Sublinear scaling of the cellular proteome with ploidy

Abstract

Ploidy changes are frequent in nature and contribute to evolution, functional specialization and tumorigenesis. Analysis of model organisms of different ploidies revealed that increased ploidy leads to an increase in cell and nuclear volume, reduced proliferation, metabolic changes, lower fitness, and increased genomic instability, but the underlying mechanisms remain poorly understood. To investigate how gene expression changes with cellular ploidy, we analyzed isogenic series of budding yeasts from 1N to 4N. We show that mRNA and protein abundance scales allometrically with ploidy, with tetraploid cells showing only threefold increase in protein abundance compared to haploids. This ploidy-dependent sublinear scaling occurs via decreased rRNA and ribosomal protein abundance and reduced translation. We demonstrate that the activity of Tor1 is reduced with increasing ploidy, which leads to diminished rRNA gene repression via a Tor1-Sch9-Tup1 signaling pathway. mTORC1 and S6K activity are also reduced in human tetraploid cells and the concomitant increase of the Tup1 homolog Tle1 downregulates the rDNA transcription. Our results suggest that the mTORC1-Sch9/S6K-Tup1/TLE1 pathway ensures proteome remodeling in response to increased ploidy.

Increased RNA and protein degradation is required for counteracting transcriptional burden and proteotoxic stress in human aneuploid cells

“…1b ). These results suggest global attenuation of gene and protein expression in the aneuploid clones, consistent with previous studies 3,4,20,23,24 .…”

“…Therefore, we conclude that both non-transformed and cancerous aneuploid cells suffer from proteotoxic stress and must develop compensatory mechanisms to overcome it. One such mechanism is the reduction of the global translation levels, which may be partly responsible for the protein-level dosage compensation observed in aneuploid cells 3,4,19,20,24 .…”

Conserved Chamber-Specific Polyploidy Maintains Heart Function inDrosophila

“…The average DNA content of the left ventricular cardiomyocytes increases about 1.7-fold at this time (Bergmann et al, 2015). We measured the nuclear volume of atrial (A) and ventricular (V) cardiomyocytes in adult human samples (see Methods), as an increase in ploidy levels leads to increases in nuclear volume (Cohen et al, 2018; Galitski et al, 1999; Huber and Gerace, 2007; Storchova et al, 2006; Yahya et al, 2022). Tissue sections of explanted donor hearts from 6 subjects (4 females and 3 males, aged in-between 33 to 44, without any history or pathology of heart diseases) were procured from the Duke Human Heart Repository (DHHR, Fig6A ).…”

Coupling of Nuclear Translocation to Cell Size Promotes Robustness to Fluctuations in YAP/TAZ Concentration

“…Given that [YAP/TAZ] is not a sole function of cell size, we believe it unlikely that YAP/TAZ size scaling serves to measure cell volume. Indeed, with many hundreds of proteins being shown to scale across cell lines (1, 5,6,11,12), size-scaling behaviour should not be considered sufficient evidence of a size-measurement system. YAP/TAZ are known to be directly regulated by the Hippo signalling pathway, which serves to phosphorylate and sequester YAP/TAZ in the cytoplasm, blunting their transcriptional activity (26,(28)(29)(30)40).…”

“…Given that [YAP/TAZ] is not a sole function of cell size, we believe it unlikely that YAP/TAZ size scaling serves to measure cell volume. Indeed, with many hundreds of proteins being shown to scale across cell lines ( 1, 5, 6, 11, 12 ), size-scaling behaviour should not be considered sufficient evidence of a size-measurement system.…”