Identification of ATPases pontin and reptin as telomerase components essential for holoenzyme assembly
Identification of ATPases pontin and reptin as telomerase components essential for holoenzyme assembly
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DOI：
10.1016/j.cell.2008.01.019
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发表时间：
2008-03-21
期刊：
影响因子：
64.5
通讯作者：
Artandi, Steven E.
中科院分区：
文献类型：
--
作者：
Venteicher, Andrew S.;Meng, Zhaojing;Artandi, Steven E.
端粒酶是一种多亚基核糖核蛋白（RNP）复合物，它将端粒重复序列添加到染色体末端。到目前为止，已经确定了三种基本的端粒酶组分：端粒酶逆转录酶（TERT），端粒酶RNA组分（TERC）和TERC结合蛋白dyskerin。很少有其他蛋白质是已知的，需要为人类端粒酶的功能，限制了我们的理解端粒酶的调控和端粒酶的作用机制。在这里，我们确定的ATP酶桥蛋白和reptin端粒酶组分通过亲和纯化的人细胞的端粒酶。桥蛋白与TERT和dyskerin直接相互作用，并且与桥蛋白和reptin结合的TERT的量在S期达到峰值，这证明了TERT的细胞周期依赖性调节。脑桥蛋白和reptin的消耗显着损害端粒酶RNP的积累，表明在端粒酶组装的重要作用。这些发现揭示了端粒酶生物合成中对额外酶的意外需求，并提出了抑制癌症端粒酶的替代方法。
Telomerase is a multisubunit ribonucleoprotein (RNP) complex that adds telomere repeats to the ends of chromosomes. Three essential telomerase components have been identified thus far: the telomerase reverse transcriptase (TERT), the telomerase RNA component (TERC), and the TERC-binding protein dyskerin. Few other proteins are known to be required for human telomerase function, limiting our understanding of both telomerase regulation and mechanisms of telomerase action. Here, we identify the ATPases pontin and reptin as telomerase components through affinity purification of TERT from human cells. Pontin interacts directly with both TERT and dyskerin, and the amount of TERT bound to pontin and reptin peaks in S phase, evidence for cell-cycle-dependent regulation of TERT. Depletion of pontin and reptin markedly impairs telomerase RNP accumulation, indicating an essential role in telomerase assembly. These findings reveal an unanticipated requirement for additional enzymes in telomerase biogenesis and suggest alternative approaches for inhibiting telomerase in cancer.