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A nascent peptide code for translational control of mRNA stability in human cells

Author

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  • Phillip C. Burke

    (Fred Hutchinson Cancer Center
    University of Washington)

  • Heungwon Park

    (Fred Hutchinson Cancer Center)

  • Arvind Rasi Subramaniam

    (Fred Hutchinson Cancer Center
    University of Washington)

Abstract

Stability of eukaryotic mRNAs is associated with their codon, amino acid, and GC content. Yet, coding sequence motifs that predictably alter mRNA stability in human cells remain poorly defined. Here, we develop a massively parallel assay to measure mRNA effects of thousands of synthetic and endogenous coding sequence motifs in human cells. We identify several families of simple dipeptide repeats whose translation triggers mRNA destabilization. Rather than individual amino acids, specific combinations of bulky and positively charged amino acids are critical for the destabilizing effects of dipeptide repeats. Remarkably, dipeptide sequences that form extended β strands in silico and in vitro slowdown ribosomes and reduce mRNA levels in vivo. The resulting nascent peptide code underlies the mRNA effects of hundreds of endogenous peptide sequences in the human proteome. Our work suggests an intrinsic role for the ribosome as a selectivity filter against the synthesis of bulky and aggregation-prone peptides.

Suggested Citation

  • Phillip C. Burke & Heungwon Park & Arvind Rasi Subramaniam, 2022. "A nascent peptide code for translational control of mRNA stability in human cells," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34664-0
    DOI: 10.1038/s41467-022-34664-0
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    References listed on IDEAS

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    1. Anna B. Loveland & Egor Svidritskiy & Denis Susorov & Soojin Lee & Alexander Park & Sarah Zvornicanin & Gabriel Demo & Fen-Biao Gao & Andrei A. Korostelev, 2022. "Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Ayala Shiber & Kristina Döring & Ulrike Friedrich & Kevin Klann & Dorina Merker & Mostafa Zedan & Frank Tippmann & Günter Kramer & Bernd Bukau, 2018. "Cotranslational assembly of protein complexes in eukaryotes revealed by ribosome profiling," Nature, Nature, vol. 561(7722), pages 268-272, September.
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