Cycles of chromosome instability are associated with a fragile site and are increased by defects in DNA replication and checkpoint controls in yeast
Cycles of chromosome instability are associated with a fragile site and are increased by defects in DNA replication and checkpoint controls in yeast
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DOI：
10.1101/gad.1392506
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发表时间：
2006-01-15
影响因子：
10.5
通讯作者：
Weinert, T
中科院分区：
文献类型：
--
作者：
Admire, A;Shanks, L;Weinert, T
我们在这里报告说，一个正常的芽殖酵母染色体（ChrVII）可以经历显着的染色体不稳定性周期。与不稳定周期相关的事件导致选择性琼脂平板上菌落的独特“扇形化”。我们发现，不稳定性开始在ChrVII上的几个网站中的任何一个，并急剧增加的DNA复制的中断或检查点控制的缺陷。我们详细研究了与一个特定染色体位点（“403位点”）相关的不稳定性周期。该位点包含多个已知会阻止复制叉的tRNA基因，当删除时，分区的总体频率就会降低。403位点的不稳定性涉及多个非等位基因重组事件，导致形成单中心易位。这种易位保持不稳定，经常发生与易位连接点相关的丢失或重组事件。这些结果表明了一个模型，其中不稳定性启动在特定的染色体位点，失速复制叉。未被检查点蛋白稳定的分叉断裂并经历多轮非等位基因重组以形成易位。一些易位保持不稳定，因为它们连接两个“不相容”的染色体区域。这种正常酵母染色体的不稳定性周期可能与哺乳动物脆性部位和癌细胞染色体的不稳定性有关。
We report here that a normal budding yeast chromosome (ChrVII) can undergo remarkable cycles of chromosome instability. The events associated with cycles of instability caused a distinctive "sectoring" of colonies on selective agar plates. We found that instability initiated at any of several sites on ChrVII, and was sharply increased by the disruption of DNA replication or by defects in checkpoint controls. We studied in detail the cycles of instability associated with one particular chromosomal site (the "403 site"). This site contained multiple tRNA genes known to stall replication forks, and when deleted, the overall frequency of sectoring was reduced. Instability of the 403 site involved multiple nonallelic recombination events that led to the formation of a monocentric translocation. This translocation remained unstable, frequently undergoing either loss or recombination events linked to the translocation junction. These results suggest a model in which instability initiates at specific chromosomal sites that stall replication forks. Forks not stabilized by checkpoint proteins break and undergo multiple rounds of nonallelic recombination to form translocations. Some translocations remain unstable because they join two "incompatible" chromosomal regions. Cycles of instability of this normal yeast chromosome may be relevant to chromosome instability of mammalian fragile sites and of chromosomes in cancer cells.