Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne, Station 19, 1015 Lausanne, Switzerland.
Nature. 2012 Aug 23;488(7412):540-4. doi: 10.1038/nature11269.
The lengths of human telomeres, which protect chromosome ends from degradation and end fusions, are crucial determinants of cell lifespan. During embryogenesis and in cancer, the telomerase enzyme counteracts telomeric DNA shortening. As shown in cancer cells, human telomerase binds the shelterin component TPP1 at telomeres during the S phase of the cell cycle, and adds ~60 nucleotides in a single round of extension, after which telomerase is turned off by unknown mechanisms. Here we show that the human CST (CTC1, STN1 and TEN1) complex, previously implicated in telomere protection and DNA metabolism, inhibits telomerase activity through primer sequestration and physical interaction with the protection of telomeres 1 (POT1)–TPP1 telomerase processivity factor. CST competes with POT1–TPP1 for telomeric DNA, and CST–telomeric-DNA binding increases during late S/G2 phase only on telomerase action, coinciding with telomerase shut-off. Depletion of CST allows excessive telomerase activity, promoting telomere elongation. We propose that through binding of the telomerase-extended telomere, CST limits telomerase action at individual telomeres to approximately one binding and extension event per cell cycle. Our findings define the sequence of events that occur to first enable and then terminate telomerase-mediated telomere elongation.
人类端粒的长度决定了细胞寿命,端粒是保护染色体末端免受降解和融合的关键因素。在胚胎发生和癌症中,端粒酶可抵抗端粒 DNA 的缩短。如在癌细胞中所显示的,人端粒酶在细胞周期的 S 期与端粒结合 shelterin 成分 TPP1,并在单个延伸轮中添加约 60 个核苷酸,之后端粒酶通过未知机制关闭。在这里,我们表明,先前涉及端粒保护和 DNA 代谢的人类 CST(CTC1、STN1 和 TEN1)复合物通过引物隔离和与端粒保护蛋白 1(POT1)-TPP1 端粒酶延伸因子的物理相互作用来抑制端粒酶活性。CST 与 POT1-TPP1 竞争端粒 DNA,并且仅在端粒酶作用下,CST 与端粒-DNA 的结合在 S/G2 晚期增加,这与端粒酶失活同时发生。CST 的耗竭允许过度的端粒酶活性,从而促进端粒的延长。我们提出,通过结合端粒酶延伸的端粒,CST 将端粒酶在单个端粒上的作用限制为每个细胞周期约一次结合和延伸事件。我们的发现定义了首先使端粒酶介导的端粒延伸能够发生,然后终止端粒酶介导的端粒延伸的一系列事件。
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