Dosage compensation plans: protein aggregation provides additional insurance against aneuploidy

Abstract

Gene dosage alterations caused by aneuploidy are a common feature of most cancers yet pose severe proteotoxic challenges. Therefore, cells have evolved various dosage compensation mechanisms to limit the damage caused by the ensuing protein level imbalances. For instance, for heteromeric protein complexes, excess nonstoichiometric subunits are rapidly recognized and degraded. In this issue of Genes & Development, Brennan et al. (pp. 1031-1047) reveal that sequestration of nonstoichiometric subunits into aggregates is an alternative mechanism for dosage compensation in aneuploid budding yeast and human cell lines. Using a combination of proteomic and genetic techniques, they found that excess proteins undergo either degradation or aggregation but not both. Which route is preferred depends on the half-life of the protein in question. Given the multitude of diseases linked to either aneuploidy or protein aggregation, this study could serve as a springboard for future studies with broad-spanning implications.

Keywords: aneuploidy; protein aggregation; protein homeostasis.

Figure 1.

Model of aggregation as a dosage compensation mechanism in aneuploid cells. (A) In euploid cells, protein complex subunits encoded on different chromosomes are produced at homeostatic levels, promoting complex assembly. (B) Additional copies of chromosomes in the aneuploid state result in a chronic proteotoxic stress partially due to substoichiometric subunits produced directly from genes encoded on the extra chromosome (chromosome I). The substoichiometric subunits engage cellular protein quality control pathways leading to degradation or aggregation. (C) The investigators show that the fate of a substoichiometric subunit depends on its half-life.