Dodgson Stacie E, Kim Sharon, Costanzo Michael, Baryshnikova Anastasia, Morse Darcy L, Kaiser Chris A, Boone Charles, Amon Angelika
Koch Institute for Integrative Cancer Research, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142 Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142.
The Donnelly Centre, University of Toronto, Toronto, Ontario M5S3E1, Canada Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S3E1, Canada.
Genetics. 2016 Apr;202(4):1395-409. doi: 10.1534/genetics.115.185660. Epub 2016 Feb 2.
Aneuploidy, an unbalanced karyotype in which one or more chromosomes are present in excess or reduced copy number, causes an array of known phenotypes including proteotoxicity, genomic instability, and slowed proliferation. However, the molecular consequences of aneuploidy are poorly understood and an unbiased investigation into aneuploid cell biology is lacking. We performed high-throughput screens for genes the deletion of which has a synthetic fitness cost in aneuploidy Saccharomyces cerevisiae cells containing single extra chromosomes. This analysis identified genes that, when deleted, decrease the fitness of specific disomic strains as well as those that impair the proliferation of a broad range of aneuploidies. In one case, a chromosome-specific synthetic growth defect could be explained fully by the specific duplication of a single gene on the aneuploid chromosome, highlighting the ability of individual dosage imbalances to cause chromosome-specific phenotypes in aneuploid cells. Deletion of other genes, particularly those involved in protein transport, however, confers synthetic sickness on a broad array of aneuploid strains. Indeed, aneuploid cells, regardless of karyotype, exhibit protein secretion and cell-wall integrity defects. Thus, we were able to use this screen to identify novel cellular consequences of aneuploidy, dependent on both specific chromosome imbalances and caused by many different aneuploid karyotypes. Interestingly, the vast majority of cancer cells are highly aneuploid, so this approach could be of further use in identifying both karyotype-specific and nonspecific stresses exhibited by cancer cells as potential targets for the development of novel cancer therapeutics.
非整倍体是一种染色体核型不平衡状态，其中一条或多条染色体的拷贝数过多或减少，会导致一系列已知的表型，包括蛋白质毒性、基因组不稳定和增殖减缓。然而，人们对非整倍体的分子后果了解甚少，且缺乏对非整倍体细胞生物学的无偏倚研究。我们对基因进行了高通量筛选，这些基因的缺失在含有单条额外染色体的非整倍体酿酒酵母细胞中具有合成适应性代价。该分析鉴定出了一些基因，这些基因缺失时会降低特定二体菌株的适应性，以及那些会损害多种非整倍体增殖的基因。在一个案例中，特定染色体的合成生长缺陷可以完全由非整倍体染色体上单个基因的特定重复来解释，这突出了个体剂量失衡在非整倍体细胞中导致染色体特异性表型的能力。然而，其他基因的缺失，特别是那些参与蛋白质转运的基因，会使多种非整倍体菌株出现合成病态。实际上，无论核型如何，非整倍体细胞都表现出蛋白质分泌和细胞壁完整性缺陷。因此，我们能够利用这个筛选来鉴定非整倍体的新的细胞后果，这些后果既依赖于特定的染色体失衡，也由许多不同的非整倍体核型引起。有趣的是，绝大多数癌细胞都是高度非整倍体，所以这种方法可能在识别癌细胞表现出的核型特异性和非特异性应激方面有进一步用途，这些应激可作为开发新型癌症治疗方法的潜在靶点。
