Preferential maintenance of critically short telomeres in mammalian cells heterozygous for mTert
Preferential maintenance of critically short telomeres in mammalian cells heterozygous for mTert
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DOI：
10.1073/pnas.062549199
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发表时间：
2002-03-19
影响因子：
11.1
通讯作者：
Harrington, L
中科院分区：
文献类型：
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作者：
Liu, Y;Kha, H;Harrington, L
缺乏端粒酶逆转录酶 mTert 的小鼠胚胎干 (ES) 细胞的长期生长会导致端粒 DNA 丢失，并增加端对端融合和非整倍性的发生率。此外，仅丢失一份 mTert 也会导致野生型 (wt) 和 mTert 无效 ES 细胞之间的端粒缩短 [Liu, Y., Snow, B. E., Handle, M. P., Yeung, D., Erdmann, N. J., Wakeham, A., Itie, A., Siderovski, D. P., Lansdorp, P. M., Robinson, M. O. & Harrington, L. (2000) 当前。生物。 10, 1459-1462]。出乎意料的是，尽管mTert(+/-) ES细胞中的平均端粒长度下降至与mTert无效ES细胞相似的水平，但mTert(+/-) ES细胞系在所有染色体末端保留了最小的端粒DNA信号。因此，在 mTert(+/-) ES 细胞系的最新传代中没有观察到端到端融合和基因组不稳定。这些数据揭示了端粒酶在平均端粒长度维持中的剂量依赖性功能与mTert杂合细胞中极短端粒选择性维持之间的功能区别。在正常细胞和肿瘤细胞中，我们认为端粒酶活性不足以维持给定的平均端粒长度，但可能提供针对端到端融合和基因组不稳定的保护优势。
Prolonged growth of murine embryonic stem (ES) cells lacking the telomerase reverse transcriptase, mTert, results in a loss of telomere DNA and an increased incidence of end-to-end fusions and aneuploidy. Furthermore, loss of only one copy of mTert also results in telomere shortening intermediate between wild-type (wt) and mTert-null ES cells [Liu, Y., Snow, B. E., Handle, M. P., Yeung, D., Erdmann, N. J., Wakeham, A., Itie, A., Siderovski, D. P., Lansdorp, P. M., Robinson, M. O. & Harrington, L. (2000) Curr. Biol. 10, 1459-1462]. Unexpectedly, although average telomere length in mTert(+/-) ES cells declined to a similar level as mTert-null ES cells, mTert(+/-) ES cell lines retained a minimal telomeric DNA signal at all chromosome ends. Consequently, no end-to-end fusions and genome instability were observed in the latest passages of mTert(+/-) ES cell lines. These data uncover a functional distinction between the dosage-dependent function of telomerase in average telomere-length maintenance and the selective maintenance of critically short telomeres in cells heterozygous for mTert. In normal and tumor cells, we suggest that telomerase activity insufficient to maintain a given average telomere length may, nonetheless, provide a protective advantage from end-to-end fusion and genome instability.