Gire Véronique
Centre de Recherche en Biochimie Macromoléculaire, CNRS, FRE 2593, Montpellier, France.
Cell Cycle. 2004 Oct;3(10):1217-20. doi: 10.4161/cc.3.10.1167. Epub 2004 Oct 13.
Loss of telomere integrity can have two outcomes with opposite predicted effects on tumorigenesis. On the one hand, shortened telomeres in normal cells may trigger cell cycle arrest, leading to tumor suppression. On the other hand, in a tumor cell in which neither the p53 nor pRb pathway is intact, shortened telomeres could initiate chromosome instability and promote tumorigenesis A major issue in telomere research is to understand how shortened dysfunctional telomeres can regulate the onset of cellular senescence. Recent studies have revealed that critically shortened or acutely uncapped telomeres share molecular features with damaged DNA. We have recently linked the phosphorylation and activation of one major DNA damage effector checkpoint kinase, Chk2, to telomere erosion in signalling cell cycle arrest in normal fibroblasts. Here, we discuss several hypotheses to explain the molecular events occurring at shortened telomeres that ultimately lead to cell cycle arrest or increased genomic instability.
端粒完整性的丧失可能产生两种结果，对肿瘤发生具有相反的预测作用。一方面，正常细胞中端粒缩短可能触发细胞周期停滞，从而导致肿瘤抑制。另一方面，在p53和pRb通路均不完整的肿瘤细胞中，缩短的端粒可能引发染色体不稳定并促进肿瘤发生。端粒研究中的一个主要问题是了解缩短的功能失调端粒如何调节细胞衰老的起始。最近的研究表明，严重缩短或急性无帽的端粒与受损DNA具有共同的分子特征。我们最近将一种主要的DNA损伤效应检查点激酶Chk2的磷酸化和激活与正常成纤维细胞中信号传导细胞周期停滞时的端粒侵蚀联系起来。在这里，我们讨论几种假说来解释在缩短的端粒处发生的最终导致细胞周期停滞或基因组不稳定性增加的分子事件。
