Liu Yie, Kha Hue, Ungrin Mark, Robinson Murray O, Harrington Lea
Ontario Cancer Institute/Amgen Research Institute, Department of Medical Biophysics, University of Toronto, 620 University Avenue, Toronto, ON, Canada.
Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3597-602. doi: 10.1073/pnas.062549199.
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., Hande, 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.
缺乏端粒酶逆转录酶（mTert）的小鼠胚胎干细胞（ES细胞）的长期生长会导致端粒DNA丢失，端对端融合和非整倍体的发生率增加。此外，仅缺失一个mTert拷贝也会导致端粒缩短，其缩短程度介于野生型（wt）和mTert缺失的ES细胞之间[Liu, Y., Snow, B. E., Hande, 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]。出乎意料的是，尽管mTert(+/-) ES细胞中的平均端粒长度下降到与mTert缺失的ES细胞相似的水平，但mTert(+/-) ES细胞系在所有染色体末端仍保留了最小的端粒DNA信号。因此，在mTert(+/-) ES细胞系的最新传代中未观察到端对端融合和基因组不稳定现象。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的选择性维持之间的功能差异。我们认为，在正常细胞和肿瘤细胞中，不足以维持给定平均端粒长度的端粒酶活性可能仍然能提供防止端对端融合和基因组不稳定的保护优势。
