Telomere extension occurs at most chromosome ends and is uncoupled from fill-in in human cancer cells.
Telomere extension occurs at most chromosome ends and is uncoupled from fill-in in human cancer cells.
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DOI：
10.1016/j.cell.2009.05.026
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发表时间：
2009-08-07
期刊：
影响因子：
64.5
通讯作者：
Wright WE
中科院分区：
文献类型：
--
作者：
Zhao Y;Sfeir AJ;Zou Y;Buseman CM;Chow TT;Shay JW;Wright WE
端粒被认为是通过端粒酶优先募集到最短的端粒来维持的。端粒酶对富含G的端粒链的延伸也被认为与常规复制机制对C链的互补合成相协调。然而，我们发现，在癌细胞中的端粒长度维持条件下，人端粒酶在每个S期延长大多数染色体末端，并且不优先招募到最短的端粒。端粒复制后，端粒酶快速延伸富含G的链，但C链的填充延迟到S期晚期。这种晚期C链填充不是通过常规的冈崎片段合成来执行的，而是通过使用一系列小的增量步骤的机制来执行的。这些发现突出了稳态与非平衡条件下端粒酶作用之间的差异，并揭示了人类端粒维持途径中的步骤，这些步骤可能为开发抗端粒酶疗法提供额外的靶点。
Telomeres are thought to be maintained by the preferential recruitment of telomerase to the shortest telomeres. The extension of the G-rich telomeric strand by telomerase is also believed to be coordinated with the complementary synthesis of the C-strand by the conventional replication machinery. However, we show that under telomere length-maintenance conditions in cancer cells, human telomerase extends most chromosome ends during each S phase and is not preferentially recruited to the shortest telomeres. Telomerase rapidly extends the G-rich strand following telomere replication but fill-in of the C-strand is delayed into late S phase. This late C-strand fill-in is not executed by conventional Okazaki fragment synthesis but by a mechanism using a series of small incremental steps. These findings highlight differences between telomerase actions during steady state versus non-equilibrium conditions and reveal steps in the human telomere maintenance pathway that may provide additional targets for the development of anti-telomerase therapeutics.
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