Semi-conservative DNA replication through telomeres requires Taz1
Semi-conservative DNA replication through telomeres requires Taz1
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DOI：
10.1038/nature04638
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发表时间：
2006-04-06
期刊：
影响因子：
64.8
通讯作者：
Cooper, JP
中科院分区：
文献类型：
--
作者：
Miller, KM;Rog, O;Cooper, JP
端粒复制是通过常规DNA复制机制和逆转录酶端粒酶的联合作用来实现的。端粒结合蛋白在控制端粒酶活性中具有关键作用;然而，关于它们在控制半保守复制中的作用知之甚少，半保守复制合成大部分端粒DNA（1）。裂殖酵母裂殖酵母中的端粒重复序列与Taz 1结合，Taz 1是一种调节多种端粒功能的调节剂（2-4）。一般认为端粒结合蛋白阻碍复制叉的进展。在这里，我们表明，相反，Taz 1是通过端粒的有效复制叉进展的关键。使用二维凝胶电泳（5），我们发现Taz 1的缺失导致端粒和内部端粒序列的复制叉停滞，无论端粒富含G的链是通过前导链还是滞后链合成复制。与此相反，Taz 1相互作用蛋白Rap 1是有效的端粒叉进展。端粒酶缺失后，taz 1 Delta端粒急剧丢失，表明taz 1 Delta端粒重复序列的维持不能通过半保守复制来维持。由于人类端粒蛋白TRF 1和TRF 2是Taz 1的直系同源物，我们预测人类TRFs中的一个或两个可能通过人类端粒协调叉通道。功能失调的人类端粒上的停滞分叉可能会加速基因组的不稳定性，从而导致肿瘤发生。
Telomere replication is achieved through the combined action of the conventional DNA replication machinery and the reverse transcriptase, telomerase. Telomere-binding proteins have crucial roles in controlling telomerase activity; however, little is known about their role in controlling semi-conservative replication, which synthesizes the bulk of telomeric DNA(1). Telomere repeats in the fission yeast Schizosaccharomyces pombe are bound by Taz1, a regulator of diverse telomere functions(2-4). It is generally assumed that telomere-binding proteins impede replication fork progression. Here we show that, on the contrary, Taz1 is crucial for efficient replication fork progression through the telomere. Using two-dimensional gel electrophoresis(5), we find that loss of Taz1 leads to stalled replication forks at telomeres and internally placed telomere sequences, regardless of whether the telomeric G-rich strand is replicated by leading-or lagging-strand synthesis. In contrast, the Taz1-interacting protein Rap1 is dispensable for efficient telomeric fork progression. Upon loss of telomerase, taz1 Delta telomeres are lost precipitously, suggesting that maintenance of taz1 Delta telomere repeats cannot be sustained through semi-conservative replication. As the human telomere proteins TRF1 and TRF2 are Taz1 orthologues, we predict that one or both of the human TRFs may orchestrate fork passage through human telomeres. Stalled forks at dysfunctional human telomeres are likely to accelerate the genomic instability that drives tumorigenesis.