van Steensel B, de Lange T
The Rockefeller University, New York 10021, USA.
Nature. 1997 Feb 20;385(6618):740-3. doi: 10.1038/385740a0.
Human telomeres, the nucleoprotein complexes at chromosome ends, consist of tandem arrays of TTAGGG repeats bound to specific proteins. In normal human cells, telomeres shorten with successive cell divisions, probably due to the terminal sequence loss that accompanies DNA replication. In tumours and immortalized cells, this decline is halted through the activation of telomerase, a reverse transcriptase that extends the telomeric TTAGGG-repeat arrays. Telomere length is stable in several immortal human-cell lines, suggesting that a regulatory mechanism exists for limiting telomere elongation by telomerase. Here we show that the human telomeric-repeat binding factor TRF1 (ref. 8) is involved in this regulation. Long-term overexpression of TRF1 in the telomerase-positive tumour-cell line HT1080 resulted in a gradual and progressive telomere shortening. Conversely, telomere elongation was induced by expression of a dominant-negative TRF1 mutant that inhibited binding of endogenous TRF1 to telomeres. Our results identify TRF1 as a suppressor of telomere elongation and indicate that TRF1 is involved in the negative feedback mechanism that stabilizes telomere length. As TRF1 does not detectably affect the expression of telomerase, we propose that the binding of TRF1 controls telomere length in cis by inhibiting the action of telomerase at the ends of individual telomeres.
人类端粒是位于染色体末端的核蛋白复合体，由与特定蛋白质结合的TTAGGG重复序列串联阵列组成。在正常人类细胞中，端粒会随着细胞的连续分裂而缩短，这可能是由于DNA复制时伴随的末端序列丢失所致。在肿瘤细胞和永生化细胞中，这种缩短通过端粒酶的激活而停止，端粒酶是一种逆转录酶，可延长端粒TTAGGG重复序列阵列。端粒长度在几种永生化人类细胞系中是稳定的，这表明存在一种调节机制来限制端粒酶对端粒的延长作用。在这里，我们表明人类端粒重复序列结合因子TRF1（参考文献8）参与了这一调节过程。在端粒酶阳性肿瘤细胞系HT1080中，TRF1的长期过表达导致端粒逐渐且持续缩短。相反，一种显性负性TRF1突变体的表达诱导了端粒延长，该突变体抑制内源性TRF1与端粒的结合。我们的结果确定TRF1是端粒延长的抑制因子，并表明TRF1参与了稳定端粒长度的负反馈机制。由于TRF1未检测到对端粒酶表达的影响，我们提出TRF1的结合通过抑制端粒酶在单个端粒末端的作用来顺式控制端粒长度。
