P53 induces senescence in the unstable progeny of aneuploid cells

Giam, Maybelline; Wong, C. K.; Low, Jun Siong; Sinelli, Matteo; Dreesen, Oliver; Rancati, Giulia

doi:10.1080/15384101.2020.1850968

Cited by 5 publications

(1 citation statement)

References 26 publications

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“…Despite these findings, aneuploidy itself has also been observed to induce substantial tumor-suppressive stresses ( Sheltzer et al 2017 ; Vasudevan et al 2020 , 2021 ). Aneuploid cells have increased metabolic requirements ( Williams et al 2008 ; Tang et al 2011 ; Stingele et al 2012 ; Sheltzer 2013 ; Dephoure et al 2014 ; Schukken et al 2020 ), display high levels of senescence ( Estrada et al 2013 ; Sheltzer et al 2017 ; He et al 2018 ; Macedo et al 2018 ; Giam et al 2020 ), show significant genomic instability ( Sheltzer et al 2011 ; Passerini et al 2016 ), and are sensitive to compounds that interfere with protein folding and turnover ( Torres et al 2010 ; Tang et al 2011 ; Donnelly et al 2014 ; Donnelly and Storchová 2015 ). Aneuploidy-associated stresses may be caused by the deregulation of gene expression, which leads to the imbalanced production of key cellular proteins.…”

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confidence: 99%

Extensive protein dosage compensation in aneuploid human cancers

Schukken

Sheltzer

2022

Genome Res.

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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 exhibit 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 an unexpectedly moderate effect on the expression of oncogenes and tumor suppressors, demonstrating 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.

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