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Control of telomere length by the human telomeric protein TRF1

机译：人类端粒蛋白TRF1控制端粒长度

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摘要

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.
机译：人端粒是染色体末端的核蛋白复合物，由与特定蛋白结合的TTAGGG重复序列串联组成。在正常人细胞中，端粒随着连续的细胞分裂而缩短，这可能是由于DNA复制伴随的末端序列丢失。在肿瘤和永生细胞中，这种下降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。端粒长度在几种永生的人类细胞系中是稳定的，这表明存在一种调节机制，可通过端粒酶限制端粒的伸长。在这里，我们表明人类端粒重复结合因子TRF1（参考文献8）参与了这一调控。端粒酶阳性肿瘤细胞系HT1080中TRF1的长期过度表达导致端粒逐渐和渐进性缩短。相反，端粒伸长是通过表达抑制内源性TRF1与端粒结合的显性阴性TRF1突变体诱导的。我们的结果确定TRF1为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不会可检测地影响端粒酶的表达，我们建议TRF1的结合通过抑制端粒酶在单个端粒末端的作用来控制顺式端粒长度。

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