Telomere dysfunction and chromosome instability.
Telomere dysfunction and chromosome instability.
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DOI：
10.1016/j.mrfmmm.2011.04.008
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发表时间：
2012-02-01
影响因子：
2.3
通讯作者：
Murnane, John P.
中科院分区：
文献类型：
--
作者：
Murnane, John P.
关键词：
染色体的末端由一个短的重复序列和相关的蛋白质组成，这些蛋白质共同形成一个帽子，称为端粒，它防止末端出现双链断裂(DSB)，并防止染色体融合。端粒重复序列的缺失或端粒蛋白的缺失可导致染色体融合，导致染色体不稳定。端粒丢失引起的染色体重排与癌细胞中发现的端粒重排相似，暗示端粒丢失是染色体不稳定导致人类癌症的重要机制。由于维持端粒的蛋白质端粒酶不足，癌细胞中的端粒可能会逐渐缩短。然而，尽管有端粒酶的表达，但癌细胞往往有很高的自发性端粒丢失，这被认为是癌基因介导的复制压力和端粒区DSB修复缺陷的共同作用的结果。哺乳动物细胞中的染色体融合主要涉及非同源末端连接(NHEJ)，这是DSB修复的主要形式。染色体融合启动染色体不稳定性，涉及断裂-融合-桥(B/F/B)周期，在该周期中，双着丝粒染色体形成桥并在细胞试图分裂时断裂，在随后的细胞周期中重复这一过程。姐妹染色单体之间的融合导致染色体末端的大型反向重复序列，这些重复序列在额外的B/F/B周期后进一步放大。B/F/B周期一直持续到染色体获得新的端粒，最常见的是通过易位另一条染色体的末端。这种不稳定并不局限于失去端粒的染色体，这种不稳定转移到了捐赠易位的染色体上。此外，扩增的区域是不稳定的，并形成染色体外DNA，可以在新的位置重新整合。因此，关于促进端粒丢失的因素及其后果的知识对于理解人类癌症中的染色体不稳定性是重要的。
The ends of chromosomes are composed of a short repeat sequence and associated proteins that together form a cap, called a telomere, that keeps the ends from appearing as double-strand breaks (DSBs) and prevents chromosome fusion. The loss of telomeric repeat sequences or deficiencies in telomeric proteins can result in chromosome fusion and lead to chromosome instability. The similarity between chromosome rearrangements resulting from telomere loss and those found in cancer cells implicates telomere loss as an important mechanism for the chromosome instability contributing to human cancer. Telomere loss in cancer cells can occur through gradual shortening due to insufficient telomerase, the protein that maintains telomeres. However, cancer cells often have a high rate of spontaneous telomere loss despite the expression of telomerase, which has been proposed to result from a combination of oncogene-mediated replication stress and a deficiency in DSB repair in telomeric regions. Chromosome fusion in mammalian cells primarily involves nonhomologous end joining (NHEJ), which is the major form of DSB repair. Chromosome fusion initiates chromosome instability involving breakage-fusion-bridge (B/F/B) cycles, in which dicentric chromosomes form bridges and break as the cell attempts to divide, repeating the process in subsequent cell cycles. Fusion between sister chromatids results in large inverted repeats on the end of the chromosome, which amplify further following additional B/F/B cycles. B/F/B cycles continue until the chromosome acquires a new telomere, most often by translocation of the end of another chromosome. The instability is not confined to a chromosome that loses its telomere, the instability is transferred to the chromosome donating a translocation. Moreover, the amplified regions are unstable and form extrachromosomal DNA that can reintegrate at new locations. Knowledge concerning the factors promoting telomere loss and its consequences is therefore important for understanding chromosome instability in human cancer.
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作者：
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通讯作者：
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影响因子：
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DOI：
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发表时间：
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影响因子：
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