Harrington Lea, Robinson Murray O
Ontario Cancer Institute/Amgen Research Institute, Department of Medical Biophysics/University of Toronto, 620 University Avenue, Toronto, ON, M5G 2C1, Canada.
Oncogene. 2002 Jan 21;21(4):592-7. doi: 10.1038/sj.onc.1205084.
The molecular cloning of telomerase and telomere components has enabled the analysis and precise manipulation of processes that regulate telomere length maintenance. In mammalian cells and in other organisms, we now recognize that disruption of telomere integrity via any one of a number of perturbations induces chromosome instability and the activation of DNA damage responses. Thus, telomere dysfunction may represent a physiological trigger of the DNA damage or apoptotic response in an analogous fashion to other genotoxic insults that introduce chromosome breaks. Initial studies in mice lacking the murine telomerase RNA and in cells expressing a dominant negative version of the telomere binding protein TRF2 revealed a strong p53-dependent response to telomere dysfunction. Yet, telomere dysfunction exhibits p53-independent effects as well, an observation supported by p53-independent responses to telomere dysfunction in p53 mutant human tumor cell lines and mouse cells. As most tumors are compromised for p53 function, examination of this p53-independent response warrants closer attention. A better understanding of this p53-independent response may prove critical for determining the ultimate utility of telomerase inhibitors in the clinic. This review will summarize our current understanding of the molecular responses to telomere dysfunction in mammalian cells.
端粒酶和端粒组分的分子克隆使得对调节端粒长度维持过程的分析和精确操控成为可能。在哺乳动物细胞和其他生物体中，我们现在认识到，通过多种扰动中的任何一种破坏端粒完整性都会诱导染色体不稳定并激活DNA损伤反应。因此，端粒功能障碍可能以类似于其他导致染色体断裂的基因毒性损伤的方式，代表DNA损伤或凋亡反应的生理触发因素。对缺乏小鼠端粒酶RNA的小鼠以及表达端粒结合蛋白TRF2显性负性版本的细胞的初步研究表明，对端粒功能障碍存在强烈的p53依赖性反应。然而，端粒功能障碍也表现出不依赖p53的效应，这一观察结果得到了p53突变的人类肿瘤细胞系和小鼠细胞中对端粒功能障碍的p53非依赖性反应的支持。由于大多数肿瘤的p53功能受损，因此对这种不依赖p53的反应进行研究值得更密切关注。更好地理解这种不依赖p53的反应可能对确定端粒酶抑制剂在临床上的最终效用至关重要。本综述将总结我们目前对哺乳动物细胞中端粒功能障碍分子反应的理解。
