Specific length and structure rather than high thermodynamic stability enable regulatory mRNA stem-loops to pause translation

Chen Bao, Mingyi Zhu, Inna Nykonchuk, Hironao Wakabayashi, David H. Mathews and Dmitri N. Ermolenko ()
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Chen Bao: University of Rochester
Mingyi Zhu: University of Rochester
Inna Nykonchuk: University of Rochester
Hironao Wakabayashi: University of Rochester
David H. Mathews: University of Rochester
Dmitri N. Ermolenko: University of Rochester

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Translating ribosomes unwind mRNA secondary structures by three basepairs each elongation cycle. Despite the ribosome helicase, certain mRNA stem-loops stimulate programmed ribosomal frameshift by inhibiting translation elongation. Here, using mutagenesis, biochemical and single-molecule experiments, we examine whether high stability of three basepairs, which are unwound by the translating ribosome, is critical for inducing ribosome pauses. We find that encountering frameshift-inducing mRNA stem-loops from the E. coli dnaX mRNA and the gag-pol transcript of Human Immunodeficiency Virus (HIV) hinders A-site tRNA binding and slows down ribosome translocation by 15-20 folds. By contrast, unwinding of first three basepairs adjacent to the mRNA entry channel slows down the translating ribosome by only 2-3 folds. Rather than high thermodynamic stability, specific length and structure enable regulatory mRNA stem-loops to stall translation by forming inhibitory interactions with the ribosome. Our data provide the basis for rationalizing transcriptome-wide studies of translation and searching for novel regulatory mRNA stem-loops.

Date: 2022
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DOI: 10.1038/s41467-022-28600-5

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