChIP) 的方法，在端粒酶缺失的年輕至老化細胞，分析其端粒重組蛋白Rad52、MRN complex或者RNA polymerase II 在端粒序列上的變化。我們發現，在酵母菌細胞的老化過程中，不管是Rad52或RNA polymerase並不會特別累積在特定代數的細胞。然而，當Def1 (RNA polymerase degradation factor)蛋白突變後，則可以發現Rad52及RNA polymerase II會大量累積在端粒上，初步推測Def1可能是經由影響chromatin structure而造成蛋白的累積。 | zh_TW |
| dc.description.abstract | Telomere, the end structure of eukaryotic chromosome, plays an important role in cellular function that allows complete replication and maintains the integrity of chromosomes. Due to the end-replication problem, the telomeres are shortened upon each cell division that eventually leads to replicative senescence. Normal human somatic cells enter senescence after ~60-80 cell divisions. Most of the cancer cells overcome senescence by activating telomerase, whereas 10-15% of the cancer cells use alternative lengthening of telomeres (ALT) pathway. The ALT pathway is mediated by mechanism through homologous recombination (HR). In Saccharomyces cerevisiae, cells that lack the telomerase RNA component, TLC1, stop dividing after ~70 cell divisions. Only rare survivors escape senescence by maintaining their telomeres through a radiation sensitive 52 (RAD52)-dependent recombination mechanism. The mechanism of how homologous recombination is activated during senescence is less clear. Telomere are transcribed into a long non-coding telomeric repeat-containing RNA, TERRA, by RNA polymerase II. TERRA can bind to telomere to form an R-loop structure which may impede the progression RNA polymerase and trigger recombination mechanism. Generally, the stalled RNA polymerase is repaired by the transcription-coupled repair (TCR) machinery or degraded by the ubiquitin-mediated proteolysis. Here the role of stalled RNAPII in Rad52-dependent telomere recombination is tested. Using chromatin immunoprecipitation (ChIP), the amount of Rad52, Mre11, and RNAPII on telomere during survivor formation are determined in Saccharomyces cerevisiae. I found that mutation in DEF1, which encodes an RNAPII degradation factor, increased the accumulation of Rad52 and RNA polymerase in telomerase-negative cells. The results indicated that stalled RNAPII may induce telomere recombination, supporting that the R-loop structure formed by TERRA might stall RNA polymerase progression to induce transcription-mediated telomere recombination. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T01:38:07Z (GMT). No. of bitstreams: 1 ntu-105-R03442014-1.pdf: 2621247 bytes, checksum: 0601dc5ca17492fd120978e6574a0070 (MD5) Previous issue date: 2016 | en |
| dc.description.tableofcontents | 口試委員審定書……………………………………………………… i
誌謝…………………………………………………………………… ii 中文摘要……………………………………………………………… iii 英文摘要……………………………………………………………… iv 目錄…………………………………………………………………… v 圖目錄………………………………………………………………… vi 縮寫檢索表……………………………………………………………vii 前言…………………………………………………………………… 1 材料方法……………………………………………………………… 9 實驗結果……………………………………………………………… 20 討論…………………………………………………………………… 25 參考文獻……………………………………………………………… 28 附圖…………………………………………………………………… 36 | |
| dc.language.iso | zh-TW | |
| dc.title | 探討酵母菌中轉錄相關之端粒重組機制 | zh_TW |
| dc.title | Analyzing the mechanism of transcription-mediated telomere recombination in Saccharomyces cerevisiae | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 105-1 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 鄧述諄,鄭子豪 | |
| dc.subject.keyword | transcription-associated recombination,telomere,Rad52,Rad26,Def1, | zh_TW |
| dc.relation.page | 45 | |
| dc.identifier.doi | 10.6342/NTU201603682 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2016-10-19 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 生物化學暨分子生物學研究所 | zh_TW |
| 顯示於系所單位： | 生物化學暨分子生物學科研究所 | |
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