Profiling of biological relationships between different molecular layers dissects regulatory mechanisms that ultimately determine cellular function. To thoroughly assess the role of protein post-translational turnover, we devised a strategy combining pulse stable isotope-labeled amino acids in cells (pSILAC), data-independent acquisition mass spectrometry (DIA-MS), and a novel data analysis framework that resolves protein degradation rate on the level of mRNA alternative splicing isoforms and isoform groups. We demonstrated our approach by the genome-wide correlation analysis between mRNA amounts and protein degradation across different strains of HeLa cells that harbor a high grade of gene dosage variation. The dataset revealed that specific biological processes, cellular organelles, spatial compartments of organelles, and individual protein isoforms of the same genes could have distinctive degradation rate. The protein degradation diversity thus dissects the corresponding buffering or concerting protein turnover control across cancer cell lines. The data further indicate that specific mRNA splicing events such as intron retention significantly impact the protein abundance levels. Our findings support the tight association between transcriptome variability and proteostasis and provide a methodological foundation for studying functional protein degradation.

Biognosys Zurich Schlieren Switzerland

Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai China

Department of Genome Integrity Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Department of Pharmacology Yale University School of Medicine New Haven CT USA

Department of Systems Biology Columbia University New York NY USA

European Molecular Biology Laboratory Heidelberg Germany

Institute for Neuroscience D HEST ETH Zurich Zurich Switzerland

Statistical Bioinformatics Lab DMLS University of Zürich Zurich Switzerland

Yale Cancer Biology Institute Yale University West Haven CT USA

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