TELOMERE LOSS - MITOTIC CLOCK OR GENETIC TIME BOMB
TELOMERE LOSS - MITOTIC CLOCK OR GENETIC TIME BOMB
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DOI：
10.1016/0921-8734(91)90018-7
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发表时间：
1991-03-01
期刊：
影响因子：
--
通讯作者：
HARLEY, CB
中科院分区：
文献类型：
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作者：
HARLEY, CB
老年学家研究细胞衰老的圣杯是体细胞有限增殖能力的机制。1973年，Olovnikov提出，由于DNA聚合酶无法完全复制染色体末端(端粒)，细胞在每一轮复制后都会丢失少量DNA，最终关键的缺失会导致细胞死亡。最近的观察表明，人类体细胞的端粒作为有丝分裂钟，在体外和体内都以复制依赖的方式随年龄缩短，支持这一理论的前提。此外，由于端粒稳定了染色体末端以防止重组，它们的丢失可以解释在传代后期(衰老)的成纤维细胞中观察到的双着丝粒染色体频率增加的原因，并为调节细胞周期退出提供了一个检查点。精子端粒比体细胞端粒更长，并随着年龄的增长而保持，这表明生殖系细胞可能表达端粒酶，端粒酶是已知在不朽的单细胞真核生物中维持端粒长度的核糖核蛋白酶。正如预测的那样，在永生的、转化的人类细胞和肿瘤细胞系中发现了端粒酶活性，但在正常体细胞中没有发现。由于许多转化的细胞和肿瘤组织的端粒非常短，端粒酶的激活可能是永生化过程中的一个晚期的、专有的事件。因此，端粒长度和端粒酶活性似乎是细胞复制历史和增殖潜力的标志；有趣的可能性仍然是，端粒丢失是一枚遗传定时炸弹，因此与细胞衰老和永生化有关。
The Holy Grail of gerontologists investigating cellular senescence is the mechanism responsible for the finite proliferative capacity of somatic cells. In 1973, Olovnikov proposed that cells lose a small amount of DNA following each round of replication due to the inability of DNA polymerase to fully replicate chromosome ends (telomeres) and that eventually a critical deletion causes cell death. Recent observations showing that telomeres of human somatic cells act as a mitotic clock, shortening with age both in vitro and in vivo in a replication dependent manner, support this theory's premise. In addition, since telomeres stabilize chromosome ends against recombination, their loss could explain the increased frequency of dicentric chromosomes observed in late passage (senescent) fibroblasts and provide a checkpoint for regulated cell cycle exit. Sperm telomeres are longer than somatic telomeres and are maintained with age, suggesting that germ line cells may express telomerase, the ribonucleoprotein enzyme known to maintain telomere length in immortal unicellular eukaryotes. As predicted, telomerase activity has been found in immortal, transformed human cells and tumour cell lines, but not in normal somatic cells. Telomerase activation may be a late, obligate event in immortalization since many transformed cells and tumour tissues have critically short telomeres. Thus, telomere length and telomerase activity appear to be markers of the replicative history and proliferative potential of cells; the intriguing possibility remains that telomere loss is a genetic time bomb and hence causally involved in cell senescence and immortalization.