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標題: | ALT細胞核膜上的端粒連結抑制端粒重組 Nuclear envelope tethering suppresses telomere-telomere recombination in ALT cells |
作者: | Hao-Jhe Sun 孫浩哲 |
指導教授: | 鄧述諄(Shu-Chun Teng) |
關鍵字: | 端粒重組,端粒連結,替代性端粒延長,SUN1,Lamin A, Telomere-telomere recombination,Telomere tethering,Alternative lengthening of telomeres,SUN1,Lamin A, |
出版年 : | 2017 |
學位: | 碩士 |
摘要: | 端粒的維持有助於染色體的穩定,端粒酶以DNA典型的複製方式使端粒延長。在癌細胞和酵母菌中,當缺乏端粒酶時,會利用替代性的重組機制來維持端粒。大部的癌細胞會表現端粒酶的活性,但有10-15%的癌細胞利用不需要端粒酶的路徑來生存,稱為替代性端粒延長(ALT)。在ALT細胞中已知端粒重組能延長端粒。在細胞週期中,許多的腳色會參與在端粒連結核膜。端粒重組時需要拓撲異構酶II和IIIα來解開拓撲壓力。為了觀察當細胞失去核膜與端粒的連結是否會影響端粒重組,我們分別選了會與RAP1和TRF2作用的SUN1和LaminA當作核膜上的目標。在ALT細胞缺乏SUN1或是Lamin A時會增加APB的形成,當表現RAP1和SUN1的融合蛋白時則會使APB的形成下降。綜合失去端粒連結和組蛋白分子伴侶ASF1的缺失可以使非ALT細胞的APB形成有加成性的增加。 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. While most cancer cell present telomerase activity, a particular population of cancers (10–15%) live with telomerase-independent pathway which is known as Alternative Lengthening of Telomeres (ALT). Telomere-telomere recombination is the pathway for telomere elongation in ALT cell. During cell cycle, telomeres tethered to the nuclear envelope and nuclear components may be involved in this process. To investigate whether telomere recombination would be affected in cells that loses telomeres tethering, we modulated SUN1 and Lamin A which interact with telomere binding proteins RAP1 and TRF2, respectively, as targets on nuclear envelop. Depletion of SUN1 or Lamin A increased ALT-associated promyelocytic leukaemia bodies (APBs) formation in ALT cells. Expression of a RAP1 and SUN1 fusion protein decreased APB signals. The combination of loosen telomere tethering and depletion of histone chaperone ASF1 synergistically induced the APB formation in non-ALT cancer cells. SUN1 or Lamin A depletion bypass the requirement of TOP3 for efficient telomere-telomere recombination. Altogether, these findings indicate that while this regular telomere territory may protect telomeres, it also displays a function to suppress telomere-telomere recombination. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/67574 |
DOI: | 10.6342/NTU201702198 |
全文授權: | 有償授權 |
顯示於系所單位: | 微生物學科所 |
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