Sublinear scaling of the cellular proteome with ploidy

Area of Science:

• Cell biology
• Genetics
• Evolutionary biology

Background:

• Ploidy variations are common in organisms and linked to diverse traits, including disease.
• Previous studies show increased ploidy alters cell size, proliferation, and fitness, but mechanisms are unclear.

Purpose of the Study:

• To investigate how gene expression and proteome scale with increasing cellular ploidy.
• To elucidate the molecular mechanisms underlying ploidy-dependent gene expression regulation.

Main Methods:

• Analysis of isogenic budding yeast series (1N to 4N).
• Quantification of mRNA and protein abundance.
• Investigation of signaling pathways including Tor1, Sch9, Tup1, mTORC1, S6K, and Tle1.

Main Results:

• mRNA and protein abundance scale sublinearly with ploidy (e.g., 4N cells have only 3x protein of 1N).
• Reduced ribosomal RNA (rRNA) and ribosomal protein levels contribute to sublinear scaling.
• Decreased Tor1 activity with increasing ploidy diminishes rRNA gene repression via the Tor1-Sch9-Tup1 pathway.
• mTORC1 and S6K activity decrease in human tetraploid cells, with Tle1 upregulation downregulating rDNA transcription.

Conclusions:

• The mTORC1-Sch9/S6K-Tup1/TLE1 pathway regulates proteome remodeling in response to increased ploidy.
• This pathway links ploidy changes to reduced translation and cellular adaptation.