García-Cao Marta, Gonzalo Susana, Dean Douglas, Blasco María A
Department of Immunology and Oncology, National Center of Biotechnology, E-28049 Madrid, Spain.
Nat Genet. 2002 Nov;32(3):415-9. doi: 10.1038/ng1011. Epub 2002 Oct 15.
The molecular mechanisms of cellular mortality have recently begun to be unraveled. In particular, it has been discovered that cells that lack telomerase are subject to telomere attrition with each round of replication, eventually leading to loss of telomere capping function at chromosome ends. Critically short telomeres and telomeres lacking telomere-binding proteins lose their functionality and are metabolized as DNA breaks, thus generating chromosomal fusions. Telomerase activity is sufficient to rescue short telomeres and confers an unlimited proliferative capacity. In addition, the tumor-suppressor pathway Cdkn2a/Rb1 has also been implicated as a barrier to immortalization. Here, we report a connection between the members of the retinoblastoma family of proteins, Rb1 (retinoblastoma 1), Rbl1 (retinoblastoma-like 1) and Rbl2 (retinoblastoma-like 2), and the mechanisms that regulate telomere length. In particular, mouse embryonic fibroblasts doubly deficient in Rbl1 and Rbl2 or triply deficient in Rbl1, Rbl2 and Rb1 have markedly elongated telomeres compared with those of wildtype or Rb1-deficient cells. This deregulation of telomere length is not associated with increased telomerase activity. Notably, the abnormally elongated telomeres in doubly or triply deficient cells retain their end-capping function, as shown by the normal frequency of chromosomal fusions. These findings demonstrate a connection between the Rb1 family and the control of telomere length in mammalian cells.
细胞死亡的分子机制最近才开始被揭示。特别是，人们发现缺乏端粒酶的细胞在每一轮复制时都会发生端粒磨损，最终导致染色体末端端粒帽功能丧失。极短的端粒和缺乏端粒结合蛋白的端粒会失去其功能，并作为DNA断裂进行代谢，从而产生染色体融合。端粒酶活性足以挽救短端粒并赋予无限增殖能力。此外，肿瘤抑制途径Cdkn2a/Rb1也被认为是细胞永生化的障碍。在这里，我们报告了视网膜母细胞瘤蛋白家族成员Rb1（视网膜母细胞瘤1）、Rbl1（视网膜母细胞瘤样1）和Rbl2（视网膜母细胞瘤样2）与调节端粒长度的机制之间的联系。特别是，与野生型或Rb1缺陷细胞相比，Rbl1和Rbl2双缺陷或Rbl1、Rbl2和Rb1三缺陷的小鼠胚胎成纤维细胞的端粒明显延长。这种端粒长度的失调与端粒酶活性增加无关。值得注意的是，双缺陷或三缺陷细胞中异常延长的端粒保留了其末端帽功能，这从染色体融合的正常频率可以看出。这些发现证明了Rb1家族与哺乳动物细胞中端粒长度控制之间的联系。
