Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 5640 Fishers Lane, Room 1524, Rockville, MD 20852, USA.
Cell Div. 2010 May 19;5(1):15. doi: 10.1186/1747-1028-5-15.
Recent data show that cells from many cancers exhibit massive chromosome instability. The traditional view is that the gradual accumulation of mutations in genes involved in transcriptional regulation and cell cycle controls results in tumor development. This, however, does not exclude the possibility that some mutations could be more potent than others in destabilizing the genome by targeting both chromosomal integrity and corresponding checkpoint mechanisms simultaneously. Three such examples of "single-hit" lesions potentially leading to heritable genome destabilization are discussed. They include: failure to release sister chromatid cohesion due to the incomplete proteolytic cleavage of cohesin; massive merotelic kinetochore misattachments upon condensin depletion; and chromosome under-replication. In all three cases, cells fail to detect potential chromosomal bridges before anaphase entry, indicating that there is a basic cell cycle requirement to maintain a degree of sister chromatid bridging that is not recognizable as chromosomal damage.
最近的数据表明，许多癌症的细胞表现出大量的染色体不稳定性。传统观点认为，参与转录调控和细胞周期控制的基因的突变逐渐积累，导致肿瘤的发展。然而，这并不排除某些突变可能比其他突变更有效地通过同时针对染色体完整性和相应的检查点机制来破坏基因组的可能性。讨论了三个这样的“单次打击”病变的例子，这些病变可能导致可遗传的基因组不稳定性。它们包括：由于黏连蛋白的不完全蛋白水解切割而导致姐妹染色单体着丝粒黏合的失败；着丝粒凝聚蛋白缺失导致的大量动静脉桥联附着；以及染色体复制不足。在所有三种情况下，细胞在进入后期之前未能检测到潜在的染色体桥，这表明细胞周期有一个基本的要求，即保持一定程度的姐妹染色单体桥接，这种桥接不会被识别为染色体损伤。
