der-Sarkissian Héra, Bacchetti Silvia, Cazes Lucien, Londoño-Vallejo José Arturo
Centre d'Etude du Polymorphisme Humain, 27 rue Julliette Dodu, Paris 75010, France.
Oncogene. 2004 Feb 12;23(6):1221-8. doi: 10.1038/sj.onc.1207152.
Maintenance of telomeres is essential for chromosome stability. In the absence of telomerase, telomeres shorten with cell division until they approach a stability threshold, at which point cells enter senescence. When senescence-signaling pathways are inactive, further telomere shortening leads to chromosome instability characterized by telomeric fusions and breakage-fusion-bridge (BFB) cycles. Since the distribution of telomere lengths among chromosome extremities is heterogeneous, we wondered about the impact of such variability on the stability of particular chromosome arms. We correlated the initial length of individual telomeres in telomerase-negative-transformed cells with the stability of the corresponding chromosome arms during the precrisis period. We show that arms carrying the shortest telomeres are the first to become unstable and this instability affects the chromosome homologues with shorter telomeres almost exclusively. The analysis of several postcrisis cell populations, which had stabilized their telomeres by re-expressing telomerase, showed that the karyotypic outcome is strongly influenced by the initial telomere length heterogeneity. The timing of telomerase re-expression also seems to play a role in limiting the extent of karyotypic changes, probably by reducing the frequency of telomeric fusions and hence BFB. Since the distribution of telomere lengths within somatic cells is proper to every individual, our results predict that the risk for a particular chromosome arm of becoming unstable early in tumorigenesis will differ between individuals and contribute directly to the heterogeneity of chromosome aberrations found in tumors.
端粒的维持对于染色体稳定性至关重要。在缺乏端粒酶的情况下，端粒会随着细胞分裂而缩短，直至接近稳定阈值，此时细胞进入衰老状态。当衰老信号通路失活时，进一步的端粒缩短会导致以端粒融合和断裂-融合-桥（BFB）循环为特征的染色体不稳定。由于染色体末端之间端粒长度的分布是不均一的，我们想知道这种变异性对特定染色体臂稳定性的影响。我们将端粒酶阴性转化细胞中单个端粒的初始长度与危机前期相应染色体臂的稳定性进行了关联分析。我们发现，携带最短端粒的染色体臂最先变得不稳定，而且这种不稳定性几乎只影响端粒较短的染色体同源物。对几个危机后细胞群体的分析表明，这些细胞通过重新表达端粒酶使端粒得以稳定，结果显示核型结果受到初始端粒长度不均一性的强烈影响。端粒酶重新表达的时间似乎也在限制核型变化程度方面发挥作用，可能是通过降低端粒融合频率从而减少BFB循环来实现的。由于体细胞内端粒长度的分布因人而异，我们的研究结果预测，在肿瘤发生早期特定染色体臂变得不稳定的风险在个体之间会有所不同，并且会直接导致肿瘤中发现的染色体畸变的异质性。
