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Destabilization of Eukaryote mRNAs by 5' Proximal Stop Codons Can Occur Independently of the Nonsense-Mediated mRNA

Barbara Gorgoni1, Yun-Bo Zhao2, J Krishnan3

  • 1Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.

Cells
|August 3, 2019
PubMed

Insights

Early stop codons destabilize mRNA by impairing ribosome recycling and re-initiation, even in yeast lacking nonsense-mediated decay (NMD). This affects mRNA stability and translation efficiency.

Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • Poly(A) binding protein (PAB) binding to the poly(A) tail is crucial for eukaryotic mRNA stability.
  • PABP interacts with translation termination factors and eIF4G, forming an mRNA closed loop.
  • The influence of stop codon proximity to the poly(A) tail on ribosome recycling and mRNA stability remains unclear.

Purpose of the Study:

  • To investigate how ribosome recycling from 5' proximal stop codons affects mRNA stability.
  • To determine if impaired ribosome recycling alone triggers mRNA instability.
  • To model the impact of ribosome recycling and poly(A) tail length on translation and mRNA fate.

Main Methods:

  • Utilized yeast strains deficient for nonsense-mediated mRNA decay (NMD).
  • Constructed reporter mRNAs with early stop codons at varying positions.
  • Employed Rli1-depletion experiments and mathematical modeling of translation dynamics.

Main Results:

  • mRNAs with early stop codons (codon 22) were unstable even in NMD-deficient yeast.
  • Stop codon readthrough did not significantly rescue mRNA stability.
  • Defective Rli1 ribosome recycling alone was insufficient to induce mRNA instability.
  • Mathematical modeling supported a model where impaired recycling from 5' proximal stop codons compromises initiation.

Conclusions:

  • Impaired ribosome recycling from 5' proximal stop codons can destabilize mRNA by affecting translation initiation.
  • A model of ribosome maturation during elongation explains how ribosomes gain competency for re-initiation on the same mRNA.
Keywords:
Saccharomyces cerevisiaemRNA decaymathematical modellingtranslationtranslational regulation

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