Aneuploidy tolerance caused by BRG1 loss allows chromosome gains and recovery of fitness

Federica Schiavoni, Pedro Zuazua-Villar, Theodoros I. Roumeliotis, Graeme Benstead-Hume, Mercedes Pardo, Frances M. G. Pearl, Jyoti S. Choudhary and Jessica A. Downs ()
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Federica Schiavoni: The Institute of Cancer Research
Pedro Zuazua-Villar: The Institute of Cancer Research
Theodoros I. Roumeliotis: The Institute of Cancer Research
Graeme Benstead-Hume: The Institute of Cancer Research
Mercedes Pardo: The Institute of Cancer Research
Frances M. G. Pearl: University of Sussex
Jyoti S. Choudhary: The Institute of Cancer Research
Jessica A. Downs: The Institute of Cancer Research

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Aneuploidy results in decreased cellular fitness in many species and model systems. However, aneuploidy is commonly found in cancer cells and often correlates with aggressive growth, suggesting that the impact of aneuploidy on cellular fitness is context dependent. The BRG1 (SMARCA4) subunit of the SWI/SNF chromatin remodelling complex is frequently lost in cancer. Here, we use a chromosomally stable cell line to test the effect of BRG1 loss on the evolution of aneuploidy. BRG1 deletion leads to an initial loss of fitness in this cell line that improves over time. Notably, we find increased tolerance to aneuploidy immediately upon loss of BRG1, and the fitness recovery over time correlates with chromosome gain. These data show that BRG1 loss creates an environment where karyotype changes can be explored without a fitness penalty. At least in some genetic backgrounds, therefore, BRG1 loss can affect the progression of tumourigenesis through tolerance of aneuploidy.

Date: 2022
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DOI: 10.1038/s41467-022-29420-3

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