Human Stn1 protects telomere integrity by promoting efficient lagging-strand synthesis at telomeres and mediating C-strand fill-in
Human Stn1 protects telomere integrity by promoting efficient lagging-strand synthesis at telomeres and mediating C-strand fill-in
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DOI：
10.1038/cr.2012.132
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发表时间：
2012-12-01
期刊：
影响因子：
44.1
通讯作者：
Chai, Weihang
中科院分区：
文献类型：
--
作者：
Huang, Chenhui;Dai, Xueyu;Chai, Weihang
端粒的维持对基因组的稳定性至关重要。新发现的Ctc1/Stn1/Ten1复合体对端粒的维持很重要，但其确切作用尚不清楚。我们在这里报道，hStn1的缺失导致人类体细胞灾难性的端粒缩短、DNA损伤反应和早期衰老。这些表型可能是由于hStn1在促进滞后链端粒DNA的有效复制方面所起的重要作用。HStn1的下调会在滞后链端粒上积累单链富含G的DNA，增加端粒的脆性，阻碍端粒DNA的合成，并延迟和损害端粒C链的合成。我们进一步表明，hStn1缺乏导致DNA聚合酶α与端粒的持续和高水平的结合，提示hStn1可能调节了olα的DNA合成活性，而不是控制olα到端粒的负载。此外，我们的数据表明hStn1不太可能是端粒覆盖复合体的一部分。我们认为hStn1可以帮助DNA聚合酶有效地复制滞后链端粒，从而实现端粒DNA的完全合成，从而防止端粒的快速丢失。
Telomere maintenance is critical for genome stability. The newly-identified Ctc1/Stn1/Ten1 complex is important for telomere maintenance, though its precise role is unclear. We report here that depletion of hStn1 induces catastrophic telomere shortening, DNA damage response, and early senescence in human somatic cells. These phenotypes are likely due to the essential role of hStn1 in promoting efficient replication of lagging-strand telomeric DNA. Downregulation of hStn1 accumulates single-stranded G-rich DNA specifically at lagging-strand telomeres, increases telomere fragility, hinders telomere DNA synthesis, as well as delays and compromises telomeric C-strand synthesis. We further show that hStn1 deficiency leads to persistent and elevated association of DNA polymerase alpha (pol alpha) to telomeres, suggesting that hStn1 may modulate the DNA synthesis activity of pol alpha rather than controlling the loading of pol alpha to telomeres. Additionally, our data suggest that hStn1 is unlikely to be part of the telomere capping complex. We propose that the hStn1 assists DNA polymerases to efficiently duplicate lagging-strand telomeres in order to achieve complete synthesis of telomeric DNA, therefore preventing rapid telomere loss.