The inner centromere–shugoshin network prevents chromosomal instability
The inner centromere–shugoshin network prevents chromosomal instability
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DOI：
10.1126/science.aaa2655
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发表时间：
2015-09
期刊：
影响因子：
56.9
通讯作者：
Yuji Tanno;Hiroaki Susumu;M. Kawamura;H. Sugimura;T. Honda;Yoshinori Watanabe
中科院分区：
文献类型：
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作者：
Yuji Tanno;Hiroaki Susumu;M. Kawamura;H. Sugimura;T. Honda;Yoshinori Watanabe
大多数癌细胞的染色体是不稳定的，会发生断裂和重排。这些异常扰乱了正常的基因调控程序，导致了癌症的发展。Tanno等人研究了几种表现出染色体不稳定性的人类细胞系。在细胞分裂过程中，同源染色体不能很好地配对。这些染色体失去了特定的染色质共价修饰，组蛋白H3赖氨酸9的甲基化，和/或染色体着丝粒上的蛋白质“胶”内聚蛋白。这两种损失都干扰了shugoshin 1蛋白的结合，而shugoshin 1蛋白是染色体正确配对和分离所必需的。干扰染色体分离与配对机制的一个关键组成部分可能导致染色体不稳定。染色体不稳定性（CIN）是癌细胞的一个主要特征，也是肿瘤进展的一个强有力的驱动因素。然而，CIN的分子机制尚不清楚。我们发现许多CIN+细胞系在保守的内部着丝粒-舒结蛋白（ICS）网络的完整性上存在缺陷，该网络协调姐妹染色单体的内聚和着丝点-微管的附着。这些缺陷主要是由着丝粒上组蛋白H3赖氨酸9三甲基化的缺失引起的，有时是染色质相关黏结蛋白的减少引起的；这两种途径分别维持着丝胞心的稳定性。人工修复ICS网络可抑制多种CIN+细胞中的染色体分离错误，包括RB-和brca1缺陷细胞。因此，ICS网络的功能障碍可能是人类肿瘤发生中CIN的关键机制。
A misstep in the chromosomes' dance The chromosomes of most cancer cells are unstable, suffering breaks and rearrangements. These aberrations perturb normal gene-regulatory programs and contribute to cancer progression. Tanno et al. studied several human cell lines that show chromosome instability. Homologous chromosomes did not pair very well with each other during cell division. These chromosomes had lost a specific chromatin covalent modification, methylation of histone H3 lysine 9, and/or the protein “glue” cohesin at the chromosomes' centromeres. Either of these losses interfered with the binding of the shugoshin 1 protein, which is required for proper chromosome pairing and segregation. Science, this issue p. 1237 Interfering with a critical component of the chromosome segregation-and-pairing machinery may cause chromosome instability. Chromosomal instability (CIN) is a major trait of cancer cells and a potent driver of tumor progression. However, the molecular mechanisms underlying CIN still remain elusive. We found that a number of CIN+ cell lines have impairments in the integrity of the conserved inner centromere–shugoshin (ICS) network, which coordinates sister chromatid cohesion and kinetochore-microtubule attachment. These defects are caused mostly by the loss of histone H3 lysine 9 trimethylation at centromeres and sometimes by a reduction in chromatin-associated cohesin; both pathways separately sustain centromeric shugoshin stability. Artificial restoration of the ICS network suppresses chromosome segregation errors in a wide range of CIN+ cells, including RB- and BRCA1-deficient cells. Thus, dysfunction of the ICS network might be a key mechanism underlying CIN in human tumorigenesis.