Telomerase activation after recruitment in fission yeast.
Telomerase activation after recruitment in fission yeast.
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DOI：
10.1016/j.cub.2014.07.035
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发表时间：
2014-09-08
期刊：
影响因子：
9.2
通讯作者：
Tomita, Kazunori
中科院分区：
文献类型：
--
作者：
Armstrong, Christine Anne;Pearson, Sian Rosanna;Amelina, Hanna;Moiseeva, Vera;Tomita, Kazunori
目前的模型描述端粒酶募集等同于激活。端粒DNA结合蛋白和端粒酶辅助蛋白以端粒长度和细胞周期依赖的方式协调端粒酶向染色体末端的募集。最近的研究表明，端粒蛋白TPP1及其结合蛋白TIN 2是哺乳动物细胞中端粒酶募集和持续合成的关键蛋白。尽管尚未确定端粒酶募集的精确分子机制，但已证明TPP 1的寡核苷酸/寡聚糖结合（OB）折叠结构域内的靶向点突变会损害端粒酶结合和持续合成能力。在裂殖酵母中，端粒酶通过端粒酶亚基Est1和Ccq 1（Pot1-Tpz 1端粒复合物（POT1-TPP1直系同源物）的组分）之间的相互作用而被募集。在这里，我们证明了端粒酶与端粒的关联不参与活动。我们描述了一个突变的Tpz1，导致关键的端粒缩短，尽管端粒的端粒酶催化亚基，Trt1的积累。此外，Est1指导的端粒酶与Ccq1的关联是短暂的，并且Est1-Ccq1相互作用并不保持端粒和端粒酶之间的桥梁。相反，Trt1与Tpz1的直接相互作用对于端粒延伸至关重要。此外，Ccq 1，这已被很好地表征为端粒酶募集，也需要激活端粒相关的端粒酶。我们的研究结果揭示了一层端粒酶调节，控制活动后招聘。Est 1-Ccq 1相互作用将端粒酶募集到端粒是短暂的。端粒酶必须与Tpz 1和Ccq 1结合才能使端粒延长。tpz 1-K75 A突变细胞尽管有端粒酶募集，但仍表现出端粒缩短。然而，Armstrong et al.发现该招募步骤不涉及活动。相反，Trt1与Tpz1的直接相互作用对于端粒延伸至关重要。Tpz1的寡核苷酸/寡糖结合倍数可能控制这种相互作用。ccq1是端粒酶的募集者，也是端粒酶激活所必需的。
Current models depict that telomerase recruitment equates to activation. Telomeric DNA-binding proteins and the telomerase accessory proteins coordinate the recruitment of telomerase to the ends of chromosomes in a telomere length- and cell-cycle-dependent manner. Recent studies have demonstrated that the telomeric protein TPP1 and its binding protein TIN2 are key proteins for both telomerase recruitment and processivity in mammalian cells. Although the precise molecular mechanism of telomerase recruitment has not yet been established, targeted point mutations within the oligonucleotide/oligosaccharide-binding (OB)-fold domain of TPP1 have been shown to impair telomerase association and processivity. In fission yeast, telomerase is recruited through an interaction between the telomerase subunit Est1 and Ccq1, a component of the Pot1-Tpz1 telomere complex (POT1-TPP1 orthologs). Here, we demonstrate that association of telomerase with telomeres does not engage activity. We describe a mutation of Tpz1 that causes critical telomere shortening despite telomeric accumulation of the telomerase catalytic subunit, Trt1. Furthermore, Est1-directed telomerase association with Ccq1 is transient, and the Est1-Ccq1 interaction does not remain the bridge between telomeres and telomerase. Rather, direct interaction of Trt1 with Tpz1 is critical for telomere elongation. Moreover, Ccq1, which has been well characterized as a telomerase recruiter, is also required for the activation of telomere-associated telomerase. Our findings reveal a layer of telomerase regulation that controls activity after recruitment. The Est1-Ccq1 interaction recruiting telomerase to the telomere is transient Telomerase must associate with Tpz1 and Ccq1 for telomere lengthening to occur tpz1-K75A mutant cells exhibit telomere shortening despite telomerase recruitment The OB-fold domain of Tpz1 modulates telomerase activity Est1 navigates telomerase to the telomere in fission yeast. However, Armstrong et al. find that this recruitment step does not engage activity. Rather, direct interaction of Trt1 with Tpz1 is crucial for telomere elongation. The oligonucleotide/oligosaccharide-binding fold of Tpz1 may control this interaction. Ccq1, a telomerase recruiter, is also required for telomerase activation.
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