nature20121213-13

来自科罗拉多大学生物尖端科学研究所(BioFrontiers Institute)的研究人员详细描述了定位在我们DNA两末端的一个抗癌药物开发的新靶点。

-2012年12月13日《自然》


中文翻译


【题目】端粒蛋白TPP1的TEL片段介导端粒酶的招募和持续合成能力

【译文】人类染色体末端被shelterin覆盖,shelterin是保护自然末端以免被识别为DNA损伤位点的蛋白复合物,也可以调控端粒复制酶——端粒酶。Shelterin包括异二聚体POT1–TPP1蛋白,它结合在末端着丝粒的单链DNA尾部。 TPP1参与招募端粒酶到端粒以及刺激端粒酶的持续合成能力(单引物结合事件后添加多种DNA重复序列)。确定这些活动的机制非常困难,主要是因为遗传干扰也会影响TPP1的重要染色体末端保护功能。本研究鉴定了在体内外保持完整的端粒加帽功能的人TPP1功能分离的突变体,虽然在结合人类端粒酶中是存在缺陷的。7个功能分离突变定位于TPP1表面的氨基酸片段,即TEL片段,它们可以招募端粒酶至端粒并促进高度持续合成能力DNA的合成,表明这两种活动是同一种分子相互作用的表现。由于在体内端粒酶和TPP1之间的相互作用是端粒酶功能所必需的,TPP1的TEL片段为抗癌药物的开发提供了新的靶点。 

英文原稿


[Title]: The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity

[Authors]:Jayakrishnan Nandakumar,1, 2 Caitlin F. Bell,1, 2, 4, 5 Ina Weidenfeld,1, 3, 5 Arthur J. Zaug,1, 2

Leslie A. Leinwand1, 3 & Thomas R. Cech1, 2, 3

[Abstract]Human chromosome ends are capped by shelterin, a protein complex that protects the natural ends from being recognized as sites of DNA damage and also regulates the telomere-replicating enzyme, telomerase. Shelterin includes the heterodimeric POT1–TPP1 protein, which binds the telomeric single-stranded DNA tail. TPP1 has been implicated both in recruiting telomerase to telomeres and in stimulating telomerase processivity (the addition of multiple DNA repeats after a single primer-binding event). Determining the mechanisms of these activities has been difficult, especially because genetic perturbations also tend to affect the essential chromosome end-protection function of TPP1. Here we identify separation-of-function mutants of human TPP1 that retain full telomere-capping function in vitro and in vivo, yet are defective in binding human telomerase. The seven separation-of-function mutations map to a patch of amino acids on the surface of TPP1, the TEL patch, that both recruits telomerase to telomeres and promotes high-processivity DNA synthesis, indicating that these two activities are manifestations of the same molecular interaction. Given that the interaction between telomerase and TPP1 is required for telomerase function in vivo, the TEL patch of TPP1 provides a new target for anticancer drug development.

原文地址

http://www.nature.com/nature/journal/v492/n7428/full/nature11648.html

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