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Extensive protein dosage compensation in aneuploid human cancers
Genome Research ( IF 6.2 ) Pub Date : 2022-07-01 , DOI: 10.1101/gr.276378.121
Klaske M Schukken 1 , Jason M Sheltzer 1
Affiliation  

Aneuploidy is a hallmark of human cancers, but the effects of aneuploidy on protein expression remain poorly understood. To uncover how chromosome copy number changes influence the cancer proteome, we conducted an analysis of hundreds of human cancer cell lines and tumors with matched copy number, RNA expression, and protein expression data. We found that a majority of proteins show dosage compensation and fail to change by the degree expected based on chromosome copy number alone. We uncovered a variety of gene groups that were recurrently buffered upon both chromosome gain and loss, including protein complex subunits and cell cycle genes. Several genetic and biophysical factors were predictive of protein buffering, highlighting complex post-translational regulatory mechanisms that maintain appropriate gene product dosage. Finally, we established that chromosomal aneuploidy has a moderate effect on the expression of oncogenes and tumor suppressors, showing that these key cancer drivers can be subject to dosage compensation as well. In total, our comprehensive analysis of aneuploidy and dosage compensation across cancers will help identify the key driver genes encoded on altered chromosomes and will shed light on the overall consequences of aneuploidy during tumor development.

中文翻译:


非整倍体人类癌症中广泛的蛋白质剂量补偿



非整倍性是人类癌症的一个标志,但非整倍性对蛋白质表达的影响仍然知之甚少。为了揭示染色体拷贝数变化如何影响癌症蛋白质组,我们对数百个人类癌细胞系和肿瘤进行了分析,并提供了匹配的拷贝数、RNA 表达和蛋白质表达数据。我们发现大多数蛋白质表现出剂量补偿,并且未能达到仅根据染色体拷贝数预期的程度变化。我们发现了多种在染色体获得和丢失时反复缓冲的基因组,包括蛋白质复合物亚基和细胞周期基因。一些遗传和生物物理因素可以预测蛋白质缓冲,突出显示维持适当基因产物剂量的复杂翻译后调节机制。最后,我们确定染色体非整倍性对癌基因和肿瘤抑制因子的表达具有中等影响,表明这些关键的癌症驱动因素也可以受到剂量补偿。总的来说,我们对癌症非整倍性和剂量补偿的全面分析将有助于识别改变染色体上编码的关键驱动基因,并将揭示肿瘤发展过程中非整倍性的总体后果。
更新日期:2022-07-01
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