The human CST complex is a terminator of telomerase activity
The human CST complex is a terminator of telomerase activity
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DOI：
10.1038/nature11269
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发表时间：
2012-08-23
期刊：
影响因子：
64.8
通讯作者：
Lingner, Joachim
中科院分区：
文献类型：
--
作者：
Chen, Liuh-Yow;Redon, Sophie;Lingner, Joachim
人类端粒的长度是细胞寿命的关键决定因素，它保护染色体末端免受降解和末端融合（1,2）。在胚胎发生和癌症中，端粒酶抵消了端粒DNA的缩短。正如在癌细胞中所显示的那样，人类端粒酶在细胞周期的S期与端粒上的庇护蛋白成分TPP1结合（4,5），并在单轮延伸中增加类似60个核苷酸(6)，之后端粒酶以未知的机制关闭。在这里，我们发现人类CST （CTC1， STN1和TEN1）复合体，先前涉及端粒保护和DNA代谢（7-11），通过引物隔离和与端粒1保护(POT1)-TPP1端粒酶加工因子的物理相互作用抑制端粒酶活性（12,13）。CST与POT1-TPP1竞争端粒DNA，在S/G2期晚期，CST-端粒-DNA结合仅在端粒酶作用下增加，与端粒酶关闭相一致。CST的消耗允许过度的端粒酶活性，促进端粒伸长。我们提出，通过端粒酶延伸端粒的结合，CST将端粒酶在单个端粒上的作用限制在每个细胞周期大约一个结合和延伸事件。我们的研究结果定义了首先启用然后终止端粒酶介导的端粒延伸的事件序列。
The lengths of human telomeres, which protect chromosome ends from degradation and end fusions(1,2), are crucial determinants of cell lifespan(3). 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(4,5) during the S phase of the cell cycle, and adds similar to 60 nucleotides in a single round of extension(6), 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(7-11), inhibits telomerase activity through primer sequestration and physical interaction with the protection of telomeres 1 (POT1)-TPP1 telomerase processivity factor(12,13). 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.