Roake Caitlin M, Artandi Steven E
Department of Medicine, Stanford University School of Medicine, Stanford, California 94305.
Cancer Biology Program, Stanford University School of Medicine, Stanford, California 94305.
Cold Spring Harb Perspect Med. 2017 May 1;7(5):a026088. doi: 10.1101/cshperspect.a026088.
Telomeres, the nucleoprotein complex at the ends of eukaryotic chromosomes, perform an essential cellular role in part by preventing the chromosomal end from initiating a DNA-damage response. This function of telomeres can be compromised as telomeres erode either as a consequence of cell division in culture or as a normal part of cellular ageing in proliferative tissues. Telomere dysfunction in this context leads to DNA-damage signaling and activation of the tumor-suppressor protein p53, which then can prompt either cellular senescence or apoptosis. By culling cells with dysfunctional telomeres, p53 plays a critical role in protecting tissues against the effects of critically short telomeres. However, as telomere dysfunction worsens, p53 likely exacerbates short telomere-driven tissue failure diseases, including pulmonary fibrosis, aplastic anemia, and liver cirrhosis. In cells lacking p53, unchecked telomere shortening drives chromosomal end-to-end fusions and cycles of chromosome fusion-bridge-breakage. Incipient cancer cells confronting these telomere barriers must disable p53 signaling to avoid senescence and eventually up-regulate telomerase to achieve cellular immortality. The recent findings of highly recurrent activating mutations in the promoter for the telomerase reverse transcriptase (TERT) gene in diverse human cancers, together with the widespread mutations in p53 in cancer, provide support for the idea that circumvention of a telomere-p53 checkpoint is essential for malignant progression in human cancer.
端粒是真核染色体末端的核蛋白复合体，其在细胞中发挥重要作用，部分原因是它能防止染色体末端引发DNA损伤反应。随着端粒在体外细胞分裂过程中逐渐缩短，或者作为增殖组织细胞衰老的正常过程，端粒的这种功能可能会受到损害。在这种情况下，端粒功能障碍会导致DNA损伤信号传导以及肿瘤抑制蛋白p53的激活，进而引发细胞衰老或凋亡。通过剔除端粒功能异常的细胞，p53在保护组织免受极短端粒影响方面发挥着关键作用。然而，随着端粒功能障碍的加剧，p53可能会加重由短端粒驱动的组织衰竭疾病，包括肺纤维化、再生障碍性贫血和肝硬化。在缺乏p53的细胞中，未受抑制的端粒缩短会导致染色体端对端融合以及染色体融合-桥-断裂循环。面对这些端粒障碍的早期癌细胞必须抑制p53信号传导以避免衰老，并最终上调端粒酶以实现细胞永生。最近在多种人类癌症中发现端粒酶逆转录酶（TERT）基因启动子存在高度反复的激活突变，以及癌症中p53的广泛突变，都支持了这样一种观点，即规避端粒-p53检查点对于人类癌症的恶性进展至关重要。
