Gilley David, Tanaka Hiromi, Herbert Brittney-Shea
Department of Medical and Molecular Genetics, The Indiana University Cancer Center, Indiana University School of Medicine, 975 West Walnut St, IB 242, Indianapolis, IN 46202-5251, USA.
Int J Biochem Cell Biol. 2005 May;37(5):1000-13. doi: 10.1016/j.biocel.2004.09.003.
Telomeres are unique DNA-protein structures that contain noncoding TTAGGG repeats and telomere-associated proteins. These specialized structures are essential for maintaining genomic integrity. Alterations that lead to the disruption of telomere maintenance result in chromosome end-to-end fusions and/or ends being recognized as double-strand breaks. A large body of evidence suggests that the cell responds to dysfunctional telomeres by undergoing senescence, apoptosis, or genomic instability. In conjunction with other predisposing mechanisms, the genomic instability encountered in preimmortal cells due to dysfunctional or uncapped telomeres might lead to cancer. Furthermore, telomere dysfunction has been proposed to play critical roles in aging as well as cancer progression. Conversely, recent evidence has shown that targeting telomere maintenance mechanisms and inducing telomere dysfunction in cancer cells by inhibiting telomerase can lead to catastrophic events including rapid cell death and increased sensitivity to other cancer therapeutics. Thus, given the major role telomeres play during development, it is important to continue our understanding telomere structure, function and maintenance. Herein, we provide an overview of the emerging knowledge of telomere dysfunction and how it relates to possible links between aging and cancer.
端粒是独特的DNA - 蛋白质结构,包含非编码的TTAGGG重复序列和端粒相关蛋白。这些特殊结构对于维持基因组完整性至关重要。导致端粒维持功能破坏的改变会导致染色体端对端融合和/或末端被识别为双链断裂。大量证据表明,细胞会通过衰老、凋亡或基因组不稳定来应对功能失调的端粒。与其他易患机制一起,由于功能失调或无帽端粒而在永生化前细胞中遇到的基因组不稳定可能导致癌症。此外,有人提出端粒功能障碍在衰老以及癌症进展中起关键作用。相反,最近的证据表明,通过抑制端粒酶靶向端粒维持机制并在癌细胞中诱导端粒功能障碍可导致灾难性事件,包括快速细胞死亡和对其他癌症治疗的敏感性增加。因此,鉴于端粒在发育过程中所起的主要作用,继续深入了解端粒的结构、功能和维持非常重要。在此,我们概述了端粒功能障碍的新知识及其与衰老和癌症之间可能联系的关系。