Loss of hPot1 function leads to telomere instability and a cut-like phenotype
Loss of hPot1 function leads to telomere instability and a cut-like phenotype
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DOI：
10.1016/j.cub.2004.12.031
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发表时间：
2004-12-29
期刊：
影响因子：
9.2
通讯作者：
Counter, CM
中科院分区：
文献类型：
--
作者：
Veldman, T;Etheridge, KT;Counter, CM
人端粒结合蛋白hPot 1在体外结合端粒DNA的最远端单链延伸，并且可能在体内结合[1，2]，以及通过桥接蛋白PTOP（也称为PIP 1或TINT 1）和TIN 2与双链端粒DNA结合蛋白TRF 1和TRF 2结合[2-7]。破坏hPot 1的DNA结合活性或其与PTOP的结合导致端粒延长，表明hPot 1在端粒长度调节中的作用[2，5，6，8]。然而，POT 1和Cdc 13 p（编码该蛋白质的结构直系同源物的分裂和出芽酵母基因）的突变导致端粒不稳定性和细胞死亡[19]。因此，hPot 1蛋白也可能用于保护人类的端粒。事实上，我们现在发现，敲低人类细胞中hPot 1的表达会导致细胞凋亡或衰老，以及端粒缔合和后期桥的增加，这是端粒不稳定的迹象[10]。此外，敲除细胞还显示间期细胞之间的染色质桥，这让人联想到在裂殖酵母中首次描述的切割表型，其中尽管染色单体分离失败，胞质分裂仍在进行[11]。然而，与酵母切割表型不同，我们认为在hPot 1敲低细胞中观察到的切割样表型是染色体末端融合的结果，并且这种融合阻碍了正确的染色体分离。我们的结论是，hPot 1保护染色体末端的非法重组，灾难性的染色体不稳定性，异常染色体分离。
The human telomere binding protein hPot1 binds to the most distal single-stranded extension of telomeric DNA in vitro, and probably in vivo [1, 2], as well as associating with the double-stranded telomeric DNA binding proteins TRF1 and TRF2 through the bridging proteins PTOP (also known as PIP1 or TINT1) and TIN2 [2-7]. Disrupting either the DNA binding activity of hPot1 or its association with PTOP results in elongated telomeres, suggesting a role for hPot1 in telomere length regulation [2, 5, 6, 8]. However, mutations to POT1 and Cdc13p, the fission and budding yeast genes encoding the structural orthologs of this protein, leads to telomere instability and cell death [1 9]. Thus, it is possible that the hPot1 protein may also serve to cap and protect telomeres in humans. Indeed, we now find that knocking down the expression of hPot1 in human cells causes apoptosis or senescence, as well as an increase in telomere associations and anaphase bridges, telltale signs of telomere instability [10]. In addition, knockdown cells also displayed chromatin bridges between interphase cells, reminiscent of the cut phenotype that was first described in fission yeast and in which cytokinesis progresses despite a failure of chromatid separation [11]. However, unlike the yeast cut phenotypes, we suggest that the cut-like phenotype observed in hPot1 knockdown cells is a consequence of the fusion of chromosome ends and that this fusion impedes proper chromosomal segregation. We conclude that hPot1 protects chromosome ends from illegitimate recombination, catastrophic chromosome instability, and abnormal chromosome segregation.