Cristofari Gaël, Lingner Joachim
Swiss Institute for Experimental Cancer Research (ISREC), Epalinges, Switzerland.
EMBO J. 2006 Feb 8;25(3):565-74. doi: 10.1038/sj.emboj.7600952. Epub 2006 Jan 19.
Stabilization of telomere length in germline and highly proliferative human cells is required for long-term survival and for the immortal phenotype of cancer-derived cells. This is achieved through expression of telomerase reverse transcriptase (TERT), which synthesizes telomeric repeats through reverse transcription of its tightly associated RNA template (TR). The telomeric repeat binding factor TRF1 inhibits telomerase at telomeres in cis in a length-dependent manner to achieve telomere length homeostasis. Here we manipulate telomerase activity over a wide range in cancer and primary cells. Concomitant overexpression of TERT and TR was necessary and sufficient to substantially increase telomerase activity. Upon overexpression, more telomerase associated with telomeres and telomeres elongated at a constant rate (up to 0.8 kb/population doubling (PD)) in a length-independent manner. Thus, in less than 50 PDs, the length of telomeres increased 3-8-fold beyond physiological size, while telomere-bound TRF1 and TRF2 increased proportionally to telomere length. Thus, long telomeres do not permanently adopt a structural state that is non-extendible. A low cellular concentration of telomerase is critical to achieve preferential elongation of short telomeres and telomere length homeostasis.
生殖系细胞和高度增殖的人类细胞中，端粒长度的稳定对于长期存活以及癌症衍生细胞的永生化表型而言是必需的。这是通过端粒酶逆转录酶（TERT）的表达来实现的，TERT通过其紧密关联的RNA模板（TR）的逆转录合成端粒重复序列。端粒重复序列结合因子TRF1以长度依赖的方式在顺式作用下抑制端粒处的端粒酶，以实现端粒长度的稳态。在此，我们在癌症细胞和原代细胞中广泛调控端粒酶活性。TERT和TR的同时过表达对于大幅提高端粒酶活性而言是必要且充分的。过表达后，更多的端粒酶与端粒结合，端粒以恒定速率（高达0.8 kb/群体倍增（PD））非长度依赖地延长。因此，在不到50个PD内，端粒长度增加至超过生理大小的3至8倍，而端粒结合的TRF1和TRF2与端粒长度成比例增加。因此，长端粒不会永久处于不可延长的结构状态。低细胞浓度的端粒酶对于实现短端粒的优先延长和端粒长度稳态至关重要。
