Abstract
How aneuploid cells tolerate chromosome arm gains or losses remains an open question. Using an isogenic human lung cell model with either chromosome 3p loss or 3q gain, combined with quantitative mass spectrometry and isotopic labeling, we reveal distinct proteostasis mechanisms for gain- and loss-type aneuploidy. Surprisingly, while compensation for 3q gain is primarily driven by increased degradation of excess protein complex subunits, 3p loss is neither counteracted by global protein degradation nor selectively reduced degradation. Rather, there is a relative upregulation in protein synthesis of those 3p-encoded proteins that participate in stable protein complexes to maintain functional complex stoichiometry. Additionally, 3p-encoded proteins that are in a complex show increased thermal stability in loss-type aneuploidy, potentially via their interactions with other proteins from euploid chromosomes. Together, our findings uncover distinct proteomic buffering strategies that enable cells to tolerate either excessive or deficient single-arm aneuploidy.