Natural proteome diversity links aneuploidy tolerance to protein turnover

Julia Muenzner, Pauline Trébulle, Federica Agostini, Henrik Zauber, Christoph B. Messner, Martin Steger, Christiane Kilian, Kate Lau, Natalie Barthel, Andrea Lehmann, Kathrin Textoris-Taube, Elodie Caudal, Anna-Sophia Egger, Fatma Amari, Matteo Chiara, Vadim Demichev, Toni I. Gossmann, Michael Mülleder, Gianni Liti, Joseph Schacherer, Matthias Selbach, Judith Berman () and Markus Ralser ()
Additional contact information
Julia Muenzner: Charité Universitätsmedizin
Pauline Trébulle: Francis Crick Institute
Federica Agostini: Charité Universitätsmedizin
Henrik Zauber: Max Delbrück Center for Molecular Medicine
Christoph B. Messner: Francis Crick Institute
Martin Steger: Evotec (München)
Christiane Kilian: Charité Universitätsmedizin
Kate Lau: Charité Universitätsmedizin
Natalie Barthel: Charité Universitätsmedizin
Andrea Lehmann: Charité Universitätsmedizin
Kathrin Textoris-Taube: Charité Universitätsmedizin
Elodie Caudal: CNRS GMGM UMR 7156
Anna-Sophia Egger: Francis Crick Institute
Fatma Amari: Charité Universitätsmedizin
Matteo Chiara: CNRS, INSERM, IRCAN
Vadim Demichev: Charité Universitätsmedizin
Toni I. Gossmann: TU Dortmund University
Michael Mülleder: Charité Universitätsmedizin
Gianni Liti: CNRS, INSERM, IRCAN
Joseph Schacherer: CNRS GMGM UMR 7156
Matthias Selbach: Max Delbrück Center for Molecular Medicine
Judith Berman: Tel Aviv University
Markus Ralser: Charité Universitätsmedizin

Nature, 2024, vol. 630, issue 8015, 149-157

Abstract: Abstract Accessing the natural genetic diversity of species unveils hidden genetic traits, clarifies gene functions and allows the generalizability of laboratory findings to be assessed. One notable discovery made in natural isolates of Saccharomyces cerevisiae is that aneuploidy—an imbalance in chromosome copy numbers—is frequent1,2 (around 20%), which seems to contradict the substantial fitness costs and transient nature of aneuploidy when it is engineered in the laboratory3–5. Here we generate a proteomic resource and merge it with genomic1 and transcriptomic6 data for 796 euploid and aneuploid natural isolates. We find that natural and lab-generated aneuploids differ specifically at the proteome. In lab-generated aneuploids, some proteins—especially subunits of protein complexes—show reduced expression, but the overall protein levels correspond to the aneuploid gene dosage. By contrast, in natural isolates, more than 70% of proteins encoded on aneuploid chromosomes are dosage compensated, and average protein levels are shifted towards the euploid state chromosome-wide. At the molecular level, we detect an induction of structural components of the proteasome, increased levels of ubiquitination, and reveal an interdependency of protein turnover rates and attenuation. Our study thus highlights the role of protein turnover in mediating aneuploidy tolerance, and shows the utility of exploiting the natural diversity of species to attain generalizable molecular insights into complex biological processes.

Date: 2024
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DOI: 10.1038/s41586-024-07442-9

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