The presence of extra chromosomes leads to genomic instability.
The presence of extra chromosomes leads to genomic instability.
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DOI：
10.1038/ncomms10754
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发表时间：
2016-02-15
影响因子：
16.6
通讯作者：
Storchová Z
中科院分区：
文献类型：
--
作者：
Passerini V;Ozeri-Galai E;de Pagter MS;Donnelly N;Schmalbrock S;Kloosterman WP;Kerem B;Storchová Z
非整倍性是癌症的标志，是以严重发育缺陷为特征的遗传疾病的基础，但解释其对细胞生理学影响的分子机制仍然难以捉摸。在这里，我们显示，使用一系列的人类细胞与确定的非整倍体核型，增加一个单一的染色体增加基因组的不稳定性。下一代测序和SNP阵列分析揭示了非整倍体中染色体重排的积累，断裂点连接模式提示复制缺陷。三体和四体细胞也显示出增加的DNA损伤和对复制应激的敏感性。引人注目的是，我们发现，非整倍体诱导的基因组不稳定性可以解释的复制解旋酶MCM 2 -7的表达减少。因此，恢复接近野生型水平的染色质结合的MCM解旋酶部分挽救了基因组不稳定性表型。因此，染色体的获得触发复制应激，从而促进基因组不稳定性并可能促成肿瘤发生。 癌细胞的标志之一是非整倍性，然而分子效应知之甚少。在这里，作者表明，三体和四体细胞显示出增加的基因组不稳定性和减少的解旋酶MCM 2 -7水平。
Aneuploidy is a hallmark of cancer and underlies genetic disorders characterized by severe developmental defects, yet the molecular mechanisms explaining its effects on cellular physiology remain elusive. Here we show, using a series of human cells with defined aneuploid karyotypes, that gain of a single chromosome increases genomic instability. Next-generation sequencing and SNP-array analysis reveal accumulation of chromosomal rearrangements in aneuploids, with break point junction patterns suggestive of replication defects. Trisomic and tetrasomic cells also show increased DNA damage and sensitivity to replication stress. Strikingly, we find that aneuploidy-induced genomic instability can be explained by the reduced expression of the replicative helicase MCM2-7. Accordingly, restoring near-wild-type levels of chromatin-bound MCM helicase partly rescues the genomic instability phenotypes. Thus, gain of chromosomes triggers replication stress, thereby promoting genomic instability and possibly contributing to tumorigenesis. One of the hallmarks of cancer cells is aneuploidy, however the molecular effects are poorly understood. Here the authors show that trisomic and tetrasomic cells display increased genomic instability and reduced levels of the helicase MCM2-7.