Passerini Verena, Ozeri-Galai Efrat, de Pagter Mirjam S, Donnelly Neysan, Schmalbrock Sarah, Kloosterman Wigard P, Kerem Batsheva, Storchová Zuzana
Max Planck Institute of Biochemistry, Am Klopferspitz 18, Martinsried 82152, Germany.
Center for Integrated Protein Science Munich, Munich, Germany.
Nat Commun. 2016 Feb 15;7:10754. doi: 10.1038/ncomms10754.
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.
非整倍体是癌症的一个标志，也是以严重发育缺陷为特征的遗传疾病的基础，然而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，我们使用一系列具有明确非整倍体核型的人类细胞表明，单条染色体的增加会增加基因组不稳定性。二代测序和SNP阵列分析揭示了非整倍体细胞中染色体重排的积累，其断点连接模式提示存在复制缺陷。三体和四体细胞也显示出DNA损伤增加以及对复制应激的敏感性增加。令人惊讶的是，我们发现非整倍体诱导的基因组不稳定性可以通过复制解旋酶MCM2-7表达的降低来解释。因此，恢复接近野生型水平的染色质结合MCM解旋酶可部分挽救基因组不稳定性表型。因此，染色体增加会引发复制应激，从而促进基因组不稳定性，并可能导致肿瘤发生。
