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      Keeping the Proportions of Protein Complex Components in Check

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          Abstract

          How do cells maintain relative proportions of protein complex components? Advances in quantitative, genome-wide measurements have begun to shed light onto the roles of protein synthesis and degradation in establishing the precise proportions in living cells: on the one hand, ribosome profiling studies indicate that proteins are already produced in the correct relative proportions. On the other hand, proteomic studies found that many complexes contain subunits that are made in excess and subsequently degraded. Here, we discuss these seemingly contradictory findings, emerging principles, and remaining open questions. We conclude that establishing precise protein levels involves both coordinated synthesis and post-translational fine-tuning via protein degradation.

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          Most cited references58

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          Global quantification of mammalian gene expression control.

          Gene expression is a multistep process that involves the transcription, translation and turnover of messenger RNAs and proteins. Although it is one of the most fundamental processes of life, the entire cascade has never been quantified on a genome-wide scale. Here we simultaneously measured absolute mRNA and protein abundance and turnover by parallel metabolic pulse labelling for more than 5,000 genes in mammalian cells. Whereas mRNA and protein levels correlated better than previously thought, corresponding half-lives showed no correlation. Using a quantitative model we have obtained the first genome-scale prediction of synthesis rates of mRNAs and proteins. We find that the cellular abundance of proteins is predominantly controlled at the level of translation. Genes with similar combinations of mRNA and protein stability shared functional properties, indicating that half-lives evolved under energetic and dynamic constraints. Quantitative information about all stages of gene expression provides a rich resource and helps to provide a greater understanding of the underlying design principles.
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            Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling.

            Techniques for systematically monitoring protein translation have lagged far behind methods for measuring messenger RNA (mRNA) levels. Here, we present a ribosome-profiling strategy that is based on the deep sequencing of ribosome-protected mRNA fragments and enables genome-wide investigation of translation with subcodon resolution. We used this technique to monitor translation in budding yeast under both rich and starvation conditions. These studies defined the protein sequences being translated and found extensive translational control in both determining absolute protein abundance and responding to environmental stress. We also observed distinct phases during translation that involve a large decrease in ribosome density going from early to late peptide elongation as well as widespread regulated initiation at non-adenine-uracil-guanine (AUG) codons. Ribosome profiling is readily adaptable to other organisms, making high-precision investigation of protein translation experimentally accessible.
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              Ribosome profiling of mouse embryonic stem cells reveals the complexity and dynamics of mammalian proteomes.

              The ability to sequence genomes has far outstripped approaches for deciphering the information they encode. Here we present a suite of techniques, based on ribosome profiling (the deep sequencing of ribosome-protected mRNA fragments), to provide genome-wide maps of protein synthesis as well as a pulse-chase strategy for determining rates of translation elongation. We exploit the propensity of harringtonine to cause ribosomes to accumulate at sites of translation initiation together with a machine learning algorithm to define protein products systematically. Analysis of translation in mouse embryonic stem cells reveals thousands of strong pause sites and unannotated translation products. These include amino-terminal extensions and truncations and upstream open reading frames with regulatory potential, initiated at both AUG and non-AUG codons, whose translation changes after differentiation. We also define a class of short, polycistronic ribosome-associated coding RNAs (sprcRNAs) that encode small proteins. Our studies reveal an unanticipated complexity to mammalian proteomes. Copyright © 2011 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                101656080
                43733
                Cell Syst
                Cell Syst
                Cell systems
                2405-4712
                2405-4720
                17 March 2020
                26 February 2020
                26 February 2021
                : 10
                : 2
                : 125-132
                Affiliations
                [1 ]Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
                [2 ]Proteome dynamics, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, 13092 Berlin, Germany
                [3 ]Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
                [4 ]These authors contributed equally
                Author notes

                AUTHOR CONTRIBUTIONS

                J.C.T., H.Z., M.S., G.-W.L., and E.M. jointly conceptualized and wrote the manuscript, whereas the majority of the formal analysis and data curation was performed by J.C.T. and H.Z.

                Article
                NIHMS1569015
                10.1016/j.cels.2020.01.004
                7195860
                32105631
                c6edfb9e-d65c-4ed9-8c80-2794362a8e3f

                This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/).

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