FEN1 contributes to telomere stability in ALT-positive tumor cells
FEN1 contributes to telomere stability in ALT-positive tumor cells
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DOI：
10.1038/onc.2008.458
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发表时间：
2009-02-01
期刊：
影响因子：
8
通讯作者：
Stewart, S. A.
中科院分区：
文献类型：
--
作者：
Saharia, A.;Stewart, S. A.
通过端粒结合蛋白中的功能丧失突变来消除端粒稳定性有助于基因组不稳定性和癌症进展。最近，Flap内切核酸酶1（FEN 1）被证明有助于尚未激活端粒维持机制的人类细胞中的端粒稳定性，这表明FEN 1功能的废除通过损害端粒稳定性和驱动基因组不稳定性来影响转化过程。在这里，我们分析了FEN 1耗尽后人类癌细胞中的端粒。我们发现，FEN 1是依赖于端粒（ALT）机制的替代延长细胞中端粒稳定所必需的。事实上，FEN 1缺失导致端粒功能障碍，其特征在于在ALT阳性细胞中形成端粒功能障碍诱导的病灶（TIF）和端对端融合。相反，在FEN1耗竭的端粒酶阳性细胞中没有观察到端粒表型，这表明正在进行的端粒酶活性保护了端粒。与此一致，我们发现端粒酶催化组分（hTERT）的表达，而不是一个无活性的等位基因拯救端粒功能障碍的FEN 1耗尽ALT细胞。我们的数据表明，FEN 1中出现的突变通过促进端粒融合和后期桥断裂循环来影响端粒稳定性和基因组保真度，这进一步驱动基因组不稳定性，从而有助于转化过程。
Abrogation of telomere stability through loss-of-function mutations in telomere binding proteins contributes to genomic instability and cancer progression. Recently, Flap endonuclease 1 (FEN1) was shown to contribute to telomere stability in human cells that had not yet activated a telomere maintenance mechanism, suggesting that abrogation of FEN1 function influences the transformation process by compromising telomere stability and driving genomic instability. Here, we analyse the telomeres in human cancer cells following FEN1 depletion. We show that FEN1 is required for telomere stability in cells that rely on the alternative lengthening of telomere (ALT) mechanism. Indeed, FEN1 depletion resulted in telomere dysfunction, characterized by formation of telomere dysfunction-induced foci (TIFs) and end-to-end fusions in ALT-positive cells. In contrast, no telomere phenotype was observed in telomerase-positive cells on FEN1 depletion, suggesting that ongoing telomerase activity protected telomeres. In consonance with this, we found that expression of the catalytic component of telomerase (hTERT) but not an inactive allele rescued telomere dysfunction on FEN1 depletion in ALT cells. Our data suggest that mutations that arise in FEN1 affect telomere stability and genome fidelity by promoting telomere fusions and anaphase-bridge-breakage cycles, which further drive genome instability and thereby contribute to the transformation process.