Feijoo Purificacion, Dominguez Daniel, Tusell Laura, Genesca Anna
Cell Biology Unit, Universitat Autonoma de Barcelona, 08193 Bellaterra, Spain.
Curr Pharm Des. 2014;20(41):6375-85. doi: 10.2174/1381612820666140630085416.
Most cancer genomes show abnormalities in chromosome structure and number, two types of aberrations that could share a common mechanistic origin through proliferation-dependent loss of telomere function. Impairment of checkpoints that limit cell proliferation when telomeres are critically short might allow unrestrained cell division. The resulting uncapped chromosomes can fuse to each other, forming unstable configurations that can bridge during mitosis. Chromatin bridges can break to generate new broken ends that will then fuse with other broken ends. Successive events of break and fusion will continuously generate unbalanced chromosomal rearrangements, leading to gene-copy gains and losses. However, chromosome bridges do not always break. Evidence has recently been obtained to suggest that telomere-dependent chromosome bridges remaining unbroken can hinder cytokinesis and yield tetraploid cells. This might constitute an unstable intermediate in tumorigenesis, as progressive losses of individual chromosomes due to geometrical defects during cell division result in subtetraploid karyotypes. Additionally, the presence of short dysfunctional telomeres in cells can also cause these cells to become sensitive to mutagens, and particularly to radiation exposure. Human individuals exhibit differences in their sensitivity to radiation, which can be relevant for choice of therapy. Telomere function may well be involved in cellular and organism responses to ionizing radiation. Since eroded telomeres are sensed and act as double-strand breaks, they can interact with radiation-induced breaks, sharply increasing the possibility of misjoining. Altogether, this scenario provides certain clues to understanding the important role of telomeres in maintaining genomic integrity.
大多数癌症基因组在染色体结构和数量上都显示出异常，这两种畸变可能通过端粒功能的增殖依赖性丧失而具有共同的机制起源。当端粒严重缩短时，限制细胞增殖的检查点受损可能会导致细胞不受控制地分裂。由此产生的无帽染色体可以相互融合，形成在有丝分裂期间能够桥接的不稳定构型。染色质桥可以断裂产生新的断裂末端，然后与其他断裂末端融合。断裂和融合的连续事件将持续产生不平衡的染色体重排，导致基因拷贝数的增加和减少。然而，染色体桥并不总是断裂。最近有证据表明，未断裂的端粒依赖性染色体桥会阻碍胞质分裂并产生四倍体细胞。这可能构成肿瘤发生过程中的一个不稳定中间体，因为在细胞分裂过程中由于几何缺陷导致的单个染色体的逐渐丢失会导致亚四倍体核型。此外，细胞中短的功能失调的端粒的存在也会使这些细胞对诱变剂敏感，尤其是对辐射暴露敏感。人类个体对辐射的敏感性存在差异，这可能与治疗方案的选择有关。端粒功能很可能参与了细胞和生物体对电离辐射的反应。由于侵蚀的端粒被感知并充当双链断裂，它们可以与辐射诱导的断裂相互作用，大大增加了错配的可能性。总之，这种情况为理解端粒在维持基因组完整性中的重要作用提供了一些线索。
